Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties

Antonella Maria Maggio

Centaurothamnus maximus (family Asteraceae), is a leafy shrub indigenous to the southwestern Arabian Peninsula. With a paucity of phytochemical data on this species, we set out to chemically characterize the plant. From the aerial parts, two newly identified guaianolides were isolated: 3β-hydroxy-4α(acetoxy)-4β(hydroxymethyl)-8α-(4-hydroxy methacrylate)-1αH,5αH, 6αH-gual-10(14),11(13)-dien-6,12-olide (1) and 15-descarboxy picrolide A (2). Seven previously reported compounds were also isolated: 3β, 4α, 8α-trihydroxy-4-(hydroxymethyl)-lαH, 5αH, 6βH, 7αH-guai-10(14),11(13)-dien-6,12-olide (3), chlorohyssopifolin B (4), cynaropikrin (5), hydroxyjanerin (6), chlorojanerin (7), isorhamnetin (8), and quercetagetin-3,6-dimethyl ether-4’-O-β-d-pyranoglucoside (9). Chemical structures were elucidated using spectroscopic techniques, including High Resolution Fast Atom Bombardment Mass Spectrometry (HR-FAB-MS), 1D NMR; 1H, 13C NMR, Distortionless Enhancement by Polarization Transfer (DEPT), and...

Phytochemistry xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect Phytochemistry journal homepage: www.elsevier.com/locate/phytochem Review Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties Maurizio Bruno a,⇑, Svetlana Bancheva b, Sergio Rosselli a, Antonella Maggio a a b STEBICEF, Section of Chemistry, University of Palermo, Viale delle Scienze, Parco d’Orleans II, 90128 Palermo, Italy Institute of Biodiversity and Ecosystem Research, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. 23, 1113 Sofia, Bulgaria a r t i c l e i n f o Article history: Received 15 October 2012 Received in revised form 5 July 2013 Available online xxxx In memory of Professor Werner Herz, Department of Chemistry, The Florida State University, Tallahassee, FL, USA, who dedicated his life to the chemistry of sesquiterpenoids. Keywords: Centaureinae Germacranes Elemanes Eudesmanes Guiaianes 13 C NMR spectral data Antimicrobial Antiprotozoal Anti-inflammatory Antitumor and cytotoxic Antiviral Effects on insects Effects on plants a b s t r a c t Asteraceae Bercht. & J. Presl is one of the biggest and most economically important plant families. The taxonomy and phylogeny of Asteraceae is rather complex and according to the latest and most reliable taxonomic classification of Panero & Funk, based on the analysis of nine chloroplast regions, the family is divided into 12 subfamilies and 35 tribes. One of the largest tribes of Asteraceae is Cardueae Cass. with four subtribes (Carlininae, Echinopinae, Carduinae and Centaureinae) and more than 2500 species. Susanna & Garcia-Jacas have organized the genera of Centaureinae (about 800 species) into seven informal groups, which recent molecular studies have confirmed: 1. Basal genera; 2. Volutaria group; 3. Rhaponticum group; 4. Serratula group; 5. Carthamus group; 6. Crocodylium group; 7. Centaurea group. This review summarizes reports on sesquiterpenoids from the Centaureinae subtribe of the Asteraceae family, as well as the 13C NMR spectral data described in the literature. It further reviews studies concerning the biological activities of these metabolites. For this work, literature data on sesquiterpenes from the Centaureinae subtribe were retrieved with the help of the SciFinder database and other similar data banks. All entries from 1958 until the end of 2011 were considered. This review is addressed to scientists working in the metabolomics field such as chemists, botanists, etc., the spectroscopic data reported make this work a good tool for structural elucidation, the biological section gives useful information to those who wish to study the structure activity relationships. Ó 2013 Elsevier Ltd. All rights reserved. Contents 1. 2. 3. 4. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sesquiterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Germacranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Elemanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Eudesmanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Guaianes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemotaxonomic remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Antimicrobial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Antiprotozoal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Anti-inflammatory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Antitumor and cytotoxic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 00 00 00 00 00 00 00 00 00 00 00 00 ⇑ Corresponding author. E-mail address: maurizio.bruno@unipa.it (M. Bruno). 0031-9422/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.phytochem.2013.07.002 Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 2 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx 5. 4.5. Antiviral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Effects on insects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7. Effects on plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8. Other activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction Asteraceae Bercht. & J. Presl is one of the biggest (more than 23,000 currently accepted species spread across 1620 genera) and most economically important plant families. In fact, many economically important weeds, for example hawkweeds (Hieracium sp.), thistles (Cirsium sp., Carduus sp. and other representatives from tribe Cardueae), yellow star thistle (Centaurea solstitialis L.) and dandelion (Taraxacum officinale) belong to the Asteraceae. Sunflowers (Helianthus annuus) are grown for the oil in their seeds and safflowers (Carthamus tinctorius) have been used for a long time as a textile dye. Artichoke (Cynara cardunculus) is an example of a crop plant belonging to this family, and many species are used as flavor herbs (marigold, various daisies, fleabane, chrysanthemums, dahlias, zinnias) or medicines (grindelia, echinacea, yarrow and 00 00 00 00 00 00 00 many others). Furthermore, pyrethrum daisies (Tanacetum coccineum) provide a popular and relatively bio-friendly insecticide (Smissen, 2003). According to the last and most reliable taxonomic classification of Panero and Funk (2002, 2008), based on analysis of nine chloroplast regions, the family is divided into 12 subfamilies and 35 tribes. One of the largest tribes of the Asteraceae is Cardueae Cass. with four subtribes (Carlininae, Echinopinae, Carduinae and Centaureinae) and more than 2500 species. Subtribe Centaureinae (about 800 species) is the most derived group and is characterized by achenes with a lateral–adaxial insertion areole, a double pappus, and, with a few exceptions, unarmed leaves (Wagenitz and Hellwig, 1996). Susanna and Garcia-Jacas (2007) have organized the genera of Centaureinae into several informal groups, which recent molecular studies have confirmed as natural: 1. Basal genera; Table 1 List of the studied Centaureinae taxa, divided into seven groups, proposed by Susanna and Garcia-Jacas. Group 1 Basal genera Group 2 Volutaria group Group 3 Rhaponticum group Group 4 Serratula group Group 5 Carthamus group Group 6 Crocodylium group Group 7 Centaurea group Aetheopappus (Cass.) Wagenitz & Hellwig Acroptilon Cass. Serratula L. s.str. Carthamus L. Crocodylium Vaill Acrolophus Cass. Amblyopogon (DC.) Wagenitz & Hellwig Amberboa Vall. (= Volutarella Cass.) Cyanopsis Cass. Cheirolophus Cass. Goniocaulon Cass. Crupina (Pers.) DC. Karvandarina Rech. f Czerniakowskya (Czerep.) Wagenitz & Hellwig Heterolophus (Cass.) Wagenitz & Hellwig Mantisalca Cass. Plagiobasis Schrenk Hyalinella (Tzvelev) Wagenitz & Hellwig Russowia C.Winkl. Odontolophoidei (Tzvelev) Wagenitz & Hellwig Odontolophus (Cass.) Wag. et Hell. Plectocephalus D.Don Psephellus Cass. Rhaponthicoides Vaill. Sosnowskya (Takht.) Wagenitz & Hellwig Stizolophus Cass. Uralepis (DC.) Wagenitz & Hellwig Xanthopsis (DC.) Wagenitz & Hellwig Zoegea L. Tricholepis DC. Valutaria Cass. Callicephalus C.A. Mey Centaurothamnus Wagenitz & Dittrich Leuzea DC. Ochrocephala Dittrich Oligochaeta (DC) K. Koch Rhaponticum Vall. Stemmacantha Cass. Phonus Hill. Aegialophila Boiss. & Heldr. Carduncellus Adans. Femeniasia Susanna Calcitrapa Adans. Centaurea L. s.str. Chartolepis Cass. Cnicus L. Colymbada Hill Corethropsis DC. Cyanus Mill. Grossheimia Sosn. & Takht. Hymenocentron (Cass.) DC. Jacea Mill. Lepteranthus (DC.) DC. Melanoloma Cass. Mesocentron (Cass.) DC. Microlophus (Cass.) DC. Paraphysis (DC.) Wagenitz Pectinastrum (Cass.) DC. Phalolepis (Cass.) DC. Plumosipappus (Czerep.) Wagenitz Pseudophaeopappus Wagenitz Pseudoseridia Wagenitz Protocyanus Dobrocz. Pteracantha Wagenitz Ptosimopappus Boiss Seridia Juss. Seridioides DC. Solstitiaria (Hill) Dobrocz. Stephanochilus Coss. & Durieu ex Benth. & Hook f. Tetramorphaea (DC.) Boiss. Triplocentron (Cass.) Spach Wagenitzia Dostàl Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 3 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx 2. Volutaria group; 3. Rhaponticum group; 4. Serratula group; 5. Carthamus group; 6. Crocodylium group; 7. Centaurea group. Basal genera – unarmed, annual to perennial herbs or shrubs with solitary or corymbose capitula and double pappus; basal chromosome numbers are usually x = 15. Volutaria group – annual to perennial herbs with heterogamous capitula and large and showy sterile radiant florets, with staminodes. Achenes have basal hilum and pappus of scales. Rhaponticum group – unarmed perennial herbs with homogamous capitula and involucral bracts with very large, scarious appendages, usually silvery-white; pappus is deciduous in a ring. Serratula group – unarmed perennial herbs or shrubslets with homogamous capitula and rudimentary appendages of bracts; achenes have basal hilum and double, easily deciduous pappus. Carthamus group – annual or perennial herbs or shrublets, usually spiny with homogamous capitula and compressed, very hard achenes, which have lateral hilum and double pappus. Crocodylium group – annual or perennial herbs with fleshy, glandular leaves and heterogamous capitula. All florets are with many stalked glands and densely sericeous achenes. Centaurea group – annual to perennial herbs or shrubs, usually unarmed with heterogamous capitula and scarious involucral bracts with a variable apical appendage, spiny or unarmed. Sterile florets are radiant and showy; achenes – oblong, compressed with lateral–adaxial insertion areole; pappus is double with pinnulate or plumose outer bristles; basal chromosome numbers are x = 7, 8, 9, 10, 11, 12. This review summarizes reports on sesquiterpenoids from the Centaureinae subtribe of the Asteraceae family, as well as the 13C NMR spectral data described in the literature. According to the taxonomic scheme of Susanna and Garcia-Jacas (2007), the genera of subtribe Centaureinae are classified in seven groups. In Table 1 are listed the Centaureinae taxa, studied so far by reason of their horology, karyology, genome size, DNA sequences, secondary metabolites, etc., as each taxon is arranged in the appropriate group, following the classification mentioned above. Some of the taxa in the Table have generic rank, while other are subgenera, sections or synonyms. Our aim was to include in the table all investigated Centaureinae taxa, but not to define their taxonomic rank. The Table contains a total of 72 taxonomic units. The larger group is Centaurea (group 7) that comprises 32 taxa. So far only 19 of the 72 representatives of the subtribe Centaureinae have been investigated for the occurrence of sesquiterpenes. As we can see from the data here reported, not only most species but also the majority of the genera of the Centaureinae have not yet been investigated for their sesquiterpene profile. The authors hope that the compilation of data provided in the present review will be helpful for people who plan to conduct further research on the Centaureinae, as they might provide first indications on which compounds to expect in members of this subtribe not yet investigated. 2. Sesquiterpenes An extensive bibliographic search identified a total of 287 different sesquiterpenes from 218 species belonging to these 19 genera, among which the most intensively studied genera is Centaurea (166 taxa). The analysis of the sesquiterpene structures of the subtribe Centaureinae allows us to point out some interesting chemotaxonomic structural features. Except for Centaurea calcitrapa, C. solstitialis and Serratula latifolia, from which also compound 287 and two bisabolanes (285–286) were isolated, in all the other taxa of Centaureinae only germacranes, elemanes, eudesmanes and guaianes occur (Fig. 1). With the exception of three eudesmanes (121, 122, 124) and four guaianes (280–283) isolated from S. latifo- Fig. 1. Sesquiterpene skeletons. lia and a few other eudesmanes occurring mainly in the genera Cheirolophus and Phonus, all the sesquiterpenes have an a-oxygenated function at C-6 that, normally, is involved in the formation of the C-6/C-12 c-lactone or, in some cases, is present as a free hydroxyl group. In contrast to other genera of the Asteraceae family, belonging to different subtribes, the oxygenated function at C-8 is almost always a-orientated and, if present, the ester side chains are often linked at this carbon, although it is possible to find the ester moiety in other positions. The 42 side chains present in the sesquiterpenoids from Centaurineae subtribe are depicted in Fig. 2 and Table 2 reports their 13C NMR spectroscopic data. All the sesquiterpenes are listed with their semi-systematic and trivial names and the genera and species, ordered alphabetically, in which the compounds have been found. By far the most common compound in the Centaureinae is cnicin (19) present in 83 taxa followed by the guaianolides cynaropicrin (162, 68 taxa), janerin (208, 38 taxa) and chlorohyssopifolin A (224, 29 taxa). 2.1. Germacranes The germacranes (68 compounds) detected in the subtribe Centaureinae are listed in Table 3. Except for the heliangolides 59–68, present in Centaurea paui, Centaurea tweediei and Centaurea sulphurea, and for a few C10(C14) enes all of them have a trans-C1(C-10)/trans-C-4 configuration. They are almost all C-6/C-12 olides with the typical exocyclic C-11/C-13 double bond or with a C-11/C-13 dihydro moiety: only compounds 51 and 52 do not have the lactone and the artemisiifolin derivatives 53–57 show a C-8/C-12 olide ring. The presence of a primary alcohol or acetoxy at C-15 and of the a-oxygenated function at C-8 are common features for almost all these germacranolides: in fact only few compounds have a C-15 methyl, mainly co-occurring with a C-4/C-5 epoxy ring, and just nine (1–3, 5, 28, 38, 48, 51, 52) are devoid of the oxygenated function at C-8. Table 4 reports a complete list of all 13C NMR spectroscopic data quoted in the literature. 2.2. Elemanes All the elemanes (29 compounds, Table 5) have an a-orientated hydroxyl or ester at C-8 (except 87 which is devoid of functionality) and an oxygenated function at C-15, mainly a primary alcohol, but in three cases (compounds 70, 83, and 85) an aldehyde. In five cases (compounds 93–97) the C-6/C- Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 4 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Fig. 2. Natural ester chains (acyl groups). 12 c-lactone is open showing a free a-hydroxyl at C-6 and a carbomethoxy function at C-12. Only compound 92 has a C-8/ C-12 c-lactone. Table 6 reports a complete list of all spectroscopic data quoted in the literature. 13 C NMR Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 5 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 2 C NMR spectral data (CDCl3) of the side chains (S.C.) in sesquiterpenoids in the Subtribe Centaureinae. 13 S.C. 10 20 30 (70 ) 40 (60 ) A B C D Ea F Fa G I Ia J Ja K L M Nb O P Q R S T U V W Y Z ZAa ZB ZBc ZCa ZD ZE ZF ZFa ZG ZHa ZHd ZHb ZJ ZK ZL ZM ZN ZOb ZP ZQ 170.5 20.8 176.0 166.1 169.7 174.8 174.5 175.1 165.2 165.7 164.3 167.0 169.9 170.1 173.1 173.9 173.1 175.0 34.1 136.2 45.9 41.9 42.2 42.4 139.0 141.0 135.0 nr 53.8 53.7 74.7 79.3 75.1 75.8 19.3 124.6 180.2 64.4 63.9 64.4 127.6 125.1 121.5 nr 52.8 52.9 51.2 51.8 50.9 68.5 18.5 18.4 15.2 13.5 14.9 13.5 62.3 61.8 62.2 nr 17.3 17.2 23.4 24.0 23.9 21.6 174.8 175.4 171.4 166.4 166.7 164.9 165.5 166.9 166.6 166.1 166.8 168.2 172.1 165.2 166.4 167.4 165.6 166.6 165.2 166.6 164.6 165.9 165.1 n.r. 165.9 167.1 164.7 166.8 76.0 41.3 43.3 126.9 128.4 115.1 127.8 136.6 130.2 135.0 126.9 128.9 38.4 112.4 131.7 132.1 131.4 142.3 141.9 142.4 138.3 131.5 130.6 n.r. 130.2 122.1 122.3 123.9 68.1 26.6 25.3 140.0 138.6 159.3 140.2 35.0 132.7 141.3 143.7 143.5 32.7 159.9 140.7 141.9 142.5 71.9 70.2 71.8 69.7 145.1 138.6 141.5 129.7 132.7 132.4 114.0 (124.1) 21.6 11.5 22.2 15.8 14.6 20.4 63.0 61.1 193.1 59.8 59.2 59.7 67.1 66.8 14.1 14.3 15.7 66.7 65.4 66.7 67.1 58.8 63.3 63.2 128.7 115.7 114.0 146.1 (111.7) 50 16.5 22.2 20.3 12.8 27.5 19.3 128.0 13.2 12.8 12.5 12.6 16.7 15.7 56.7 55.7 63.8 127.0 125.3 127.2 127.6 56.8 62.5 62.5 133.3 162.6 163.7 150.0 100 200 170.3 175.0 20.6 21.0 71.5 36.4 171.1 20.9 176.4 22.1 171.4 20.8 171.1 n.r. 20.5 20.8 55.6 56.0 51.8 300 131.0 400 ,800 116.2 500 ,700 130.9 600 156.2 Ref. Cardona et al. (1997) not reported in the literature Bruno et al. (2011) Bruno et al. (2011) Khan et al. (2004a) Bruno et al. (2011) Khan et al. (2004a) Marco et al. (1992) Bruno et al. (2011) Khan et al. (2005a) Buděšinský and Šaman (1995) Bruno et al. (2011) Hamburger et al. (1993) Hamburger et al. (1993) Hamburger et al. (1993) Dai et al. (2001) Hamburger et al. (1993) Bruno et al. (2005a) not reported in the literature Fernandez et al. (1989) Buděšinský and Šaman (1995) Buděšinský and Šaman (1995) Buděšinský and Šaman (1995) Bruno et al. (2011) Buděšinský and Šaman (1995) Buděšinský and Šaman (1995) Buděšinský and Šaman (1995) Youssef (1998) Bruno et al. (2011) Youssef and Frahm (1994a) Youssef and Frahm (1994a) Bruno et al. (2011) Bruno et al. (2011) Bruno et al. (2011) Youssef (1998) Buděšinský and Šaman (1995) Csapi et al. (2010) Barrero et al. (1997a) Santos et al. (1995) Karioti et al. (2002) Buděšinský and Šaman (1995) Saroglou et al. (2005) Cardona et al. (1991) Buděšinský and Šaman (1995) Stevens et al. (1991) Buděšinský and Šaman (1995) Khan et al. (2008) n.r. = not reported. a In MeOD. b In acetone-d6. c In CD2Cl2/DMSO-d6 7:1. d In DMSO-d6. 2.3. Eudesmanes 2.4. Guaianes The eudesmane (44 compounds, Table 7) all have a trans fused decalin moiety. Many of them carry a free b-oriented hydroxyl group at C-1 and an aldehyde at C-4 that can be a or b oriented. The stereochemistry of C-4 can easily be determined by 1H NMR spectra. In fact, in the case of 15b-CHO (compounds 103,107, 109,111,113,117,119,138) the signal of the aldehydic proton can be found in the range 9.94–9.91 d (brs), whereas if the aldehydic group is a-orientated (compounds 101,102,104,105,108,110, 112,115,118,137), the proton signal is up-field shifted (9.68–9.33 d, d, J = 4.2–3.9 Hz). Also some eudesmanes show the presence of a carboxy or carbomethoxy group at C-12, rather than the c-lactone. Table 8 reports a complete list of all 13C NMR spectroscopic data quoted in the literature. Guaianes comprise the most numerous class, containing 143 compounds (Table 9). They have all a 1,5-cis junction and, with the exception of compounds 280–283, isolated from S. latifolia, they are all trans-6,12 lactones. The presence of a C-8 oxygenated function (a-alcohol or ester, never ketone) is also a common feature. There are, however, a few exceptions: 216 and 283 carry an oxygenated function in C-1, while a few compounds carry this function on C-9 (151, 153, 155, 156, 271). Also the occurrence of a C-10/C-14 double bond is a common functionality, and only 152, 154, 262, 272, 273, and 280–282 have a different structural moiety. Guaianes listed in Table 9 were grouped on the basis of the C-4/C-15 functionality: double bound (142–205), epoxyde (206–216), chlorohydrine (217–235), diol (236–261), methyl Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 6 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 3 Germacranes isolated from taxa of the Subtribe Centaureinae. No Structure Name Taxa Ref. 1 costunolide Centaurea acaulis Bentamane et al. (2005) Centaurea kurdica Centaurea kurdica Appendino and Özen (1993) Appendino and Özen (1993) 3a,15-Dihydroxy-costunolide Centaurea lusitanica Nowak et al. (1989a), Nowak (1992) Salonitenolide Aegialophila pumila Centaurea achaia Centaurea affinis Centaurea alba Centaurea alba ssp. caliacrae Centaurea alba ssp. deusta Centaurea aspera Centaurea aspera ssp. scorpiurifolia Centaurea aspera ssp. stenophylla Centaurea bombycina Centaurea calcitrapa Centaurea crithmifolia El-Marsy et al. (1984) Skaltsa et al. (2000a) Janaćković et al. (2004) Fernandez et al. (1995) Geppert et al. (1983) Geppert et al. (1983) Barrero et al. (1995) Barrero et al. (1995) O O 2 8-Desoxy-salonitenolide; 15-hydroxycostunolide OH O HO O 3 HO O HO O 4 HO O O Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea crocodylium derventana eriophora friderici grisebachii iberica malacitana maroccana melitensis orphanidea paniculata paui Centaurea pontica Centaurea pseudomaculosa Centaurea salonitana Centaurea stoebe Centaurea weldeniana Cheriolophus intybaceus Cnicus benedictus 5 Stenophyllolide OH HO O O 15-Hydroxy-8a-isobutyryloxycostunolide; 40 -desoxyarctiopicrin 6 O Barrero et al. (1995), Marco et al. (2005) Barrero et al. (2000) Geppert et al. (1983), Jakupovic et al. (1986) Geppert et al. (1983), Gousiadou and Skaltsa (2003) Horoszkiewicz-Hassan and Nowak (2001) Tešević et al. (1998a) Geppert et al. (1983) Geppert et al. (1983) Djeddi et al. (2008a) Sham’yanov et al. (1998) Barrero et al. (1988), Barrero et al., 1995 Barrero et al. (2000) Barrero et al. (1989) Gousiadou and Skaltsa (2003) Geppert et al. (1983) Cardona et al. (1997), Gousiadou and Skaltsa (2003) Geppert et al. (1983) Turdybekov et al. (1989), Adekenov (1995) Suchy et al. (1967), Rybalko et al. (1975), Gonzalez et al. (1977a), Daniewski et al. (1992), Nowak et al. (1996) Huneck et al. (1986a) Geppert et al. (1983) Marco et al. (1994) Vanhaelen-Fastre and Vanhaelen (1974), Vanhaelen-Fastre and Vanhaelen (1976), Vanhaelen and Vanhaelen-Fastre (1975), Tsankova et al. (1994) Marco et al. (2005) Barrero et al. (1995) Centaurea aspera Centaurea aspera ssp. scorpiurifolia Centaurea aspera ssp. stenophylla Sanchez Paradera et al. (1968), Gonzalez et al. (1977a), Picher et al. (1984a), Amigo et al. (1984), Barrero et al. (1995), Marco et al. (2005) Centaurea aspera ssp. subinermis Cardona et al. (1991) Centaurea lusitanica Nowak et al. (1996) Centaurea malacitana Barrero et al. (1988), Barrero et al. (1995), Barrero et al. (1997a) Cheiroluphus intybaceus Marco et al. (1994) Cheiroluphus mauritanicus Marco et al. (1994) O HO O O Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 7 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 3 (continued) No Structure Name Taxa Ref. 7 8a-(20 -methyl-20 -propenoyl)salonitenolide; 15-hydroxy-8a-(amethylacryloyl)-costunolide Centaurea achaia Cheiroluphus intybaceus Cheirolophus hortigenus Skaltsa et al. (2000a) Marco et al. (1994) Marco et al. (1994) Onopordopicrin Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Cheirolophus x hortigenus Cheiroluphus intybaceus Skaltsa et al. (2000a) Marco et al. (2005) Marco et al. (2005) Sarg et al. (1989) Barrero et al. (2000) Barrero et al. (1989) Trendafilova et al. (2007) Bruno et al. (1996) Youssef (1998) Lonergan et al. (1992) Gonzalez et al. (1984), Nowak et al. (1986a) Fortuna et al. (2001), Cabral et al. (2008), Bach et al. (2011) Marco et al. (1994) Marco et al. (1994) salonitenolide-8-(40 hydroxyisobutyrate); arctiopicrin Centaurea eryngioides Centaurea gigantea Centaurea melitensis Sarg et al. (1989) Shoeb et al. (2007a) Barrero et al. (1989) amarin Centaurea amara Centaurea malacitana Centaurea nicaensis Gonzalez et al. (1980a) Barrero et al. (1988) Bruno et al. (1996) 8a-Angeloyl-salonitenolide Centaurea aspera ssp. stenophylla Marco et al. (2005) Arbutifolin Centaurea arbutifolia Gonzalez et al. (1981) 8a-(40 -hydroxy-30 -methylbutanoyl)salonitenolide Centaurea achaia Centaurea gigantea Skaltsa et al. (2000a) Shoeb et al. (2007a) 8a-(40 -hydroxy-20 -methyl-20 butenoyl)-salonitenolide Centaurea achaia Skaltsa et al. (2000a) OH 8a-(50 -hydroxytigloyl)-salonitenolide Centaurea achaia Centaurea glomerata Cheiroluphus intybaceus Skaltsa et al. (2000a) El-Marsy et al. (1985) Marco et al. (1994) OH 8a-(50 -hydroxyangeloyl)salonitenolide Centaurea aspera ssp. stenophylla Marco et al. (2005) Centaurea moesiaca Trendafilova et al. (2007) Centaurea phrygia Tsankova and Ognyanov (1985) Cnicus benedictus Tsankova et al. (1994) O O HO O O 8 O OH O HO O O 9 O OH O HO O O 10 OAc O O HO achaia aspera aspera ssp. stenophylla eryngioides incana melitensis moesiaca nicaensis scoparia sonchifolia tagananensis tweediei O O 11 O O HO O O 12 O O HO O O 13 O OH O HO O O 14 O OH O HO O O 15 O O HO O O 16 O O HO O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 8 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 3 (continued) No Structure Name Taxa Ref. 17 8a-(40 -hydroxyangeloyl)salonitenolide Centaurea glomerata El-Marsy et al. (1985) 8a-(40 -acetoxyangeloyl)salonitenolide Centaurea aspera ssp. stenophylla Marco et al. (2005) Centaurea malacitana Barrero et al. (1997a) Cnicin El-Marsy et al. (1984) Mezache et al. (2010) Bruno et al. (2001) Janać ković et al. (2004), Tešević et al. (2007) Gonzalez et al. (1977a), Nowak et al. (1986a) Centaurea aggregata Nowak et al. (1984), Gousiadou and Skaltsa (2003) Centaurea alba Gonzalez et al. (1977a), Fernandez et al. (1995) Centaurea alexandrina Ismail et al. (1986) Centaurea aplopea Nowak et al. (1984), Gousiadou and Skaltsa (2003) Centaurea aplopea ssp. lunensis Nowak et al. (1984), Gousiadou and Skaltsa (2003) Centaurea araneosa Farrag et al. (1993) Centaurea arenaria Nowak et al. (1984), Gousiadou and Skaltsa (2003), Tešević et al. (2007), Csapi et al. (2010) Centaurea arenaria ssp. majorowii Nowak et al. (1984), Gousiadou and Skaltsa (2003) Centaurea arenaria ssp. odesana Nowak et al. (1984), Gousiadou and Skaltsa (2003) Centaurea aspera Geppert et al. (1983), Barrero et al. (1995) Centaurea aspera ssp. Barrero et al. (1995) scorpiurifolia Centaurea aspera ssp. stenophylla Barrero et al. (1995), Marco et al. (2005) Centaurea attica Skaltsa et al. (1999), Gousiadou and Skaltsa (2003) Centaurea attica ssp. drakiensis Nowak et al. (1984), Gousiadou and Skaltsa (2003) Centaurea attica ssp. ossaea Nowak et al. (1984), Gousiadou and Skaltsa (2003) Centaurea bombycina Barrero et al. (2000) Centaurea bruguierana Rustaiyan et al. (1982), Harraz et al. (1994) Centaurea calcitrapa Drozdz (1967), Rybalko et al. (1975), Gonzalez et al. (1977a), Gonzalez et al., 1978a, Karawya et al. (1975), Geppert et al. (1983), Jakupovic et al. (1986), Marco et al. (1992) Centaurea calolepis Baykan Erel et al. (2011) Centaurea calvescens Nowak et al. (1984), Gousiadou and Skaltsa (2003) Centaurea castellana Gonzalez et al. (1977a) Centaurea cineraria Nowak et al. (1984), Gousiadou and Skaltsa (2003) Centaurea cinerar. ssp. Bruno et al. (1998) busambarensis Centaurea cineraria ssp. umbrosa Bruno and Herz (1988);Gousiadou and Skaltsa (2003) Centaurea cineraria var. circae Nowak et al. (1984), Gousiadou and Skaltsa (2003) Centaurea crocodylium Horoszkiewicz-Hassan and Nowak (2001) Centaurea cuneifolia Salan and Öksük (1999), Gousiadou and Skaltsa (2003), Tešević et al. (2007) Centaurea cuneifolia ssp. pallida Nowak et al. (1984), Gousiadou and Skaltsa (2003) Centaurea derventana Tešević et al. (1998a) Centaurea deusta Karioti et al. (2002) Centaurea diffusa Drozdz (1966), Rybalko et al. (1975), Gonzalez et al. (1977a), Milkova et al. (1993), Fortuna et al. (2002), Gousiadou and Skaltsa (2003), Cabral et al. (2008), Bach et al. (2011) O O HO OH O O 18 O O HO OAc O O 19 O OH O HO O O OH Aegialophila pumila Amberboa lippii Centaurea aegialophila Centaurea affinis Centaurea africana Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 9 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 3 (continued) No Structure Name Taxa Ref. C. diffusa var. brevispina = C. bovina Centaurea eriophora Centaurea eryngioides Centaurea exarata Nowak et al. (1984), Gousiadou and Skaltsa (2003) Geppert et al. (1983) Sarg et al. (1989) Nowak et al. (1984), Nowak et al. (1986a), Gousiadou and Skaltsa (2003) Tešević et al. (2007) Barrero et al. (2000) Nowak et al. (1984), Gousiadou and Skaltsa (2003), Djeddi et al. (2008a) Nowak et al. (1984), Gousiadou and Skaltsa (2003) Drozdz (1967), Rybalko et al. (1975), Gonzalez et al. (1977a), Sham’yanov et al. (1998) Nowak et al. (1984), Gousiadou and Skaltsa (2003) Nowak et al. (1984), Gousiadou and Skaltsa (2003) Geppert et al. (1983), Nowak (1992), Nowak et al. (1996) Rybalko et al. (1975), Gonzalez et al. (1977a), Kelsey and Locken (1987), Landau et al. (1994), Gousiadou and Skaltsa (2003), Meepagala et al. (2006) Barrero et al. (1988), Barrero et al. (1995, 1997a) Nowak et al. (1984), Gousiadou and Skaltsa (2003) Maymò et al. (1999) Barrero et al. (2000), Bentamene et al. (2007) Drozdz (1968), Gonzalez et al. (1977a) Trendafilova et al. (2007) Barrero et al. (2000) Bruno et al. (1995) Bruno et al. (1996) Nowak et al. (1984), Gousiadou and Skaltsa (2003) Drozdz (1967), Rybalko et al. (1975), Gonzalez et al. (1977a) Ali et al. (1987) Nowak et al. (1984), Gousiadou and Skaltsa (2003) Bruno et al. (2002) Centaurea glaberima (Tricholepis) Centaurea granatensis Centaurea grisebachi Centaurea grisebachi ssp. confusa Centaurea iberica Centaurea kartschiana Centaurea leucophaea Centaurea lusitanica Centaurea maculosa Centaurea malacitana Centaurea mantoudii Centaurea mariolensis Centaurea maroccana Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea micranthos moesiaca monticola napifolia nicaensis orphanidea Centaurea ovina Centaurea pallescens Centaurea pallidior Centaurea paniculata ssp. castellana Centaurea paui Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Cardona et al. (1997), Gousiadou and Skaltsa (2003) pelia Nowak et al. (1984), Gousiadou and Skaltsa (2003) pseudomaculosa Adekenov et al. (1979, 1986a), Adekenov (1995) raphanina ssp. mixta Panagouleas et al. (2003) rhenana ssp. savranica Nowak et al. (1984), Gousiadou and Skaltsa (2003) rocheliana Geppert et al. (1983) rothmalerana Santos et al. (1995) sphaerocephala Bruno et al. (1994) spinosa Nowak et al. (1984), Gousiadou and Skaltsa (2003), Saroglou et al. (2005) splendens Tešević et al. (2007) squarrosa Tarasov et al. (1973), Gonzalez et al. (1977a), Isamukhamedova et al. (1977) stoebe Suchy and Herout (1962), Rybalko et al. (1975), Gonzalez et al. (1977a), Huneck et al. (1986a), Tešević et al. (2007) sulphurea Geppert et al. (1983), Gonzalez et al. (1984), Barrero et al. (2000), Lakhal et al. (2010) thessala ssp. drakiensis Skaltsa et al. (1999), Georgiadou et al. (2000), Gousiadou and Skaltsa (2003) transiens Nowak et al. (1984), Gousiadou and Skaltsa (2003) tymphaea Nowak et al. (1984), Gousiadou and Skaltsa (2003) (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 10 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 3 (continued) No Structure Name Taxa Ref. Centaurea tymphaea ssp. brevispina Centaurea vallesiaca Nowak et al. (1984), Gousiadou and Skaltsa (2003) Geppert et al. (1983), Landau et al. (1994), Gousiadou and Skaltsa (2003) Nowak et al. (1984), Koukoulitsa et al. (2002), Gousiadou and Skaltsa (2003) Korte and Beckmann (1958), Suchy et al. (1959a), Suchy et al. (1959b), Suchy et al. (1960), Vanhaelen-Fastre (1968), Vanhaelen-Fastre (1972), Samek et al. (1969), Rybalko et al. (1975), VanhaelenFastre and Vanhaelen (1976), Tsankova et al. (1994), Kataria (1995) Karioti et al. (2002) Centaurea zuccariniana Cnicus benedictus Cnicin 30 -O-acetyl 20 O O HO OAc O O Cnicin 40 -O-acetyl 21 O OAc O HO Centaurea deusta OH OH O O 22 8a-(40 ,50 -dihydroxytigloyloxy)salonitenolide OH O Centaurea moesiaca Trendafilova et al., 2007 Centaurea alba Fernandez et al. (1995) Centaurea aspera Barrero et al. (1995) Centaurea aspera ssp. Barrero et al. (1995) scorpiurifolia Centaurea aspera ssp. stenophylla Barrero et al. (1995), Marco et al. (2005) Centaurea attica Skaltsa et al. (1999), Gousiadou and Skaltsa (2003) Centaurea calcitrapa Jakupovic et al. (1986), Marco et al. (1992) Centaurea cineraria ssp. umbrosa Bruno and Herz (1988), Gousiadou and Skaltsa (2003) Centaurea derventana Tešević et al. (1998a) Centaurea deusta Karioti et al. (2002) Centaurea diffusa Fortuna et al. (2002) Centaurea malacitana Barrero et al. (1988, 1995, 1997a) Centaurea mariolensis Maymò et al. (1999) Centaurea maroccana Barrero et al. (2000) Centaurea moesiaca Trendafilova et al. (2007) Centaurea monticola Barrero et al. (2000) Centaurea napifolia Bruno et al. (1995) Centaurea orphanidea Gousiadou and Skaltsa (2003) Centaurea paniculata ssp. Bruno et al. (2002) castellana Centaurea paui Cardona et al. (1997), Gousiadou and Skaltsa (2003) Centaurea sphaerocephala Bruno et al. (1994) Centaurea spinosa Saroglou et al. (2005) Centaurea thessala ssp. drakiensis Skaltsa et al. (1999), Georgiadou et al. (2000), Gousiadou and Skaltsa (2003) Centaurea zuccariniana Koukoulitsa et al. (2002) Cnicus benedictus Tsankova et al. (1994) Centaurea achaia Skaltsa et al. (2000a) OH O HO O O 23 OH O OAc 8a-O-(40 -acetoxy-20 hydroxymethylbuten-20 -oyloxy)salonitenolide Centaurea spinosa Salonitenolide-8-O-(40 -acetoxy-50 hydroxy-angelate) Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Saroglou et al. (2005) O HO O O 24 OH O O HO O O OAc Fernandez et al. (1995) Marco et al. (2005) Marco et al. (2005) Barrero et al. (2000) Karioti et al. (2002) Tešević et al. (1998a) Djeddi et al. (2008a) Trendafilova et al. (2007) Cardona et al. (1997), Gousiadou and Skaltsa (2003) Centaurea stoebe Huneck et al. (1986a) Centaurea thessala ssp. drakiensis Skaltsa et al. (1999) alba aspera aspera ssp. stenophylla bombycina deusta derventana grisebachi moesiaca paui Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 11 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 3 (continued) No Structure Name Taxa Ref. 25 Centaurea moesiaca Trendafilova et al. (2007) OH OH 1b,15-dihydroxy-8a-(3,4-dihydroxy2- methylenebutanoyloxy)4E,10(14),11(13)-germacratriene12,6a- olide Centaurea moesiaca Trendafilova et al. (2007) OH OH 1a,15-dihydroxy-8a-(3,4-dihydroxy2- methylenebutanoyloxy)4E,10(14),11(13)-germacratriene12,6a- olide stizolin Stizolophus balsamita Mukhametzhanov et al. (1969a, 1971), Rybalko et al. (1975), Gonzalez et al. (1977a),Nowak (1992), Suleimenov et al. (2005a) 9a-hydroxypartenolide Zoegea baldshuanica Buděšinský et al. (1984), Nowak (1992), Nowak et al. (1996) 8a,9a-dihydroxypartenolide Stizolophus balsamita Mukhametzhanov et al. (1969a), Nowak et al. (1996), Nowak (1992) 8,15-dihydroxy-1(10)-epoxygermacr-4-ene Centaurea sphaerocephala Bruno et al. (1994) 1(10)-en-4a,5b-epoxy-8a-(40 hydroxysenecioate)-germacrane Centaurea coronopifolia Öksüz and Ayyildiz (1986) stizolicin Centaurea coronopifolia OH O O O HO 26 O OH O O O HO O 27 OH O O O 28 OH O O O 29 OH OH O O O 30 O OH O HO O 31 O OH O O O O 32 OH O balsamin Stizolophus balsamita Mukhametzhanov et al. (1969b, 1970), Rybalko et al. (1975), Öksüz and Ayyildiz (1986) Mukhametzhanov et al. (1969c), Rybalko et al. (1975), Gonzalez et al. (1977a), Naidenova et al. (1988) Rybalko et al. (1975), Cassady et al. (1984), Nowak (1992) Rybalko et al. (1976), Nowak (1992) 9-epi-balsamin Centaurea coronopifolia Stizolophus balsamita Öksüz and Ayyildiz (1986) Suleimenov et al. (2005a) 8a-(40 -hydroxy-sencioyloxy)-9ahydroxy-parthenolide; 9-epi-40 hydroxybalsamin Centaurea coronopifolia Öksüz and Ayyildiz (1986) Stizolophus balsamita Nowak et al. (1989b, 1996), Nowak (1992), Suleimenov et al. (2005a) OH Centaurea solstitialis O O O Stizolophus balsamita O 33 OH O O O O O 34 OH O O O O O 35 OH O OH O O O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 12 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 3 (continued) No Structure 36 OH Name Taxa 11b,13-dihydrosalonitenolide Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea O HO O 37 8-oxo-15-hydroxygermacra1(10),E,4Z-dien-11bH-12,6a-olide O Ref. achaia alba aspera calcitrapa maroccana nicaensis paui Centaurea pullata Centaurea aspera Skaltsa et al. (2000a) Fernandez et al. (1995) Marco et al. (2005) Marco et al. (1992) Barrero et al. (2000) Medjroubi et al. (2003a) Cardona et al. (1997), Gousiadou and Skaltsa (2003) Djeddi et al. (2008b) Marco et al. (2005) O HO O 38 OH 11bH,13-dihydrostenophyllolide Centaurea aspera Marco et al. (2005) Centaurea aspera ssp. stenophylla Marco et al. (2005), Picher et al. (1984b) Centaurea aspera ssp. subinermis Cardona et al. (1991) 11bH,13-dihydroonopordopicrin Centaurea glomerata El-Marsy et al. (1985) dihydroamirin Centaurea amara Centaurea nicaensis Gonzalez et al. (1980a) Bruno et al. (1996) 11,13-dihydroarbutifolin Centaurea arbutifolia Gonzalez et al. (1981) 8a-(40 -hydroxy-30 -methylbutanoyl)11b,13- dihydrosalonitenolide Centaurea achaia Skaltsa et al. (2000a) 8a-(40 -hydroxy-20 -methyl-20 butenoyl)-11b,13dihydrosalonitenolide Centaurea glomerata El-Marsy et al. (1985) 11b,13-dihydro-19-desoxycnicin Centaurea pullata Benayache et al. (1992), Djeddi et al. (2007) 11b,13-dihydrocnicin Centaurea nicaensis Centaurea pullata Bruno et al. (1996), Medjroubi et al. (2003a) Benayache et al. (1992), Djeddi et al. (2007) 8a-O-(40 -acetoxy-50 hydroxyangeloyl)-11b,13dihydrosalonitenolide Centaurea pullata Djeddi et al. (2007) 11,13-dihydrostizolin Stizolophus balsamita Suleimenov et al. (2005a) O HO O 39 O OH O O HO O 40 O OAc O O HO O 41 O O O HO O 42 O OH O O HO O 43 O OH O O HO O 44 O OH O O HO O 45 O OH O OH O HO O 46 OH O O OAc O HO O 47 OH O O O Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 13 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 3 (continued) No Structure Name Taxa Ref. 48 11a,13-dihydro-8desoxysalonitenolide Centaurea kurdica Appendino and Ö zen (1993) 11a,13-dihydrosalonitenolide Centaurea calcitrapa Marco et al. (1992) Cebellin M Centaurea bella Nowak (1992, 1993a,b), Nowak et al. (1996) germacra-1(10),4-dien-6b-ol Phonus arborescens Barrero et al. (1997b) shiromool Phonus arborescens Barrero et al. (1997b) artemisiifolin Centaurea castellana Gonzalez et al. (1984), Gousiadou and Skaltsa (2003) Nowak et al. (1996) Gonzalez et al. (1973a, 1977a) Gonzalez et al. (1984) Nowak et al. (1996) Vanhaelen-Fastre and Vanhaelen (1976) Nowak et al. (1996) Gonzalez et al. (1973a, 1977a) Gonzalez et al. (1984) Nowak et al. (1996) O HO O 49 OH O HO O 50 OH O AcO O 51 OH 52 O OH 53 O O OH HO 54 15-Acetylartemisiifolin O O OH AcO 55 Scabiolide O Centaurea polyacantha Centaurea seridis Centaurea sonchifolia Centaurea sphaerocephala Cnicus benedictus Centaurea polyacantha Centaurea seridis Centaurea sonchifolia Centaurea sphaerocephala Centaurea solstitialis Suchy et al. (1962a,b, 1965a, 1968), Rybalko et al. (1975), Gonzalez et al., 1977a Mukhametzhanov et al. (1969c) isospiciformin Stizolophus balsamita Nowak et al. (1989b, 1996), Nowak (1992) Salonitolide Centaurea salonitana Suchy et al. (1965b), Rybalko et al. (1975), Gonzalez et al. (1977a), Daniewski et al. (1992) Gonzalez et al. (1973a, 1977a) Centaurea scabiosa O OH AcO O OH O 56 O O O OH 57 O O Centaurea seridis OH HO 58 OH O O Onopordopicrin-valine dimeric adduct Centaurea aspera ssp. stenophylla Marco et al. (1991), Marco et al., 2005 15-acetoxy-8a-hydroxy-7aH,6bHgermacra-4E, 1(10),11(13)-trien12,6-olide Centaurea paui Cardona et al. (1997) 15-acetoxy-1b,8a-dihydroxy7aH,6bH- germacra4E,10(14),11(13)-trien-12,6-olide Centaurea paui Cardona et al. (1997), Gousiadou and Skaltsa (2003) O O N O HO O O HO 59 OH O O O OH OH AcO OH O AcO 60 O N O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 14 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 3 (continued) No Structure Name Taxa Ref. 61 15-acetoxy-1b-hydroperoxy-8ahydroxy-7aH,6bH-germacra4E,10(14),11(13)-trien-12,6-olide Centaurea paui Cardona et al. (1997), Gousiadou and Skaltsa (2003) 15-acetoxy-1b,10a-epoxy-8ahydroxy- 7aH,6bH-germacra4E,11(13)-dien-12,6-olide Centaurea paui Cardona et al. (1997), Gousiadou and Skaltsa (2003) 8-(40 -hydroxy-methacroyloxy)-15oxohelianga-1(10)-4,11(13)-trien6,12-olide Centaurea tweediei Fortuna et al. (2001) OOH OH O AcO O 62 O OH O AcO O 63 OH O O CHO O O 15-acetoxy-8a-O-(3,4-dihydroxy-2Centaurea paui methylene-butanoyloxy)- 7aH,6bHgermacra-4E,1(10),11(13)-trien-12,6olide Centaurea sulphurea Cardona et al. (1994) 15-acetoxy-8a-O-(3,hydroxy4acetoxy-2-methylenebutanoyloxy)- 7aH,6bH-germacra4E,1(10),11(13)-trien-12,6-olide Centaurea paui Cardona et al. (1994) Sulphurein Centaurea sulphurea Lakhal et al. (2010) Cardona et al. (1997), Gousiadou and Skaltsa (2003) OH 15-acetoxy-8a-O-(3,4-dihydroxy-2methylene-butanoyloxy)- 1bhydroxy-7aH,6bH-germacra4E,10(14), 11(13)-trien-12,6-olide Centaurea paui OH Centaurea paui Cardona et al. (1997), Gousiadou and Skaltsa (2003) OH OH 15-acetoxy-8a-O-(3,4-dihydroxy-2methylene-butanoyloxy)- 1bhydroperoxy-7aH,6bH-germacra4E,10(14), 11(13)-trien-12,6-olide 64 O OH O OH O AcO Lakhal et al. (2010) O 65 O OAc O OH O AcO O 66 O OH O CHO OH O O 67 OH O O O AcO 68 O OOH O O AcO O O (262–283) and C15-nor (284). Table 10 reports a complete list of all 13 C NMR spectroscopic data quoted in the literature. In contrast to the other classes of sesquiterpenes, the guaianes of Centaurineae have a large variety of side chain esters linked at C-8 and many of them have a stereogenic center at C-20 . A useful tool has been identify in order to determinate the absolute stereochemistry of the C-20 carbon of the side chain. In fact as reported in Table 11 the 1H NMR values of the epimeric side chains are practically identical whereas the diagnostic signal is H13b. In the case of a C-20 R stereochemistry it resonates in the range (CDCl3) d 5.56–5.64, instead for a C-20 S stereochemistry the range is d 5.71–6.07 (Table 11). 2.5. Others Four sesquiterpenes with different skeletons are listed in Table 12 and the 13C NMR spectroscopic data of carabrone (287) is inserted in Table 10. 3. Chemotaxonomic remarks The analysis of sesquiterpene skeletons (Table 13) occurring in the 210 taxa belonging to the subtribe Centaureinae, reveals the presence of two main classes: 75 taxa contain exclusively guaianetype sesquiterpenes whereas 68 taxa contain exclusively germacrane-type sesquiterpenes. Only 12 skeleton combinations among the 15 possible occur in this subtribe. No taxa contains at the same time all the four skeletons neither guaines, eudesmanes and elemanes, nor elemanes alone. Only five species do not contain either guianes or germacranes (Centaurea cadmea, Centaurea granata, Centaurea hierapolitana, Centaurea phyllocephala, Centaurea pamphilica). Furthermore,Centaurea conifera, Centaurea incana, Centaurea salonitana, Centaurea scabiosa and C. solstitialis have been shown to have germacranes, guaianes or eudesmane depending on the collection place. It is noteworthy that only one species (Centaurea chilensis) contains both guaines and elemanes but they were found in two separate investigations. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 C 1a1 2a2 4a3 5n:r: 4 6a5 7a5 8a6 8b3 8c7 9c7 9d8 10n:r: 4 11a3 13a2 13d8 14a9 15a5 16a3 18a3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 10 20 30 40 50 100 200 127.1 26.3 39.5 140.1 127.3 81.9 50.4 28.2 41.0 136.9 141.5 170.5 119.6 16.1 17.3 126.5 28.6 35.4 143.3 128.8 80.1 50.5 27.7 40.8 137.7⁄ 139.5⁄ 170.2 120.0 15.9 61.2 128.7 26.3 35.0 143.6 128.5 76.5 54.7 70.9 52.5 134.0 136.3 171.1 127.0 16.9 60.9 127.4⁄ 25.3 34.5 143.3 126.0⁄ 77.8 46.6 35.7 79.5 140.0 n.r. 169.5 119.0 10.4 58.7 129.5 26.4 34.7 143.8 128.8 77.2 52.9 72.3 48.9 132.6 135.4 169.7 125.4 16.7 61.5 176.0 34.1 19.3 18.5 129.6 26.4 34.7 143.8 128.7 77.1 53.1 72.9 48.8 132.7 135.5 169.8 125.3 16.8 61.6 166.1 136.2 126.4 18.4 129.7 26.0 34.5 144.5 127.9 77.3 52.8 72.8 48.8 132.1g 135.2g 170.5h 125.6 16.6 60.5 165.0h 139.6g 125.7 60.9 129.8 26.3 34.7 144.2 128.4 76.6 53.0 73.1 48.7 132.4 135.4 169.9 125.5 16.8 61.3 165.1 139.4 126.3 62.1 129.9 26.4 34.5 144.7 128.6 76.9 53.0 73.2 48.7 132.6 136.9 169.8 124.3 16.5 60.4 165.2 141.5 123.7 60.8 130.1 26.8 34.9 145.0 128.6 77.1 52.9 73.1 49.2 133.3 137.0 170.3 128.8 16.8 60.6 174.8 43.4 64.3 14.0 129.5 25.7 34.0 144.9 128.5 77.3 52.4 72.8 48.4 132.3 135.9 171.0 124.8 15.7 59.6 174.7 42.7 63.6 12.8 130.4 26.8 34.9 145.1 129.0 77.4 53.5 74.0 49.1 133.0 137.4 170.1 123.9 16.9 60.9 165.5 141.6 127.2 67.9 129.5 26.3 34.7 143.8 128.8 76.7 53.0 72.2 49.0 132.7 135.6 169.8 125.1 16.9 61.5 166.8 127.3 139.5 15.9 20.5 129.5 26.3 34.7 143.8 128.7 76.6 52.7 72.5 49.0 132.6 135.3 169.7 125.8 16.7 61.4 172.1 38.4 32.7 61.7 16.7 129.8 26.4 33.8l 144.9 128.3 76.9 52.0 72.7 48.7 132.7 136.9 170.2 124.7 17.1 59.7 174.1 38.3 33.4 65.9 17.0 129.6 26.3 29.7 143.7 128.6 76.4 53.0 72.9 48.7 133.2 135.5⁄ 169.7 125.2 16.7 61.5 166.1 135.0⁄ 141.3 59.8 12.8 129.7 26.4 34.8 143.7 128.6 76.5 53.1 73.0 48.8 132.6 135.5 169.7 125.3 16.8 61.6 166.2 132.1 141.5 14.4 56.9 129.8 26.3 34.7 143.9 128.6 76.6 53.0 72.8 48.9 132.4 135.5 169.8 125.3 16.8 61.5 166.1 131.6 141.7 15.9 64.9 129.8 26.3 34.6 143.9 128.6 76.7 52.9 73.0 48.8 132.4 135.6 169.7 125.0 16.8 61.5 165.7 128.2 140.1 62.8 19.7 170.8 20.9 C 19b3 19c10 19e11 21a3 22e12 24a3 25b13 26b13 27a14 28a14 35a15 36a16 36b17 36a;n 17 37a3 38a18 39a2 44a19 45a19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 10 20 30 40 50 100 200 129.8 26.1 34.6 144.6 128.0 77.1 53.0 73.1 48.6 132.1 135.3 170.5 125.5 16.7 60.7 165.1 139.7 70.8 65.8 127.1 130.8 26.8 35.5 145.6 129.6 78.7 54.1 74.6 47.0 133.1 137.3 172.0 125.2 17.0 60.9 166.6 142.4 71.8 66.7 127.2 130.9 26.9 35.2 145.5 129.7 78.7 54.1 74.5 49.0 133.2 137.4 172.1 125.3 17.0 60.7 166.6 142.3 71.9 66.7 127.0 129.9 26.3 34.7 144.1 128.4 76.4 53.0 73.3 48.6 132.3 135.4 169.8 125.3 16.8 61.5 164.6 138.8 69.5 67.3 127.8 171.3 20.8 131.1 27.4 35.4 145.7 130.1 78.9 54.2 74.8 48.9 133.0 137.6 172.5g 125.9 17.4 61.1 167.5g 133.7 147.2 59.7 57.0 129.8 26.1 34.6 144.3 128.2 76.9 52.7 73.3 48.7 132.1 135.4 170.2 125.3 16.8 60.8 164.8 131.7 140.3 62.8 62.3 171.1 20.8 77.2 34.2 28.0 147.6g 121.8 75.2 50.9 73.3 29.5 136.8 137.1 170.2h 121.8 118.1 61.0 164.4h 139.7g 70.5 65.4 126.9 76.2 33.9 28.3 147.4g 121.7 75.9 50.3 73.8 30.1 136.6 137.0 170.8h 121.6 117.9 61.1 164.2h 140.1g 72.4 66.0 127.1 128.0 24.7 35.7 61.5 66.4 78.3 52.2 71.3 52.0 130.0 134.0 169.8 128.5 18.1 17.4 121.9 23.5 36.3 61.3 66.6 82.4 37.6 37.6 71.4 137.5 139.8 169.4 121.1 16.4 17.3 126.6g 23.5h 35.9h 60.7 66.8i 80.6i 34.0i 75.5i 75.5i 133.7 133.5j 169.6 125.5 13.9k 17.1k 166.1 111.8g 160.5j 66.6 15.5k 128.2 25.9 34.7 142.6 129.3 76.6 59.9 71.4 52.2 133.9 40.6 180.3 17.3 16.8 60.4 128.6 26.1 34.9 142.7 129.5 76.4 60.1 72.0 52.9 133.9 40.8 179.9 17.6 17.1 61.1 129.4 26.1 35.0 138.0 131.6 76.1 58.2 72.9 49.1 132.9 40.3 177.7 17.0 16.8 61.6 170.7 21.2 169.8 21.0 132.3 24.8 33.4 145.1 128.3 75.3 64.4 203.6 57.4 126.5 40.5 177.1 13.6 16.0 60.1 127.2⁄ 25.4 34.6 141.8 127.7⁄ 78.5# 51.0 35.9 78.8# 139.1 41.2 177.6 12.5 10.0 59.7 129.4⁄ 26.1 34.7 142.8 129.0⁄ 76.1 58.3 73.8 49.0 132.6 40.2 178.0 17.0 16.6 61.5 165.3 139.3 126.3 62.4 129.3 25.7 34.3 143.3g 128.3 76.3 58.0h 73.3 48.8 132.4g 39.9h 178.9 16.6 16.3 60.3 166.6 137.0g 34.9 60.6 127.4 129.2 25.5 34.1 143.1g 128.0 76.3 57.8h 73.1 48.6 132.1g 39.8h 178.9i 16.0 16.4 59.8j 164.8i 139.7g 70.3 65.3j 126.2 C 46a20 48a21 49a;n 17 51a;o 22 53a23 53c23 f;m 5824 59a25 60a26 62a26 64a25 65a25 66a27 67a26 68a26 1 2 3 4 5 6 129.3 26.0 34.5 142.9 128.7 75.9 125.6 25.2 40.9 141.8 129.3 79.2 129.3 26.5 35.3 137.1 130.8 75.0 121.3 25.2 35.7 133.0 131.4 68.6 128.9 24.9 36.1 140.4 128.9 69.2 131.3 26.1 32.1 141.6 129.7 71.4 129.8 26.5 35.0 144.6 129.2⁄ 77.4 127.6 24.5 25.8 134.8 125.7 76.7 72.0 31.0 24.5 134.7 125.7 75.0 61.5 26.3 24.7 134.0 125.3 75.2 128.5 24.6 27.0 134.2 125.4 76.5 128.7 24.7 27.1 134.3 125.3 76.4 127.8 24.1 22.3 142.0 146.7 75.6 72.3 31.1 24.5 134.2 125.3 74.7 85.7 26.2 24.4 134.4 125.6 74.5 170.9 20.7 ⁄ 15 (continued on next page) M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 Table 4 C NMR data of germacranes. 13 16 169.1 20.8 n.r. 20.9 170.5 20.9 177.6 69.5 32.1 20.1 19.0 n.r. = not reported. a In CDCl3. b In CDCl3/MeOD. c In acetone-d6. d In DMSO-d6. e In CD3OD. f In pyridine-d5. g,h,i,j,k Inverted with respect to the original paper. l Amended with respect to the original paper. m Spectrum not assigned in the original paper. n As acetate. o P/b,a/N conformer. ⁄, ,# These values may be interchanged. 1 Hibasami et al. (2003); 2Lazari et al. (1998); 3Marco et al. (2005); 4Barrero et al. (1988); 5Marco et al. (1994); 6Lonergan et al. (1992); 7Barrero et al. (1989); 8Shoeb et al. (2007a); 9Garcia et al. (1996); 10Santos et al. (1995); 11Csapi et al. (2010); 12Skaltsa et al. (2000a); 13Trendafilova et al. (2007); 14Bruno et al. (1991a); 15Suleimenov et al. (2005a); 16Medjroubi et al. (2003a); 17Marco et al. (1992); 18Cardona et al. (1991); 19Benayache et al. (1992); 20Djeddi et al. (2007); 21Appendino and Özen (1993); 22Barrero et al. (1999); 23Jimeno et al. (2004); 24Marco et al. (1991); 25Cardona et al. (1994); 26Cardona et al. (1997); 27Lakhal et al. (2010). 50.0 74.4 41.1 139.0 138.2 169.0 127.2 120.4 66.2 164.8 138.3 71.2 65.7 127.0 170.7 20.9 50.2 74.2 40.2 143.5 138.1 168.9 127.2 116.3 66.1 164.7 139.1 71.3 65.7 127.0 170.5 20.8 49.1 69.1 45.5 131.6 132.8 169.2 129.9 15.0 194.0 164.8 139.3 70.1 65.0 126.1 50.5 69.5 46.3 131.1 136.7 169.1 127.4 16.8 66.9 164.4 138.5 70.2 67.4 127.1 170.5 20.8 171.3 20.9 50.5 70.1 46.1 131.1 136.7 169.5 127.5 16.7 66.8 164.8 139.4 70.9 65.7 126.6 170.5 20.8 52.6 67.4 49.0 56.3 137.2 170.4 128.4 16.7 66.6 52.3 72.5 43.0 144.3 137.5 n.r. 127.7 115.4 66.2 52.5 67.3 49.0 132.1 136.3 169.9 127.7 16.9 67.0 52.9 74.1 49.4 133.1 47.0 178.3 49.6 16.9 60.8# 165.9 142.5 124.1 61.2# 52.3 81.3 42.7 128.6 138.1 170.7 126.3 21.5 61.1 50.7 81.1 41.0 129.6 135.1 171.4 127.4 21.1 61.5 49.3 24.3 39.0 135.7 31.7 21.5 21.2 17.0 16.4 53.4 70.7 47.5 133.4 39.6 178.1 10.6 16.6 61.7 170.7 21.2 169.8 20.9 57.9 73.6 49.0 132.6 39.8 177.8 16.9 16.5 61.3 164.5 131.5 140.4 62.7 62.4 170.6 20.7 7 8 9 10 11 12 13 14 15 10 20 30 40 50 100 200 1000 2000 3000 49.5 26.6 35.3 137.2 40.9 179.7 10.8 15.9 60.7 46a20 C Table 4 (continued) 48a21 49a;n 17 51a;o 22 53a23 53c23 58f;m 24 59a25 60a26 62a26 64a25 65a25 66a27 67a26 68a26 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Starting from botanical considerations the distribution of sesquiterpenes within the groups of Centaureinae provides useful information. Almost all of the six genera (39 taxa) belonging to the first group of Centaureinae, named ‘‘Basal genera’’ (Psephellus, Rhaponticoides, Cheirolophus, Plectocephalus, Stizolophus and Zoegea) contain guaianes with the exception of Stizolophus and Zoegea which show the presence of germacranes only. The representatives of Psephellus usually contain only guaianes. All the analyses (incl. molecular approaches) confirm that Rhaponticoides (=Centaurea sect. Centaurea) and related taxa are a very isolated group of species. This group is always placed in a basal position, far removed from the bulk of the genus (Garcia-Jacas et al., 2006). A recent survey of Centaureinae and Plectocephalus (Susanna et al., 2011), based on nuclear internal transcribed spacers (ITS) analyses, identified Stizolophus and Zoegea as sisters to the rest of this group. Four of the five species included in the second group of Centaureinae, Volutaria, contain only guaianes, the fifth species,Amberboa lippii, in addition has the germacrane 19. All the taxa of the third group, Rhaponticum, except Leuzea conifera and Raponticum uniflorum, possess guaianes. This group of about 40 species ranged among the early branching taxa of Asteraceae, Centaureinae, according to the recent phylogenetic reconstructions based on molecular data (Hidalgo et al., 2006). The fourth group (Serratula) contains only guaianes and eudesmanes. The only studied species of the fifth group (Carthamus) Carthamus arborescens, contains germacranes and eudesmanes, but not guaianes, while the studied species of the sixth group, Crocodylium, – germacranes and elemanes. The ITS phylogeny suggests that Aegialophila and Crocodylium form a strongly supported clade, more connected to the Carthamus complex than to the Acrocentron group (Garcia-Jacas et al., 2006). With regard to the seventh group, Centaurea, we analyzed data about the sesquiterpenoids of 153 taxa belonging to 19 sections: Acrocentron, Calcitrapa, Acrolophus, Phalolepis, Jacea, Seridia, Microlophus, Tetramorphaea, Lepteranthus, Cheirolepis, Cyanus, Cynaroides, Cheirolepis, Ptosimopappus, Melanoloma, Pseudophaeopappus, Solstitiaria, Chartolepis, Grossheimia. Our research on sesquiterpenoids of the 63 taxa of sections Acrolophus and Phalolepis shows that all representatives, except Centaurea exarata and C. incana, do not contain guaianes. The results of molecular investigations pointed out that these sections are consistently associated in well-supported clades (BS = 100%, PP = 1 0), named Acrolophus–Phalolepis (Garcia-Jacas et al., 2000). These sections are morphologically similar, and the separation of Acrolophus and Phalolepis is clearly artificial. C. exarata, in contrast to the other representatives of the group contains guaianes. Its affiliation into the Acrolophus sect. is not also supported by the recent molecular studies placing it in the section Jacea (clade Jacea–Lepteranthus), although this inclusion is not supported by morphological studies. However, the chromosome number of C. exarata (x = 11) coincides with the basic number found in the Jacea sect., a fact that justifies its inclusion in this section. Our results do not seem to support the recognition of Jacea and Lepteranthus as separate sections and these data are in accordance with the molecular survey (Garcia-Jacas et al., 2006). The section Seridia, comprising taxa found exclusively in the western Mediterranean area, never contain guaianes. On the other hand the section Solstitiaria has mainly guaianes and the sections Micrlophus and Chartolepis contain guaianes exclusively. The representatives of the sect. Cyanus usually do not contain sesquiterpenoids. In this study, information about two species of this section and their sesquiterpenoid profile, characterized by the presence of guaianes only, is included. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 17 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 5 Elemanes isolated from taxa of the Subtribe Centaureinae. No Structure 69 OH Name Taxa Dehydromelitensin Centaurea Centaurea Centaurea Centaurea Centaurea O HO Ref. aegialophila amara aspera ssp. stenophylla aspera ssp. subinermis castellana O C. cineraria ssp. busambarensis Centaurea cuneifolia 70 8a-hydroxy-15-oxo-5,7aH,6bHelema-1,3,11(13)- trien-12,6-olide OH CHO Centaurea Centaurea Centaurea Centaurea grisebachii malacitana napifolia paui Centaurea Centaurea Centaurea Centaurea pullata salonitana sphaerocephala paui Bruno et al. (2001) Gonzalez et al. (1980a) Picher et al. (1984a) Cardona et al. (1991) Gonzalez et al. (1984);Gousiadou and Skaltsa (2003) Bruno et al. (1998) Salan and Öksük (1999), Gousiadou and Skaltsa (2003) Djeddi et al. (2008a) Barrero et al. (1995, 1988) Bruno et al. (1995) Cardona et al. (1997), Gousiadou and Skaltsa (2003) Gonzalez et al. (1974a, 1977a) Salan and Öksük (2003) Bruno et al. (1994) Cardona et al. (1997), Gousiadou and Skaltsa (2003) O O 71 OAc HO dehydromelitensin 8a-acetate Centaurea bruguierana Harraz et al. (1994) dehydromelitensin 8-(20 methylpropanoate) Centaurea chilensis Negrete et al. (1993) dehydromelitensin 8-(20 -methyl-20 propenoate) Centaurea chilensis Negrete et al. (1993) hierapolitanin A Centaurea hierapolitana Karamenderes et al. (2007a) 8a-(40 -hydroxy-methacryloyl)dehydromelitensin Centaurea achaia Centaurea eryngioides Centaurea tagananensis Cheirolophus intybaceus Skaltsa et al. (2000a), Koukoulitsa et al. (2002) Sarg et al. (1989) Gonzalez et al. (1984), Nowak et al. (1986a) Marco et al. (1994) 11,13-dehydromelitensin bhydroxyisobutyrate Centaurea melitensis Gonzalez et al. (1975, 1977a) hierapolitanin B Centaurea hierapolitana Karamenderes et al. (2007a) Isoarbutifolin Centaurea arbutifolia Gonzalez et al. (1981) O O 72 O O HO O O 73 O O HO 74 O O OH O O HO O O 75 OH O O HO O O 76 O OH O HO 77 O O OH OH O O AcO O O 78 O O HO O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 18 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 5 (continued) No Structure 79 OH Name Taxa Ref. 8a (50 -hydroxyangeloyl)-11,13dehydromelitensin Centaurea phrygia El-Marsy et al. (1985) 8a-(30 ,40 -dihydroxy-20 -methylenebutanoyloxy)- dehydromelitensin; isocnicin Centaurea aegialophila Bruno et al. (2001) Centaurea attica Skaltsa et al. (1999), Gousiadou and Skaltsa (2003) Marco et al. (1992), Aboul-Ela (1994) Bruno et al. (1998) Bruno and Herz (1988), Gousiadou and Skaltsa (2003) Salan and Öksük (1999), Gousiadou and Skaltsa (2003) Karioti et al. (2002) Djeddi et al. (2008a) Trendafilova et al. (2007) Bruno et al. (1995) Gousiadou and Skaltsa (2003) Bruno et al. (2002) Lazari et al. (2008) Saroglou et al. (2005) Skaltsa et al. (2000b), Georgiadou et al. (2000), Gousiadou and Skaltsa (2003) Koukoulitsa et al. (2002) Tsankova et al. (1994) Karioti et al. (2002) O O O HO O 80 O OH O OH O HO Centaurea calcitrapa Centaurea cinerar. ssp. busambarensis Centaurea cineraria ssp. umbrosa O Centaurea cuneifolia Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea 81 O OAc O OH 8a-(30 -hydroxy-40 -acetoxy-20 methylene-butanoyloxy)dehydromelitensin Centaurea zuccariniana Cnicus benedictus Centaurea deusta 8a-(40 ,50 -dihydroxy-tigloyloxy)11,13-dehydromelitensin Centaurea achaia Fortuna et al. (2002) Bruno et al. (1995) Lazari et al. (2008) Bruno et al. (1994) Skaltsa et al. (2000b), Georgiadou et al. (2000), Gousiadou and Skaltsa (2003) Skaltsa et al. (2000a) 8a-(30 ,40 -dihydroxy-20 -methylenebutanoyloxy)-15-oxo-5, 7aH,6bHelema-1,3,11(13)-trien-12,6-olide Centaurea diffusa Centaurea paui Centaurea spinosa Fortuna et al. (2002) Cardona et al. (1994) Saroglou et al. (2005) Melitensin Centaurea Centaurea Centaurea Centaurea Centaurea amara aspera ssp. stenophylla aspera ssp. subinermis calcitrapa melitensis Centaurea Centaurea Centaurea Centaurea Centaurea napifolia nicaensis pullata tagananensis paui Gonzalez et al. (1980a) Tortajada et al. (1988), Picher et al. (1984a) Cardona et al. (1991) Marco et al. (1992) Gonzalez et al. (1971, 1975, 1977a, 1978a), Rybalko et al. (1975) Bruno et al. (1995) Medjroubi et al. (2003a) Djeddi et al. (2008b) Gonzalez et al. (1984), Nowak et al. (1986a) Cardona et al. (1997), Gousiadou and Skaltsa (2003) Centaurea Centaurea Centaurea Centaurea Centaurea O HO O 82 OH O deusta grisebachi moesiaca napifolia orphanidea paniculata ssp. castellana phyllocephala spinosa thessala subsp. drakiensis diffusa napifolia phyllocephala sphaerocephala thessala ssp. drakiensis OH O O HO O 83 O OH O CHO OH O O 84 OH O HO O 85 OH CHO 8a-hydroxy-15-oxo-5,7aH,6,11bHelema-1,3-dien- 12,6-olide O O 86 OβDglucose HO melitensin-8a-O-b-Dglucopyranoside Centaurea salonitana Salan and Öksük (2003) O O Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 19 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 5 (continued) No Structure 87 Name Taxa Ref. 8-deoxy-11b-hydroxy-melitensin Centaurea castellana Gonzalez et al. (1984), Gousiadou and Skaltsa (2003) 11,13-dihydroisoarbutifolin Centaurea arbutifolia Gonzalez et al. (1981) 8a-O-(40 -hydroxy-20 methylenebutanoyloxy)-melitensin Centaurea pullata Djeddi et al. (2008b) Melitensin b-hydroxyisobutyrate Centaurea melitensis Gonzalez et al. (1975, 1977a) 5a,6b,7a,8b,11b(H)-15-hydroxy-8(10 ,20 -dihydroxyethyl)-acryloelema1,3-dien-6,12-olide Centaurea nicaensis Bruno et al. (1996), Medjroubi et al. (2003a) Isomelitensin Centaurea aspera ssp. subinermis Cardona et al. (1991) Methyl 8a,6a,15-trihydroxyelema1,3,11(13)-trien-12-oate Centaurea aspera ssp. subinermis Cardona et al. (1992) Elemacarmanin Centaurea achaia Skaltsa et al. (2000a), Koukoulitsa et al. (2002) Marco et al. (2005) Marco et al. (1994) OH HO O O 88 O O HO O O 89 O OH O HO O O 90 O OH O HO O O 91 O OH O HO OH O O 92 O O HO OH 93 OH CO2Me HO OH 94 O OH Centaurea aspera Cheirolophus intybaceus O CO2Me HO OH OH O OH CO2Me Methyl 8a-(30 ,40 -dihydroxy-20 methylene-butanoyloxy)-6a,15dihydroxyelema-1,3,11(13)-trien-12oate OAc O OH CO2Me Methyl 8a-(30 -hydroxy-40 -acetoxy20 -methylene-butanoyloxy)-6a, 15dihydroxyelema-1,3,11(13)-trien-12oate 95 O HO O Marco et al. (2005) OH 97 Methyl 8a-O-(40 -acetoxy-50 hydroxyangelate)-6a,15dihydroxyelema-1,3,11(13)-trien-12oate OH O O CO2Me HO Centaurea aspera ssp. stenophylla Centaurea deusta Centaurea paui OH 96 HO Centaurea spinosa Centaurea deusta Skaltsa et al. (1999), Gousiadou and Skaltsa (2003) Karioti et al. (2002) Cardona et al. (1997), Gousiadou and Skaltsa (2003) Saroglou et al. (2005) Karioti et al. (2002) Centaurea attica OAc OH Our study presents data of the sesquiterpenoids from 16 taxa of the sect. Acrocentron. This group is defined mainly on the basis of pollen type, but also by achene characters, involucral bracts morphology and molecular data (ITS spacers of the nuclear ribosomal DNA). The representatives contain all main types of sesquiterpenoids – germacanes, elemanes, eudesmanes, guaianes. In order to find further correlations among taxa, based only on the sesquiterpene composition, a statistical approach was used (see Supporting information). The cluster analysis of the taxa belonging to subtribe Centaurinae according to the presence/absence of single sesquiterpenes, carried out by Primer 6 programme (Clarke and Gorley, 2006), allow us to draw some considerations. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 20 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 6 C NMR data of elemanes. 13 C 69a1 70a2 72a3 73a3 74b4 75a5 76a6 77b4 80a7 83a8 84a9 85a2 89a10 91a9 92a11 93a12 94a13 95a2 97a14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 10 20 30 40 50 100 200 OCH3 146.1 112.7 114.9 143.9 50.6 78.8 55.0 67.5 49.8 41.9 137.4 169.7 120.5 18.9 67.3 145.5 112.6 137.7 144.8 46.2 77.4 55.0 67.6 49.4 42.0 137.2 n.r. 120.6 18.2 193.6 147.9 113.0 113.3 145.6 51.8 80.0 53.1 70.4 46.2 43.0 139.1 171.4 119.6 19.3 66.7 173.7 35.2 19.1 19.0 147.9 113.0 113.3 145.6 51.7 80.0 53.0 71.0 46.1 42.9 139.1 171.4 119.6 19.3 66.7 167.7 137.4 127.0 18.4 143.8 113.1 112.5 145.1 51.9 78.7 52.3 70.5 42.2 46.3 138.6 169.2 117.8 66.5 65.5 166.2 136.7 125.4 17.7 145.6 113.1 115.1 143.6 50.6 78.6 52.3 69.6 45.0 41.9 136.6 169.2 120.2 18.7 67.3 165.3 139.1 126.7 62.3 145.6 112.6 113.7 143.5⁄ 50.2 78.8 51.9 68.8 44.7 41.6 136.3⁄ 170.0 120.5 18.2 66.1 174.8 42.1 63.9 13.0 143.8 114.5 116.0 138.2 51.8 78.5 51.2 70.3 41.8 46.4 139.7 169.8 119.5 65.5 66.5 165.5 141.5 124.8 60.3 145.6 113.1 115.1 143.6 50.6 78.7 52.4 69.7 45.0 41.9 136.7c 169.1 120.1 18.4 67.3 165.2 139.0c 71.2 64.8 127.5 144.9 113.1 137.9 144.5 46.1 77.4 52.2 69.6 44.6 42.0 136.4 169.2 120.3 17.9 193.6 165.1 139.0 71.0 65.8 127.5 146.3 112.5 114.5 144.4 50.4 78.7 58.4 68.8 49.4 41.7 41.5 178.6 14.3 18.9 67.3 145.7 112.5 137.4 145.3 46.6 77.3 58.5 69.0 49.3 41.8 41.4 179.0 14.3 18.3 193.5 145.6 112.8 114.6 144.0 50.1 78.2 55.9 70.4 44.8 41.1 40.8 178.1 13.8 18.5 67.1 166.0 136.6 35.0 61.3 127.8 145.8 113.0 114.8 144.1 50.3 78.4 56.0 70.7 44.9 41.6 41.0 177.8 14.1 18.7 67.2 165.3 139.0 71.1 65.7 127.4 146.5 112.4 116.8 145.3 57.6⁄ 76.4 57.4⁄ 71.3 42.8 n.r. 41.6 179.1 14.3 19.8 67.5 146.9 111.7 114.7 146.6c 55.5 70.7 58.1 67.8 47.1 40.1 138.4c 167.7 128.6 18.7 67.7 146.3 111.9 114.9 146.2 55.3 71.0 54.6 70.9 43.5 40.2 138.0 167.2 128.3 18.3 67.7 165.4 139.4 125.8 62.2 146.2 112.1 114.9 146.2 55.3 70.9 54.7 71.1 43.5 40.2 138.0 167.1 128.4 18.3 67.8 165.2 139.1 71.6 65.7 126.8 52.1 52.0 52.0 146.2 112.1 115.0 146.3 55.3 71.0 54.8 71.4 43.6 40.3 138.0 167.2 128.7 18.3 67.8 164.9 131.4 140.8 63.9 62.9 170.8 20.9 52.1 170.6 21.3 a b e n.r.=not reported. In CDCl3. In DMSO-d6. Inverted with respect to the original paper. 1 Cardona et al. (1989); 2Cardona et al. (1997); 3Negrete et al. (1993); 4Karamenderes et al. (2007a); 5Marco et al. (1994); 6El-Moghazy et al. (2002); 7Bruno and Herz (1988); Cardona et al. (1994); 9Medjroubi et al. (2003a); 10Djeddi et al. (2008b);11Cardona et al. (1991); 12Cardona et al. (1992); 13Tortajada et al. (1988); 14Marco et al. (2005). ⁄ These values may be interchanged. 8 Two taxa show the lowest grade of resemblance with respect to all the others: C. solstitialis and C. scoparia both of seventh group. The Psephellus are divided in two taxonomic groups containing the same compounds: the first one representing the sect. Psephellus (Psephellus carthalinicus, Psephellus colchicus, Psephellus daghestanicus, Psephellus dealbatus, Psephellus karabaghensis, Psephellus nogmovii, Psephellus somcheticus and Psephellus zangezuri) to which also Psephellus taochius can be added; the second group joining the sects. Leucophyllae and Hypoleucae (Psephellus leucophyllus, Psephellus declinatus and Psephellus hypoleucus) (Fig. 3). Although Centaurea phaedopappoides belongs to the Psephellus group, it is instead correlated by a superimposable occurrence of the same three compounds with the following taxa: Stemmamarca rhapontica, Centaurea thracica, Centaurothamnus maximus, Leuzea rhaponticoides and Leuzea rhapontica ssp.helenipholia. This group is also close to other four taxa: Stemmamarca carthamoides, Centaurea isaurica, Centaurea janeri and Centaurea marshalliana, the latter belonging to Psephellus group too. A close resemblance was found among Centaurea ragusina, Centaurea sventenii, Centaurea canariensis, Centaurea deflexa and Amberboa tubiliflora in which almost the same sesquiterpenes occur (Fig. 3). Most species of the Acrolophus section is strictly correlated by cluster analysis and represent the largest group (38 taxa) (Fig. 4), although this correlation is based on the occurrence of only one sesquiterpene, cnicin (19), widely diffused in this section. In spite of this, three taxa, not belonging to the Acrolophus section (Centaurea granatensis, Centaurea raphanina ssp. mixta of the Colymbada section and Centaurea rocheliana of the Jacea section), are grouped in this cluster. Other groups are close and they are characterized by the presence of 19 and/or salonitenolide (4) along with few other sesquiterpenes. In these clusters, besides taxa of the Acrolophus section (Centaurea mariolensis, Centaurea monticola, C. exarata), taxa of the Calcitrapa sect. (Centaurea iberica, Centaurea pontica), Colymbada sect. (Centaurea crocodylium and Centaurea aegialophila), Seridia sect. (Centaurea eriophora), Jacea sect. (Centaurea weldeniana), Phalolepis sect. (Centaurea alba ssp. caliacrae and C. alba ssp. deusta), Tetramorphaea sect. ( Centaurea brugueriana) and Rhaponticoides sect. (Centaurea africana) are represented. All of them have been classified in the seventh group with the exception of C. africana belonging to the first group. Five taxa of the Acrolophus sect. (Centaurea cuneifolia, Centaurea cineraria ssp. busambarensis, C. cineraria ssp. umbrosa, Centaurea paniculata ssp. castellana, Centaurea zuccariniana) along with C. aegialophila (Colymbada sect.) seem to represent a separate cluster from the other Acrolophus taxa, containing cnicin (19) with other compounds (69, 80, 104). Other minor groups, correlated by the same sesquiterpene composition, can be observed in the full dendrogram reported in Supporting information. On the basis of these observations it seem possible to consider cnicin (19) and salonitenolide (4), having the same sesquiterpene skeleton, as markers of Acrolophus section as other authors have already stated (Gousiadou and Skaltsa, 2003). Starting from this last consideration, we grouped compounds according to the same sesquiterpene skeleton having the same oxidation state and neglecting any ester side chain occurring (Supporting information). The cluster analysis of this new set of data discloses new information (Figs. 5 and 6). The groups obtained by this model were clearly wider and only ones with maximum similarity are considered. A first cluster of Centaurea grisebachi, Centaurea orphanidea, Centaurea thessala ssp. drakiensis and C. zuccariniana, all belonging to the Acrolophus section, was obtained. Two other taxa resulted close to it: Centaurea malacitana and C. phyllocephala both included in the seventh group as Acrolophus. The greatest cluster, formed by 56 taxa, includes almost all the species belonging to the Acrolophus section along with some other ones of seventh group with the exception of Centaurea derventana and Centaurea glaberima for which the exact placing in the sections is not ascertained. Another interesting cluster involves species of the Acrolophus section and precisely C. grisebachi, C. orphanidea, C. thessala ssp. drakiensis and C. zuccariniana. These taxa show a peculiarity with respect to the other Acrolophus taxa because they contain not only germacranes but also elemanes and eudesmanes. Eight taxa of the seventh group are joined in a cluster: four of Acrolophus (C. cineraria ssp. busambarensis, C. cineraria ssp. umbrosa, C. cuneifolia and C. paniculata ssp. castellana); two of Colymbada Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 21 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 7 Eudesmanes isolated from taxa of the Subtribe Centaureinae. No Structure 98 H Name Taxa Ref. b-cyclocostunolide Centaurea acaulis Bentamane et al. (2005) Santamarin Centaurea acaulis Centaurea ornata Centaurea uniflora ssp. nervosa Bentamane et al. (2005) Navarro et al. (1990) Appendino et al. (1986) Reynosin Centaurea kurdica Centaurea uniflora ssp. nervosa Appendino and Özen (1993) Appendino et al. (1986) Sonchucarpolide Cheirolophus sempervirens Marco et al. (1994) Stoebenolide Centaurea paui Cardona et al. (1997), Gousiadou and Skaltsa (2003) Huneck et al. (1986a) O O 99 OH H O O 100 OH H O O 101 OH H CHO O O 102 OH Centaurea stoebe H CHO O O 103 OH 8a-hydroxy-4-epi-sonchucarpolide Centaurea grisebachi Centaurea orphanidea C. thessala ssp. drakiensis Djeddi et al. (2008a) Gousiadou and Skaltsa (2003) Skaltsa et al. (2000b),Georgiadou et al. (2000), Koukoulitsa et al. (2002), Gousiadou and Skaltsa (2003) 8a-hydroxy-sonchucarpolide Centaurea zuccariniana Koukoulitsa et al. (2002) 1-hydroxy-8-methacryloxy-15oxoeudesm-11(13)-en-6,12-olide Centaurea tweediei Fortuna et al. (2001) vahlenin Centaurea hyssopifolia Gonzalez et al. (1974b, 1977a), Nowak et al. (1986a) Gonzalez et al. (1973b, 1978b), Nowak et al. (1986a) OH H CHO O O 104 OH OH H CHO O O 105 OH O O H CHO O O 106 OH Centaurea linifolia O O H O O 107 8a-(40 -hydroxy-methacryloyloxy)4-epi-sonchucarpolide Centaurea achaia Skaltsa et al. (2000a) OH OH 8a-(40 -hydroxy-methacryloyloxy)sonchucarpolide Centaurea achaia Cheirolophus x hortigenus Skaltsa et al. (2000a) Marco et al. (1994) OH O O H CHO O O 108 OH O O H CHO O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 22 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 7 (continued) No Structure 109 OH O Taxa Ref. Centaurea attica Skaltsa et al. (2000b), Gousiadou and Skaltsa (2003) Djeddi et al. (2008a) Barrero et al. (1997a) Trendafilova et al. (2007) Gousiadou and Skaltsa (2003) Lazari et al. (2008) Saroglou et al. (2005) Georgiadou et al. (2000), Gousiadou and Skaltsa (2003) OH O H CHO Name Malacitanolide Centaurea grisebachi Centaurea malacitana Centaurea moesiaca Centaurea orphanidea Centaurea phyllocephala Centaurea spinosa Cent. thessala ssp. drakiensis OH O O 110 OH O Centaurea grisebachi Centaurea spinosa Djeddi et al. (2008a) Saroglou et al. (2005) 8a-(30 -hydroxy-40 -acetoxy-20 methylene-butanoyloxy)-4- episonchucarpolide; 40 -acetylmalacitanolide Centaurea attica Skaltsa et al. (2000b) Centaurea deusta Koukoulitsa et al. (2002), Karioti et al. (2002) Djeddi et al. (2008a) Trendafilova et al. (2007) Gousiadou and Skaltsa (2003) Saroglou et al. (2005) Koukoulitsa et al., 2002, Karioti et al. (2002) OH O H CHO 4-epi-malacitanolide OH O O 111 OH O OAc O H CHO OH O O 112 OH O OAc O H CHO OH 8a-(30 -hydroxy-40 -acetoxy-20 methylene-butanoyloxy)sonchucarpolide; 40 -acetyl-4-epimalacitanolide Centaurea Centaurea Centaurea Centaurea Centaurea grisebachi moesiaca orphanidea spinosa deusta Centaurea grisebachi Djeddi et al. (2008a) 8a-O-(40 -acetoxy-20 -hydroxymethylbuten-20 -oyloxy)-4-episonchucarpolide Centaurea spinosa Saroglou et al. (2005) 4a-hydroxy-8a-O-(40 -acetoxy-50 hydroxyangelate)-11(13)eudesmen-12,6a-15,1b-diolide Centaurea aspera ssp. subinermis Cardona et al. (1991) 8a-hydroxy-11b,13-dihydroonopordaldehyde Centaurea granata Centaurea pullata Medjroubi et al. (1998) Djeddi et al. (2008b) 4a,8a-dihydroxy-11bH-eudesma12,6a-15, 1b-diolide Centaurea aspera ssp. subinermis Cardona et al. (1991) 8a-hydroxy-11b,13-4-episonchucarpolide Centaurea pullata Djeddi et al. (2008b) 8a-O-(40 -hydroxy-20 -methylenebutanoyloxy)-11b,13dihydrosonchucarpolide Centaurea pullata Djeddi et al. (2007) 8a-O-(40 -hydroxy-20 -methylenebutanoyloxy)-11b,13- dihydro-4epi -sonchucarpolide Centaurea pullata Djeddi et al. (2007) O O 113 OH OH O OAc O H CHO O O 114 OH H O O O O H OH OAc O O 115 OH H CHO O O 116 H OH O O H OH O O 117 OH OH H CHO O O 118 OH O OH O H CHO O O 119 OH O OH O H CHO O O Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 23 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 7 (continued) No Structure 120 OH H Name Taxa Ref. 11-epi-dihydroreynosin Centaurea ornata Navarro et al. (1990) Alantolactone Serratula latifolia Rustaiyan and Feramarzi (1988) Ivalin Centaurea cadmea Serratula latifolia Karamenderes et al. (2007b) Rustaiyan and Feramarzi (1988) Isocostic acid; 12-carboxy3,11(13)-eudesmadiene Cheirolophus mauritanicus Marco et al. (1994) Costic acid Cheirolophus mauritanicus Serratula latifolia Marco et al. (1994) Rustaiyan and Feramarzi (1988) 4-epi-illicic acid Cherirolophus mauritanicus Marco et al. (1994) 3-oxo-1,2-dehydrocostic acid Cheirolophus x hortigenus Cherirolophus sempervirens Marco et al. (1994) Marco et al. (1994) 3-oxo-1,2-dehydrocostic acid methyl ester Centaurea arguta Gadeschi et al. (1989) 3-hydroxy-1,2-dehydrocostic acid Centaurea canariensis ssp. subexpinnata Cheirolophus sempervirens Bohlmann and Gupta (1981) 3-hydroxy-1,2-dehydrocostic acid methyl ester Centaurea arguta Gadeschi et al. (1989) Hierapolitanin C Centaurea hierapolitana Karamenderes et al. (2007a) Hierapolitanin D Centaurea hierapolitana Karamenderes et al. (2007a) 1b,6a-dihydroxy-4(15)-eudesmene Centaurea conifera (Leuzea conifera) Fernandez et al. (1995) Pterodontriol D Centaurea pamphylica Shoeb et al. (2007b) Rhaponticol Rhaponticum uniflorum Cheng et al. (1995), Wei et al. (1997), Zhang et al. (2010) 1b,4a,6a,15-tetrahydroxyeudesmane Centaurea aspera ssp. subinermis Cardona et al. (1992) O O 121 O O 122 HO O O H 123 CO2H H 124 CO2H H 125 CO2H H HO 126 O CO2H H 127 O CO2Me H 128 HO CO2H H 129 HO CO2Me H 130 Marco et al. (1994) OH O HO HO 131 O H OH CO2H OH O HO HO 132 O OH HO OH H 133 CO2H OH OH H HO H OH 134 OH OH H 135 OH OH HOH2C H OH OH (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 24 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 7 (continued) No 136 Structure OH O Name Taxa Ref. Methyl 1,6-dihydroxy-8methacryloxyeudesm-11(13)-en15-oic acid-12-oate Centaurea tweediei Fortuna et al. (2001) 4-epi-carmanin Centaurea achaia Skaltsa et al. (2000a) atticin Centaurea attica Skaltsa et al. (2000b) 4,5-dioxo-10-epi-4,5-seco-ceudesmol-20 -O-acetyl-b-Dfucopyranoside Phonus arborescens Barrero et al. (1997b) 10-epi-c-eudesmol-b-Dfucopyranoside Phonus arborescens Barrero et al. (1997b) 10-epi-c-eudesmol-20 -O-acetyl-b- Phonus arborescens Barrero et al. (1997b) O COOMe H OH COOH 137 OH O O CO2Me H CHO OH 138 OH OH O H CHO OH OAc O OH COOMe 139 OH O O O O OH AcO 140 OH O O OH HO 141 OH D-fucopyranoside O O OH AcO (C. aegialophila and Centaurea eryngioides); one of Jacea (Centaurea phrygia) and one of Tetramorphea (C. brugueriana). The separation of Psephellus in two groups is still effective in this model but other species are involved. This time, the taxa belonging to the Psephellus group (Psephellus sect.) are joined with Chartolepis biebersteinii, Centaurea hermannii and also with C. phaedopappoides, S. rhapontica, C. thracica, C. maximus, L. rhaponticoides, L. rhapontica ssp.helenipholia that, in the previous single compound analysis, resulted rather separated from the Psephellus group. The others Psephellus taxa (sects. Leucophyllae and Hypoleucae) are grouped with Cheirolophus junoniaus, Cheirolophus teydis, Cheirolophus uliginosus, Cheirolophus sventenii, Centaurea americana, C. canariensis, all belonging to first group as Psephellus, with Centaurea collina, Centaurea ptosimopappoides, Centaurea kotschy, C. ragusina, Centaurea debeauxii ssp. thuillieri (all of seventh group) and with Amberboa divaricata, Centaurea pabotii and Tricholepis glaberrima. Finally, using this model, Centaurea aspera ssp. subinermis, C. paui and Acroptilon repens are the taxa showing the lowest resemblance in this subtribe. 4. Biological activity 4.1. Antimicrobial Antimicrobial activity of cynoropicrin (162) was screened using 22 strains including Gram+ and Gram bacteria and the yeasts Candida albicans and Candida tropicalis. The MIC varied from 100 to 2500 lg/mL, against the strains of bacteria and yeasts evaluated (Schinor et al., 2004). Antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa was also demonstrated (Modonova et al., 1986). Cnicin (19) and cynaropicrin (162) have been identified as potent, irreversible inhibitors of the bacterial enzyme MurA of E. coli and P. aeruginosa showing an activity comparable to fosfomycin expecially for the latter bacterial strain (IC50 = 10.5 lM). They covalently bind the thiol group of Cys115 and their unsaturated ester side chain has pivotal impor- tance for the inhibition of MurA. These results provided evidence that MurA is a target protein of sesquiterpene lactones (SLs), which is probably highly relevant for their known antibacterial effect (Bachelier et al., 2006). Further studies established the structure of the antibacterial target enzyme MurA in complex with its substrate UNAG (UDPN-acytilglucosamine) and its potent inhibitor cnicin (19) by Xray. The structure reveals that MurA has catalyzed the formation of a covalent adduct between cnicin and UNAG. This adduct, formed by an unusual ‘‘anti-Michael’’ 1,3-addition of UNAG to an a,b-unsaturated carbonyl side chain of cnicin, inhibits MurA (Steinbach et al., 2008). Cnicin (19) has bactericidal activity against Bordetella bronchiseptica, P. aeruginosa, S. aureus, Brucella abortus (Karawya et al., 1975; Vanhaelen-Fastre, 1972) and, starting from salonitenolide (4), several esters have been prepared. Cnicin (19), salonitenolide (4), the elemane 80 and several synthetic compounds were tested for their antibacterial activity against Bacillus cereus, Bacillus subtilis, P. aeruginosa, S. aureus, Streptococcus faecalis, E. coli, Proteus mirabilis and Salmonella typhi. The 8,15-diesters showed a good activity (MIC = 6.25–12.5 lg/mL), comparable with that of cnicin (19) (MIC = 3.12–12.5 lg/mL). The 15-monoester compounds were not very active indicating that esterification at the C-8 position is an important structural feature for antibacterial properties (Bruno et al., 2003). Compounds 19, 21, 23,80, 83, 95, 109, 110, 111 and 113 isolated from Centaurea spinosa, were tested in vitro against three Gram+ and three Gram bacteria. They were all inactive against tested Gram bacteria whereas compounds 83, 110 and 113 showed an activity against Micrococcus flavus from four to six times higher than streptomycin (MIC = 0.6, 0.6 and 0.4 lg/mL, respectively) and compounds 19, 21, 23, 80 and 83 showed a moderate activity against B. cereus (Saroglou et al., 2005). Also compound 32 exhibited moderate antibacterial activity only toward Gram+ bacteria (Suleimenov et al., 2005b). Compounds 36, 44, 45, 46, 84, 89, 115, 117, 118 and 119, isolated from Centaurea pullata, were tested Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 C 98a1 99a1 100a1 101e2 103a3 104a4 107a5 108b6 109c7 110a8 111a3 112a9 113a8 114a10 115b11 116a10 117a5 118a12 119a12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 10 20 30 40 50 100 200 41.9 21.7 39.8 144.4 55.1 80.1 50.1 22.9 36.0 38.7 139.7 170.7 116.5 18.1 109.2 75.2 32.8 121.3 133.4 52.2 81.5 51.0 21.2 34.3 40.9 139.1 171.0 116.6 11.0 23.2 78.3 31.4 33.6 142.5 53.1 79.6 49.7 21.5 35.8 43.0 139.4 170.5 116.6 11.6 110.6 79.6 29.2 24.9 48.7 48.9 83.2 50.0 23.2 37.3 41.9 140.0 170.9 116.8 21.2 203.3 76.4 25.6 20.6 43.8 46.7 74.4 55.0 65.8 47.3 41.2 136.5 172.5 119.2 11.8 200.1 77.1 24.3 28.3 47.7 48.2 78.8 55.5 67.4 47.2 40.7 136.8 170.8 120.8 13.0 202.6 78.0 27.2 22.4 44.9 48.9 76.1 53.8 69.9 43.9 41.5 136.3 169.2 120.5 13.9 201.8 165.2 139.0 126.7 62.3 76.4 24.3 27.6 47.6 48.0 78.9 52.6 69.5 42.5 40.7 136.0 169.0 120.3 12.6 203.3 165.3 139.4 126.0 61.0 75.9 26.7 21.8 44.7 47.2 76.0 52.3 69.5 43.4 41.0 137.5 169.3 118.7 13.4 203.7 165.2 141.9 70.2 65.4 125.3 76.9 24.6 23.1 47.8 48.1 78.8 55.3 69.5 43.5 41.9 136.6 170.2 120.2 12.8 202.2 166.5 76.3 27.6 22.6 47.5h 48.2 78.6 52.7 69.8 43.6h 40.8 136.0 169.2 120.4 14.1 201.8 164.6 138.3 69.7 67.1 127.6 171.4 20.8 77.8 27.8 23.1 46.0 48.4 76.1 54.0 70.5 44.2 41.9 136.6 169.6 121.2 15.6 211.0 165.1 130.6 138.6 63.3 62.5 171.1 20.5 76.0⁄ 30.2 38.5 n.r. 57.3# 74.2⁄ 51.5# 69.1⁄ 42.7 n.r. 135.4 n.r. 120.0 13.2 n.r. n.r. n.r. 141.5 63.2 62.5 n.r. 20.8 26.1 19.3 40.4 48.9 48.4 79.2 59.2 68.3 51.5 35.1 41.2 178.0 14.3 19.3 203.2 76.3⁄ 30.3 38.6 n.r. 57.7# 74.0⁄ 57.3# 68.3⁄ 46.9 n.r. 40.5 n.r. 14.3 13.5 n.r. 78.2 27.3 22.4 45.1 48.6 76.0 59.8 68.9 48.3 41.2 41.7 178.5 14.3 14.2 202.1 71.5 65.9 127.6 78.0 27.1 22.7 44.9 48.8 76.1 53.7 69.7 43.8 41.5 136.4 171.5 120.8 13.9 201.9 164.7 138.3 69.7 67.1 128.1 171.5g n.r. 76.9 28.1 24.1 47.6 47.7 78.1 56.3 70.3 42.3 40.5 40.3 176.3 13.8 12.7 202.0 166.1 136.6 35.1 61.3 128.3 77.7 27.6 23.6 45.0 48.4 75.7 56.9 70.1 43.5 40.8 40.1 177.4 13.8 13.9 201.7 165.9 137.0 35.1 61.4 127.3 C 120n:r: 13 121a2 122e14 123a15 124a1 125a6 126a16 128a16 130f17 131f17 132a18 133e19 133f20 134a21 135a22 137a23 138a3 139d24 140a24 141d24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 10 20 30 40 50 60 100 200 OCH3 78.5 31.5 36.2 143.0 53.2 78.3 48.3 20.4 33.7 42.8 38.8 179.9 9.7 11.7 110.5 41.0 22.2 36.8 41.1 133.0 122.3 46.3 77.0 42.2 34.3 142.1 170.6 119.9 17.2 17.6 41.2 66.3 47.5 147.3 45.7 27.6 40.6 76.8 51.9 34.1 142.8 170.0 119.5 19.1 108.2 27.3 22.8 121.0 134.6 46.7 40.0 40.1 37.7 29.3 32.2 145.1 172.0 125.0 15.5 21.0 41.8 23.4 41.1 145.3 49.9 27.4 39.4 30.0 36.8 35.9 150.5 172.2 124.6 16.3 105.4 43.8 18.0 41.4⁄ 72.2 51.8 27.5 40.1 26.4 41.2⁄ 33.7 145.2 172.2 124.9 18.7 30.1 161.2 126.9 189.3 145.5 47.9 26.8 38.5 28.8 36.8 37.5 145.2 171.9 125.6 17.8 118.2 141.6 127.1 70.7 150.2 47.5 28.7 39.2 29.2 37.7 37.8 145.2 172.2 125.2 19.2 104.6 35.9 27.5 81.6 151.0 44.3 29.8 39.8 27.1 40.7 35.5 147.0 169.9 121.5 15.3 108.5 101.4 74.0 77.2 70.3 76.4 61.4 34.0 27.5 82.1 72.2 48.7 26.1 40.6 23.0 44.3 33.7 147.1 170.0 121.2 18.0 20.1 101.5 73.7 76.9 70.4 76.8 61.5 49.0 31.9 35.1 146.2 55.9 67.0 49.3 18.2 36.3 41.7 26.0 16.2 21.1 11.6 107.8 79.3 29.4 36.7 72.7 47.9 73.1 51.2 23.4 41.4 41.5 25.9 24.5 25.1 14.7 22.6 76.6 29.5 32.0 69.0 47.9 73.1 51.2 24.7 34.0 34.0 28.8 24.8 29.1 14.1 22.7 36.0 22.9 37.0 146.9 43.3 41.2 77.1 70.2 43.4 37.0 153.4 64.6 114.7 16.6 105.5 80.5 28.0⁄ 29.6⁄ n.r. 57.6 75.6 51.8 22.3⁄ 39.7⁄ 39.1 29.6 18.5# 20.7# 12.8# 80.4 77.1 27.8 24.0 48.5 50.8 70.9 55.9 70.5 41.3 38.8 137.2 166.9 129.3 12.0 202.7 165.2 139.1 125.9 62.3 78.0 26.7 22.3 45.0 48.8 76.2 53.9 70.3 44.0 n.r. n.r n.r. 128.7 11.9 203.6 n.r. n.r. 69.6 67.4 127.6 18.6 36.8 43.6 208.0 214.8 39.8 50.4 21.9 39.2 48.3 78.6 23.1 22.0 25.4 29.8 96.0 73.4 72.6 73.0 70.8 16.9 170.2 21.2 38.8 19.1 32.2 134.7 124.9 38.3 44.4 21.9 24.8 34.2 81.2 26.8 26.2 19.7 23.3 97.2 71.7 72.1 74.1 70.3 16.6 39.6 19.7 32.7 134.9 125.1 38.8 45.0 22.8 25.4 34.5 80.6 27.2 25.7 19.8 23.2 95.8 73.5 72.6 73.2 70.6 16.9 170.1 21.2 ⁄ g 52.1 n.r. 20.6 52.1 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx n.r. = not reported. a In CDCl3. b In CDCl3/MeOD. c In DMSO-d6. d In acetone–d6. e In pyridine-d5. f In CD3OD. g Amended with respect to the original paper. hAmended by authors [Z. Naturforsch. C. , (2004), 59c, 612]. ⁄, ,# These values may be interchanged. 1Yang et al., 1997; 2Buděšinský and Šaman (1995); 3Skaltsa et al., 2000b; 4Koukoulitsa et al. (2002); 5Lazari et al., 1998; 6Marco et al. (1994); 7Barrero et al., 1997a; 8Saroglou et al. (2005); 9Karioti et al., 2002; 10 Cardona et al. (1991); 11Medjroubi et al., 1998; 12Djeddi et al., 2007; 13Navarro et al., 1990; 14Karamenderes et al., 2007b; 15Fontana et al. (2007); 16Al-Sheddi et al., 2002; 17Karamenderes et al., 2007a; 18Su et al., 1995; 19Zhao, 1997; 20Shoeb et al., 2007b; 21Wei et al., 1997; 22Cardona et al., 1992; 23Skaltsa et al., 2000a; 24Barrero et al., 1997b. 25 Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 Table 8 C NMR data of eudesmanes. 13 26 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 Guaianes isolated from taxa of the Subtribe Centaureinae. No Structure 142 H Name Taxa Ref. Dehydrocostus lactone Centaurea chilensis Negrete et al. (1984) 8a-hydroxy-dehydrocostus lactone Centaurea canariensis ssp. subexpin. Centaurea chilensis Cheirolophus x hortigenus Cheirolophus sempervirens Bohlmann and Gupta (1981), Nowak et al. (1986a) Negrete et al. (1984) Marco et al. (1994) Marco et al. (1994) Centaurea chilensis Negrete et al. (1988a) Centaurea floccosa Negrete et al. (1988a) 8a-methacryloyloxydehydrocostus lactone Centaurea canariensis ssp. subexpin. Bohlmann and Gupta (1981), Nowak et al. (1986a) Subexpinnatin; 3desoxycynaropicrin Centaurea canariensis ssp. subexpin. Bohlmann and Gupta (1981), Gonzalez et al. (1982), Gonzalez Collado et al. (1986a) zaluzanin C Centaurea ptosimopappa Cheirolophus x hortigenus Cheirolophus sempervirens Çelik et al. (2006) Marco et al. (1994) Marco et al. (1994) Zaluzanin D Centaurea acaulis Centaurea ptosimopappa Bentamane et al. (2005) Çelik et al. (2006) H O O 143 H OH H O O 144 8a-acetoxy-dehydrocostus lactone H OAc H O O 145 H O H O O O 146 H O H OH O O O 147 H HO H O O 148 H AcO H O O 149 H HO OH Acroptilon repens Desacylcynaropicrin; 8hydroxyzaluzanin C; 8desacylsauprin; deacylaguerin A Amberboa muricata H O Amberboa tubiliflora O Centaurea aegyptiaca Centaurea behen Centaurea Centaurea Centaurea Centaurea canariensis canariensis ssp. subexpin. chilensis clementei Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea collina deflexa floccosa kotschyi linifolia ornata ptosimopappa ragusina scoparia Zha and Hou (2008) Gonzalez et al. (1973b, 1977a), Khan et al. (2010) Omar et al. (1983), Ahmed et al. (1990), Khan et al. (2010) Sarg et al. (1987) Rustaiyan et al. (1981a),Ohno et al. (1973),Nowak et al. (1986a) Gonzalez et al. (1977a, 1978c,a, 1980b) Gonzalez et al. (1977a, 1978c,a, 1980b) Negrete et al. (1988a) Gonzalez et al. (1977a), Massanet et al. (1983), Nowak et al. (1986a), Gonzalez Collado et al. (1986a) Fernandez et al. (1989) Chicca et al. (2011) Negrete et al. (1988a) Öksüz and Putun (1983) Gonzalez et al. (1977a), Nowak et al. (1986a) Bastos et al. (1994) Çelik et al. (2006) Mahmoud et al. (1986) Youssef and Frahm (1994b), Helal et al. (1997) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 27 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 150 Name Kandavanolide H AcO OH Taxa Ref. Centaurea solstitialis Centaurea sventenii Centaurea tagananensis Cheirolophus x hortigenus Cheirolophus junoniaus Cheirolophus mauritanicus Cheirolophus uliginosus Grossheimia macrocephala Gonzalez et al. (1983), Jakupovic et al. (1986) Gonzalez et al. (1977a) Gonzalez et al. (1984), Nowak et al. (1986a) Marco et al. (1994) Gonzalez et al. (1993) Marco et al. (1994) Marco et al. (1994) Barbetti et al. (1985), Piacentini et al. (1986), Piacentini et al., 1987 Bentamane et al. (2005) Rustaiyan and Ardebili (1984) Vajs et al. (1999) Daniewski et al. (1993), Nowak et al. (1996) Centaurea Centaurea Centaurea Centaurea acaulis kandavanensis nicolai salonitana H O O 151 HO OH H 2a,9b-dihydroxy-dehydrocostus Acroptilon repens lactone Zhao et al. (2006) salograviolide B Centaurea nicolai Centaurea salonitana Vajs et al. (1999) Daniewski et al. (1993), Nowak et al. (1996) 3-deacetyl-9-O-acetylsalograviolide A Centaurea nicolai Vajs et al. (1999) H O O 152 O H AcO OH H O O 153 OAc H HO OH H O O 154 HO CH Cl 2 H 14-chloro-10-b-hydroxy-10(14)- Centaurea acaulis dihydrozaluzanin D Bentamane et al. (2005) 9-acetylsalograviolide A Centaurea nicolai Vajs et al. (1999) Salograviolide A; 9bhydroxykandavanolide Centaurea ainetensis Ghantous et al. (2008), El-Najjar et al. (2008), Al-Saghir et al. (2009) Rustaiyan and Ardebili (1984) Vajs et al. (1999) Daniewski et al. (1992), Rychlewska et al. (1992), Nowak et al. (1996) AcO H O O 155 OAc H AcO OH H O O 156 OH H AcO Centaurea kandavanensis Centaurea nicolai Centaurea salonitana OH H O O 157 H HO 40 -nor-20 -methoxy-cynaropicrin Grossheimia macrocephala Barbetti et al. (1985) Aguerin A Centaurea arbutifolia Centaurea canariensis Centaurea pabotii Centaurea salonitana Cheirolophus junoniaus Cheirolophus mauritanicus Cheirolophus metlesicsii Cheriolophus sempervirens Cheirolophus teydis Gonzalez et al. (1981) Gonzalez et al. (1977a, 1978c) Marco et al. (1992) Daniewski et al. (1993) Gonzalez et al. (1993) Marco et al. (1994) Gonzalez et al. (1993) Marco et al. (1994) Gonzalez et al. (1993) O OCH3 H O O O 158 H HO O H O O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 28 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 159 H AcO Name Taxa Ref. Acetylaguerin A Cheirolophus metlesicsii Gonzalez et al. (1993) Aguerin B; aaguerin b Acroptilon repens Amberboa tubuliflora Centaurea arguta Centaurea behen Stevens (1982), Nowak et al. (1986a) Ahmed et al. (1990)a, Khan et al. (2010) Gadeschi et al. (1989) Rustaiyan et al. (1981a), Öksüz et al. (1982), Nowak et al. (1986a) Gonzalez et al. (1977a, 1978c) Gonzalez et al. (1977a, 1978c, 1982), Gonzalez Collado et al. (1986a) Chicca et al. (2011) Gonzalez et al. (1977a, 1978c,b), Nowak et al. (1986a) Medjroubi et al. (2005) Mahmoud et al. (1986) Bruno et al. (1991b) Gonzalez et al. (1977a, 1978c) Öksük and Topçu (1994) Marco et al. (1994) Gonzalez et al. (1993) Marco et al. (1994) Barbetti et al. (1985) Cis et al. (2006), Zhang et al. (2010) Huneck and Knapp (1986) Nowak (1993a,b);Nowak et al. (1996) Daniewski et al. (1993)a; Nowak et al. (1996) Jakupovic et al. (1986) Nowak et al. (1986b,a, 1996);Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1990, 1992) Nowak (1992), Nowak et al. (1996) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b) Nowak et al. (1986b,a, 1996), Nowak (1992) Huneck and Knapp (1986) Stevens (1982), Jakupovic et al. (1986), Nowak et al. (1986a), Zhao et al. (2006), Zha and Hou (2008) Forgacs et al. (1981), Rojatkar et al. (1997) Gonzalez et al. (1973b, 1977a), Nowak et al. (1986a), Khan et al. (2010) Harrison and Kulshreshtha (1984), Khan et al. (2010) Omar et al. (1983), Ahmed et al. (1990), Khan et al. (2010) Nowak (1992), Nowak et al. (1996) El Dahmy et al. (1985) Gonzalez et al. (1977a), Nowak et al. (1986a) Ohno et al. (1973), Nowak et al. (1986a) Gadeschi et al. (1989) Rustaiyan et al. (1981a), Öksüz et al. (1982), Nowak et al. (1986a) Nowak (1992, 1993a,b), Daniewski and Nowak (1993) Gonzalez et al. (1977a), Massanet et al. (1983), Nowak et al. (1986a), Gonzalez Collado et al. (1986a) Gonzalez et al. (1977a, 1978c,a, 1980b) Gonzalez et al. (1977a), Gonzalez Collado et al. (1985, 1986a), Nowak et al. (1986a) Geppert et al. (1983), Nowak et al. (1986a) Chicca et al. (2011) O H O O O 160 H HO O H O O Centaurea canariensis Centaurea canariensis ssp. subexpin. O Centaurea deflexa Centaurea linifolia 161 Centaurea musimomum Centaurea ragusina Centaurea solstitialis ssp. schouwii Centaurea sventenii Chartolepis glastifolia Cheirolophus x hortigenus Cheirolophus teydis Cheirolophus uliginosus Grossheimia macrocephala Rhaponticum pulchrum Rhaponticum uniflorum 15-deoxyrepin; salograviolide C Centaurea bella Centaurea salonitana Centaurea solstitialis Psephellus carthalinicus a The stereochemistry of the side Psephellus colchicus Psephellus daghestanicus chain was not indicated in the original paper. Here it is given on Psephellus dealbatus Psephellus declinatus the basis of the NMR values. Psephellus hypoleucus Psephellus karabaghensis Psephellus leucophyllus H HO O O H O O O 162 cynaropicrin; sauprin H HO O H OH O O O Psephellus nogmovii Psephellus somcheticus Psephellus taochius Psephellus zangezuri Rhaponticum uniflorum Acroptilon repens Amberboa divaricata Amberboa muricata Amberboa ramosa Amberboa tubuliflora Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea adjarica aegyptiaca africana americana arguta behen Centaurea bella Centaurea clementei Centaurea canariensis Centaurea canariensis ssp. subexpin. Centaurea debeauxii ssp. thuillieri Centaurea deflexa Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 29 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure Name Taxa Ref. Centaurea exarata Nowak et al. (1986a), Gousiadou and Skaltsa (2003) Yayli et al. (2006) Öksük et al. (1994) Rosselli et al. (2006a) Nowak et al. (1986a) Öksüz and Putun (1983) Gonzalez et al. (1977a), Nowak et al. (1986a) Medjroubi et al. (2005) Bastos et al. (1994) Nowak et al. (1986a, 1989a, 1996), Nowak (1992) Çelik et al. (2006) Öksük and Serin (1997) Mahmoud et al. (1986) Kaminskii et al. (2010a), Kaminskii et al. (2010b), Kaminskii et al., 2010c, Kaminskii et al. (2011) Dawidar et al. (1989), Youssef and Frahm (1994b) Bruno et al. (1991b) Gonzalez et al. (1983), Merrill and Stevens (1985), Jakupovic et al. (1986), Wang et al. (1991), Hamburger et al. (1991), Cheng et al. (1992), Hay et al. (1994), Tešević et al. (1998b) Gonzalez et al. (1977a) Gonzalez et al. (1984), Nowak et al. (1986a) Nowak et al. (1986a, 1989a, 1996),Nowak (1992) Muhammad et al. (2003) Nowak et al. (1986c, 1996),Nowak (1992) Nowak et al. (1986a,c, 1996), Nowak (1992) Nowak et al. (1986a,c, 1996), Nowak (1992) Nowak et al. (1986c, 1996), Nowak (1992) Marco et al. (1994) Gonzalez et al. (1993) Marco et al. (1994) Marco et al. (1994) Gonzalez et al. (1993) Marco et al. (1994) Daniewski et al. (1982), Barbetti et al. (1985), Nowak et al. (1986a), Piacentini et al. (1986), Piacentini et al., 1987 Nowak et al. (1988), Nowak (1992) Nowak et al. (1988, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak (1992), Nowak et al. (1996) Nowak (1992), Nowak et al. (1996) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak (1992), Nowak et al. (1996) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak (1992), Nowak et al. (1996) Nowak (1992), Nowak et al. (1996) Nowak et al. (1986b,a, 1996), Nowak (1992) Cis et al. (2006), Zhang et al. (2010) Nowak et al. (1986a), Berdin et al. (1999) Huneck and Knapp (1986) Nowak et al. (1986a, 1988, 1996), Nowak (1990, 1992), Sorova et al. (2008), Kokoska and Janovska (2009) Nowak et al. (1986a, 1996) Singhal et al. (1982), Nowak et al. (1986a), Bhattacharyya et al. (1996) Serkerov and Aleskerova (1982) Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea helenoides hermannii hololeuca hyssopifolia kotschyi linifolia musimomum ornata phaeopappoides Centaurea Centaurea Centaurea Centaurea ptosimopappa ptosimopappoides ragusina scabiosa Centaurea scoparia Centaurea solstitialis sspschouwii Centaurea solstitialis Centaurea sventenii Centaurea tagananensis Centaurea thracica Centaurothamnus maximus Chartolepis bieberstenii Chartolepis glastifolia Chartolepis intermedia Chartolepis pterocaula Cheirolophus x hortigenus Cheirolophus junoniaus Cheirolophus mauritanicus Cheirolophus sempervirens Cheirolophus teydis Cheirolophus uliginosus Grossheimia macrocephala Leuzea rhapontica ssp. helenifolia Leuzea rhaponticoides Psephellus carthalinicus Psephellus colchicus Psephellus daghestanicus Psephellus dealbatus Psephellus declinatus Psephellus hypoleucus Psephellus karabaghensis Psephellus leucophyllus Psephellus nogmovii Psephellus somcheticus Psephellus zangezuri Rhaponticum pulchrum Rhaponticum serratuloides Rhaponticum uniflorum Stemmamarca carthamoides Stemmamarca rhapontica Tricholepis glaberrima 163 HO acroptin H O H Acroptilon repens OH O O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 30 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 164 H Cl HO Taxa Ref. Centaurea kotschyi Centaurea linifolia Psephellus nogmovii Psephellus somcheticus Psephellus taochius Psephellus zangezuri Centaurea paboti Cheirolophus mauritanicus Öksüz and Putun (1983), Gürkan et al. (1998) Gonzalez et al. (1977a, 1978b), Nowak et al. (1986a) Medjroubi et al. (2005) Nowak et al. (1996) Jakupovic et al. (1986), Tešević et al. (1998b) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b, 1996),Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1990, 1992) Nowak (1992), Nowak et al. (1996) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b) Nowak et al. (1986b,a, 1996), Nowak (1992) Marco et al., 1992 Marco et al. (1994) Centaurea collina Centaurea ornata Fernandez et al. (1987)a, 1989a Navarro et al., 1990 OH O H Name Linichlorin B Centaurea musimomum Centaurea salonitana Centaurea solstitialis Psephellus carthalinicus Psephellus colchicus Psephellus daghestanicus Psephellus dealbatus Psephellus declinatus Psephellus hypoleucus Psephellus karabaghensis Psephellus leucophyllus O O O 165 Deacylcynaropicrin 8-O-[(S)-30 hydroxy-20 -methylpropionate] H HO O H OH O O O 166 H (2’S)-17,18-dihydroxy-aguerin A; 3a-dihydro-4(15)dehydrogrosshemin-a,bdihydroxyisobutyrate OH HO OH O H O O O 167 H a The side chain reported in the original paper has been amended (20 R)-17,18-dihydroxy-aguerin A Centaurea kotschyi OH HO OH O H Öksüz and Putun (1983) O O O 168 H HO O H (1S,3S,5R,6R,7R,8S)-8-tigloyloxy- Centaurea scoparia 3-hydroxyguai4(15),10(14),11(13)-triene-6,12olide Helal et al. (1997) Cebellin F Centaurea scoparia Chartolepis glastifolia Nowak et al. (1986d, 1989a, 1996, 1992) Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Helal et al. (1997) Nowak et al. (1986c, 1996) 8a-hydroxy-3b-(benzoyloxy)1aH,5aH,6bH,7aH-guai4(15),10(14),11(13)-trien-6,12olide Centaurea scoparia Youssef (1998) 3b,8a-O-di-(40 -hydroxytygloyl)1aH, 5aH,6bH,7aH-guai4(15),10(14),11(13)-triene-6, 12-olide Centaurea scoparia Helal et al. (1997) O O O 169 H HO Centaurea adjarica Centaurea bella O OH H O O O 170 O H O OH H O O 171 H O OH O O H O O HO O Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 31 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 172 O O Name Taxa Ref. Cebellin K Centaurea bella Nowak (1992, 1993a,b), Nowak et al. (1996) Cebellin N Centaurea bella Daniewski and Nowak (1993), Nowak (1993a,b), Nowak et al. (1996) Cebellin L Centaurea bella Nowak (1992, 1993a,b), Nowak et al. (1996) Cebellin O Centaurea bella Daniewski and Nowak (1993), Nowak (1993a,b), Nowak et al. (1996) Repdiolide Acroptilon repens Centaurea adjarica Centaurea bella Stevens (1982), Nowak et al. (1986a) Nowak et al. (1989a, 1996), Nowak (1992) Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Cis et al. (2006), Zhang et al. (2010) Berdin et al. (2001) Nowak et al. (1988, 1996), Nowak (1992), Kokoska and Janovska (2009) Rustaiyan et al. (1981b), Rustaiyan and Nazarians (1984) H OH H O O 173 O O H OH H O O 174 O O H HO H O O 175 O O H HO H O O 176 HO H HO O H Rhaponticum pulchrum Rhaponticum serratuloides Stemmacantha carthamoides O O O 177 HO H HO O H 2,3-dihydroxy-8methacryloyloxydehydrocostuslactone Acroptilon repens Cebellin B Centaurea bella Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Cebellin A Centaurea bella Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) 3-Desoxysolstitialin A Centaurea imperialis Rustaiyan et al. (1984) O O O 178 O O H HO OH H O O 179 O O H HO OH H O O 180 H OH OH H O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 32 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 181 Name Taxa Ref. Solstitialin A Centaurea depressa Centaurea imperialis Centaurea solstitialis Akkol et al. (2009) Rustaiyan et al. (1984) Thiessen et al. (1969), Thiessen and Hope (1970), Rybalko et al. (1975), Gonzalez et al. (1977a, 1983), Sakakibara et al. (1977), Merrill and Stevens (1985), Naidenova et al. (1988), Wang et al. (1991), Hamburger et al. (1991), Cheng et al. (1992), Tešević et al. (1998b), Yesilada et al. (2004), Gürbüz and Yesilada (2007), Akkol et al. (2009) 3-Acetylsolstitialin A Centaurea solstitialis Wang et al. (1991), Hamburger et al. (1991), Cheng et al. (1992) 13-Acetylsolstitialin A Centaurea Centaurea Centaurea Centaurea Subexpinnatin C Centaurea canariensis ssp. subexpin. Gürkan et al. (1998) Akkol et al. (2009) Rustaiyan et al. (1984) Zarghami and Heinz (1969), Gonzalez et al. (1977a, 1983), Wang et al. (1991), Hamburger et al. (1991), Cheng et al. (1992), Hay et al. (1994), Tešević et al. (1998b), Yesilada et al. (2004), Gürbuz et al. (2006), Gürbüz and Yesilada (2007), Akkol et al. (2009),Ozcelik et al. (2009) Gonzalez Collado et al. (1985, 1986a) Subexpinnatin B Centaurea canariensis ssp. subexpin. Gonzalez Collado et al. (1985, 1986a) OH Clementein B Centaurea clementei Gonzalez Collado et al. (1986b,a) OH Clementein Centaurea clementei Massanet et al. (1983), Gonzalez Collado et al. (1986b,a) 8a-hydroxy-11b-13Hdehydrocostus lactone Amberboa ramosa Centaurea canariensis ssp. subexpin. Khan (2004) Bohlmann and Gupta (1981), Nowak et al. (1986a) 3-epi-11,13-dihydrodeacylcynaropicrin Amberboa ramosa Centaurea canariensis ssp. subexpin. Khan (2004), Khan et al. (2010) Gonzalez Collado et al. (1985, 1986a) H HO OH OH H O O 182 H AcO OH OH H O O 183 H HO OH OAc H behen depressa imperialis solstitialis O O 184 H OH H O O O 185 O H OH O H O O O 186 O H HO O H O O O 187 O H HO O H O O O 188 H OH H O O 189 O H HO OH H O O Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 33 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure Name Taxa Ref. HO 11b,13-dihydrodeacylcynaropicrin; 11bH11,13-dihydro-deacylaguerin A Amberboa ramosa Centaurea canariensis ssp. subexpin. Centaurea collina Centaurea paboti Centaurea ptosimopappa Centaurea ptosimopappoides Centaurea salonitana Centaurea solstitialis Cheirolophus junoniaus Cheirolophus mauritanicus Cheirolophus metlesicsii Cheirolophus teydis Cheirolophus uliginosus Tricholepis glaberrima Khan et al. (2005a), Ibrahim et al. (2010) Gonzalez Collado et al. (1985, 1986a) Fernandez et al. (1989) Marco et al., 1992 Çelik et al. (2006) Öksük and Serin (1997) Salan and Öksük (2003) Tešević et al. (1998b) Gonzalez et al. (1993) Marco et al. (1994) Gonzalez et al. (1993) Gonzalez et al. (1993) Marco et al. (1994) Singhal et al., 1982 11bH-11,13-dihydro-aguerin A Cheirolophus mauritanicus Cheirolophus metlesicsii Marco et al. (1994) Gonzalez et al. (1993) deacylcynaropicrin 8-O-[(S)-3hydroxy-2-methylpropionate] Cheirolophus mauritanicus Marco et al. (1994) 11b,13-dihydroaguerin B Cheirolophus uliginosus Marco et al. (1994) 11b,13-dihydrocynaropicrin Cheirolophus uliginosus Marco et al. (1994) Deacylcynaropicrin 8-O-(2S,3dihydroxy-2-methylpropionate) Centaurea collina Fernandez et al., 1987a, 1989a 11bH-11,13dihydrodesacylcynaropicrin-8b-D-glucoside; 3b-hydroxy11b,13-dihydro-8a-O-b -Dglucozaluzanin C Centaurea chilensis Negrete et al. (1988b) 190 H OH H O O 191 H HO O H O O O 192 H HO O H OH O O O 193 H HO O H O O O 194 H HO O H OH O O O 195 H OH HO OH O H O O O 196 H HO O-β-D-glucoside H O O 197 H OCH3 HO O H O O OCH3 Centaurea scoparia 3b-hydroxy-8a-(30 ,40 dimethoxybenzoyloxy)-11b, 13dihydro-1aH,5aH,6bH,7aHguai-4(15), 10(14)-dien-6,12olide Youssef (1998) 8a-hydroxy-11a-13Hdehydrocostus lactone Khan et al. (2005a, 2010) O 198 H Amberboa ramosa OH H O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 34 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 199 H HO OH H O Name Taxa Ref. 8a-hydroxy-11a,13dihydrozaluzanin C; 11aH11,13-dihydro-deacylaguerin A; 11a,13-dihydrodeacylcynaropicrin Centaurea aegyptiaca Centaurea ptosimopappa El Dahmy et al. (1985) Çelik et al. (2006) Centaurea scoparia Cheirolophus metlesicsii Centaurea salonitana Centaurea sinaica Helal et al. (1997), Kakuda et al. (1998) Gonzalez et al. (1993) Salan and Öksük (2003) Al-Easa et al. (1990) 11a,13-dihydro-8amethacryloyloxy-zaluzanin C Leuzea longifolia Santos et al. (1988) 11a,13-dihydro-8a-(20 hydroxymethyl)-acryloyloxyzaluzanin C Leuzea longifolia Santos et al. (1988) 11a,13-dihydro-3bmethacryloyloxy-zaluzanin C Leuzea longifolia Santos et al. (1988) 11a,13-dihydro-3bmethacryloyloxy-zaluzanin C Leuzea longifolia Santos et al. (1988) O 200 sinaicin H AcO OH H O O 201 H HO O H O O O 202 H HO O H OH O O O 203 H O OH H O O OH O 204 H O OH H O O O 205 H HO 8a-hydroxy-11a,13-dihydro-13- Acroptilon repens N-pyrrolidin-zaluzanin C; Zha and Hou (2008) 8-desacylrepin Centaurea aegyptiaca Centaurea scoparia Centaurea solstitialis Sarg et al. (1987) Helal et al. (1997) Jakupovic et al. (1986) 8-deacyloxy-8a(methylacryloxy)-subteolide; 19-desoxyjanerin; 17,18desoxyrepin Centaurea adjarica Centaurea bella Nowak et al. (1996) Daniewski and Nowak (1993), Nowak (1993a,b), Nowak et al. (1996) Massiot et al. (1986) Medjroubi et al. (2005) Jakupovic et al. (1986) Öksük and Topçu (1994) Cis et al. (2006), Zhang et al. (2010) Stevens (1982), Rustaiyan and Nazarians (1984), Nowak et al. (1986a), Jakupovic et al. (1986) Nowak et al. (1986d, 1989a, 1996), Nowak (1992) Sarg et al. (1987) Bruno et al. (2005a) OH H O N O 206 H HO OH O H O O 207 H HO O O H O O O 208 Janerin H HO O O H OH Centaurea incana Centaurea musimomum Centaurea solstitialis Chartolepis glastifolia Rhaponticum pulchrum Acroptilon repens Centaurea adjarica O O O Centaurea aegyptiaca Centaurea babylonica Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 35 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure Name Taxa Ref. Centaurea bella Geppert et al. (1983), Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Bruno et al. (1998) Öksük et al. (1994) Rosselli et al. (2006)° Massiot et al. (1986) Flamini et al., 2004 Gonzalez et al. (1977a,b) Nowak et al. (1989a, 1996), Nowak (1992) Medjroubi et al. (2005) Nowak et al. (1986a, 1989a, 1996), Nowak (1992) Çelik et al. (2006) Youssef and Frahm (1994b) Sarg et al. (1988) Merrill and Stevens (1985) Nowak et al. (1989a, 1996), Nowak (1992) Appendino et al. (1986) Muhammad et al. (2003) Nowak et al. (1986c, 1996), Nowak (1992) Nowak et al. (1986a,c, 1996), Nowak (1992) Nowak et al. (1986c, 1996), Nowak (1992) Nowak et al. (1988, 1992) Nowak et al. (1988, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al., 1986b, 1996, Nowak (1992) Nowak et al. (1986c, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak (1992), Nowak et al. (1996) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b) Nowak et al. (1986b,a, 1996), Nowak (1992) Cis et al. (2006), Zhang et al. (2010) Nowak et al. (1988, 1996), Nowak (1992), Kokoska and Janovska (2009) Nowak et al. (1996) Evstratova et al., 1966;Rybalko et al. (1975), Gonzalez et al. (1977a), Rustaiyan et al. (1981b), Stevens (1982), Mallabaev et al. (1982), Rustaiyan and Nazarians (1984), Nowak et al. (1986a), Stevens et al. (1990), Robles et al. (1997) Nowak et al. (1989a, 1996), Nowak (1992) Sarg et al. (1987) Bruno et al. (2005a) Geppert et al. (1983), Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Bruno et al. (1998) Rosselli et al. (2006a) Evstratova et al. (1969, 1972), Rybalko et al. (1975), Gonzalez et al. (1977a) Medjroubi et al. (2005) Kaminskii et al., 2010b, Krasnov et al. (2011) Merrill and Stevens (1985), Jakupovic et al. (1986), Hamburger et al. (1993) Nowak et al. (1986c, 1996), Nowak (1992) Nowak et al. (1986a,c, 1996), Nowak (1992) Nowak et al. (1986c, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak (1992), Nowak et al. (1996) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b) Nowak et al. (1986b,a, 1996), Nowak (1992) Bruno et al. (1998) Massiot et al. (1986) Merrill and Stevens (1985), Hamburger et al., 1993 Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea conifera (=Leuzea conifera) hermannii hololeuca incana isaurica janeri marshalliana musimomum phaeopappoides Centaurea ptosimopappa Centaurea scoparia Centaurea sinaica Centaurea solstitialis Centaurea thracica Centaurea uniflora ssp. nervosa Centaurothamnus maximus Chartolepis bieberstenii Chartolepis glastifolia Chartolepis pterocaula Leuza rhapontica ssp. helenifolia Leuzea rhaponticoides Psephellus carthalinicus Psephellus colchicus Psephellus daghestanicus Psephellus dealbatus Psephellus karabaghensis Psephellus nogmovii Psephellus somcheticus Psephellus taochius Psephellus zangezuri Rhaponticum pulchrum Stemmamarca carthamoides 209 Repin H HO O O O H Stemmamarca rhapontica Acroptilon repens O O Centaurea Centaurea Centaurea Centaurea O adjarica aegyptiaca babylonica bella Centaurea conifera (=Leuzea conifera) Centaurea hololeuca Centaurea hyrcanica Centaurea musimomum Centaurea scabiosa Centaurea solstitialis 210 subluteolide H HO O O O H Chartolepis bieberstenii Chartolepis glastifolia Chartolepis pterocaula Psephellus carthalinicus Psephellus colchicus Psephellus daghestanicus Psephellus dealbatus Psephellus karabaghensis Psephellus nogmovii Psephellus somcheticus Psephellus taochius Psephellus zangezuri Centaurea conifera (=Leuzea conifera) Centaurea incana Centaurea solstitialis O O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 36 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 211 H OH HO H Taxa Ref. Centaurea babylonica Bruno et al. (2005a) Chlorohyssopifolin C; acroptilin Acroptilon repens Centaurea scoparia Centaurea uniflora ssp. nervosa Evstratova et al., 1967, 1971, 1973, Gonzalez et al. (1977a), Rustaiyan et al. (1981b), Mallabaev et al., 1982, Rustaiyan and Nazarians (1984) Nowak et al. (1986d, 1989a, 1996), Nowak (1992) Bruno et al. (2005a) Geppert et al. (1983), Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Evstratova et al., 1972, Rybalko et al. (1975), Gonzalez et al. (1977a) Gonzalez et al., 1974b, 1977a, Nowak et al. (1986a) Massiot et al. (1986) Gonzalez et al. (1977a, 1978b), Nowak et al. (1986a) Nowak et al. (1989a, 1996), Nowak (1992) Merrill and Stevens (1985), Jakupovic et al. (1986) Nowak et al. (1986c, 1996), Nowak (1992) Nowak et al. (1986a,c, 1996), Nowak (1992) Nowak et al. (1986c, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak (1992), Nowak et al. (1996) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b) Nowak et al. (1986b,a, 1996), Nowak (1992) Berdin et al. (1999) Nowak (1992) Nowak et al. (1986d, 1993a,b), Nowak et al. (1996) Helal et al. (1997) Appendino et al. (1986) epoxyrepdiolide Acroptilon repens Centaurea aegyptiaca Stevens (1982), Nowak et al. (1986a) Sarg et al. (1987) 8a-tigloyloxy-2a,3b-dihydroxy4a- epoxydehydrocostulactone Centaurea uniflora ssp. nervosa Appendino et al. (1986) Cebellin I Centaurea adjarica Nowak et al., 1986d, 1989a, 1996, Nowak (1992) Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) OH O O Name Babylin A O O O 212 H Cl HO OH O O H Centaurea adjarica O O Centaurea babylonica Centaurea bella O Centaurea hyrcanica Centaurea hyssopifolia Centaurea incana Centaurea linifolia Centaurea marshalliana Centaurea solstitialis 213 cebellin P H HO Chartolepis bieberstenii Chartolepis glastifolia Chartolepis pterocaula Psephellus carthalinicus Psephellus colchicus Psephellus daghestanicus Psephellus dealbatus Psephellus karabaghensis Psephellus nogmovii Psephellus somcheticus Psephellus taochius Psephellus zangezuri Rhaponticum serratuloides Centaurea adjarica Centaurea bella O O OH H O O O 214 HO H HO O O H O O O 215 HO H HO O O H O O O 216 HO HO Centaurea bella O O H O O O 217 Chlorohyssopifolin B H HO HO Cl OH H Amberboa ramosa Centaurea aegyptiaca Centaurea hyssopifolia Centaurea linifolia O O Centaurea scoparia Khan (2004, 2010) El Dahmy et al. (1985) Gonzalez et al. (1972a, 1977a), Rybalko et al. (1975), Nowak et al. (1986a) Gonzalez et al. (1977a, 1978b), Nowak et al. (1986a) Youssef and Frahm, 1994a, Helal et al. (1997) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 37 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 218 H HO HO Cl Name Taxa Ref. 19-deoxychlorojanerin; linochlorin A; elegin Acroptilon repens Mallabaev et al., 1982, Jakupovic et al. (1986) Centaurea adjarica Centaurea aegyptiaca Centaurea bella Nowak et al. (1996) El Dahmy et al. (1985) Daniewski and Nowak (1993), Nowak (1993a,b), Nowak et al. (1996) Öksük et al. (1994) Gonzalez et al. (1977a, 1978b), Nowak et al. (1986a) Medjroubi et al. (2005) Dawidar et al., 1989 Tešević et al. (1998b) Öksük and Topçu (1994) Jakupovic et al. (1986) Khan (2004), Khan et al. (2005a, 2010) Nowak et al. (1989a, 1996), Nowak (1992) El Dahmy et al. (1985) Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Fernandez et al. (1995) Öksük et al. (1994) Gonzalez et al. (1977a,b) Nowak et al. (1989a, 1996), Nowak (1992) Medjroubi et al. (2005) Nowak et al. (1989a, 1996), Nowak (1992) Çelik et al. (2006) Dawidar et al., 1989, Youssef and Frahm (1994a), Mattern et al., 1996 Sarg et al. (1988) Yesilada et al. (2004), Gürbuz et al. (2006), Gürbüz and Yesilada (2007), Ozcelik et al. (2009) Nowak et al. (1989a, 1996), Nowak (1992) Muhammad et al. (2003) Nowak et al. (1986c, 1996), Nowak (1992) Nowak et al. (1986a,c, 1996), Nowak (1992) Nowak et al. (1986c, 1996), Nowak (1992) Nowak et al., 1988, Nowak (1992) Nowak et al. (1988, 1996), Nowak (1992) Cis et al. (2006), Zhang et al. (2010) Nowak et al. (1988, 1996), Nowak (1992), Kokoska and Janovska (2009) Nowak et al. (1996) O H O O Centaurea hermannii Centaurea linifolia O 219 Chlorojanerin; cebellin C H HO HO Cl O H OH O O Centaurea musimomum Centaurea scoparia Centaurea solstitialis Chartolepis glastifolia Acroptilon repens Amberboa ramosa Centaurea adjarica Centaurea aegyptiaca Centaurea bella Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea Centaurea O conifera (=Leuzea conifera) hermannii janeri marshalliana musimomum phaeopappoides ptosimopappa scoparia Centaurea sinaica Centaurea solstitialis Centaurea thracica Centaurothamnus maximus Chartolepis bieberstenii Chartolepis glastifolia Chartolepis pterocaula Leuza rhapontica ssp. helenifolia Leuzea rhaponticoides Rhaponticum pulchrum Stemmamarca carthamoides Stemmamarca rhapontica 220 Khan et al., 2004a, 2010 O Amberboa ramosa 4b-(chloromethyl)-3b,4adihydroxy,8a- [(S)-3-hydroxy-2methyl-propionyloxy]-1aH,5aH, 6bH,7aH-guaia-10(14),11(13)dien-6,12-olide Amberboa ramosa Khan et al., 2004a, 2010 O 4b-(chloromethyl)-3b,4adihydroxy,8a- [(S)-2carboxypropionoxy]1aH,5aH,6bH, 7aH-guaia10(14),11(13)- dien-6,12-olide 17,18-epoxy-19-deoxychlorojanerin; solstiziolide Centaurea adjarica Nowak (1992), Nowak et al. (1996) Centaurea aegyptiaca Centaurea bella Centaurea solstitialis El Dahmy et al. (1985) Nowak (1992, 1993a,b), Nowak et al. (1996) Merrill and Stevens (1985), Jakupovic et al. (1986) Centaurea incana Centaurea solstitialis Chartolepis glastifolia Massiot et al. (1986) Merrill and Stevens (1985) Öksük and Topçu (1994) H HO HO Cl O H O OH O 221 H HO HO Cl O COOH H O O 222 H HO HO Cl O O H O O O 223 epi-solstiziolide H HO HO Cl O O H O O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 38 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 224 H Cl HO HO Cl Taxa Ref. Acroptilon repens Harley-Mason et al. (1972), Gonzalez et al. (1977a), Cassady et al. (1979), Rustaiyan et al. (1981b), Mallabaev et al. (1982), Rustaiyan and Nazarians (1984) Nowak et al. (1989a, 1996), Nowak (1992) El Dahmy et al. (1985) Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Fernandez et al., 1995 Evstratova et al., 1972, Rybalko et al. (1975) Gonzalez et al. (1972a, 1977a), Rybalko et al. (1975), Nowak et al. (1986a) Rustaiyan et al. (1984) Gonzalez et al. (1977a, 1978b), Nowak et al. (1986a) Medjroubi et al. (2005) Gonzalez et al. (1974a, ?), Gousiadou and Skaltsa (2003) Helal et al. (1997) Sarg et al. (1988), Al-Easa et al. (1990) Sakakibara et al. (1977), Cassady et al. (1979), Jakupovic et al. (1986), Tešević et al. (1998b), Gürbuz et al. (2006), Ozcelik et al. (2009) Nowak et al. (1986c, 1996),Nowak (1992) Nowak et al. (1986a,c, 1996), Nowak (1992), Öksük and Topçu (1994) Nowak et al. (1986c), Nowak (1992), Nowak et al. (1996) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b,a, 1996), Nowak (1992) Nowak et al. (1986b, 1996), Nowak (1992) Nowak (1992), Nowak et al. (1996) Nowak et al. (1986b, 1996), Nowak (1992) Nowak et al. (1986b) Nowak et al. (1986b,a, 1996), Nowak (1992) Berdin et al. (1999) Jiang et al. (1996) Dai et al. (2001) Fernandez et al. (1995) OH O H Name chlorohyssopifolin A; centaurepensin; hyrcanin Centaurea adjarica Centaurea aegyptiaca Centaurea bella O O O Centaurea conifera (=Leuzea conifera) Centaurea hyrcanica Centaurea hyssopifolia Centaurea imperialis Centaurea linifolia Centurea musimomum Centaurea nigra Centaurea scoparia Centaurea sinaica Centaurea solstitialis Chartolepis bieberstenii Chartolepis glastifolia Chartolepis pterocaula 225 H Cl HO HO Cl Psephellus carthalinicus Psephellus colchicus Psephellus daghestanicus Psephellus dealbatus Psephellus karabaghensis Psephellus nogmovii Psephellus somcheticus Psephellus taochius Psephellus zangezuri Rhaponticum serratuloides Rhaponticum uniflorum Serratula strangulata chlorohyssopifolin A 17-epi; 17- Centaurea conifera (=Leuzea conifera) epi -centaurepensin Centaurea musimomum Centaurea solstitialis Chartolepis glastifolia OH O H O O Medjroubi et al. (2005) Tešević et al. (1998b) Öksük and Topçu (1994) O 226 227 H OH HO HO Cl Serratula strangulata Dai et al. (2001) chlorohyssopifolin E Centaurea aegyptiaca Centaurea hyssopifolia Centaurea linifolia Sarg et al. (1987) Gonzalez et al. (1974b, 1977a) Gonzalez et al. (1977a, 1978b), Nowak et al. (1986a) Chlorohyssopifolin D Centaurea hyssopifolia Centaurea linifolia Gonzalez et al. (1974b, 1977a) Gonzalez et al. (1977a, 1978b), Nowak et al. (1986a) OH O H 17-O-(p-hydroxyphenylethanol)-centaurepensin O O O 228 H OH HO HO Cl OCH2CH3 O H O O O 229 deacetylcentaurepensin-8-O-(40 - Centaurea adjarica hydroxy)-tiglate; cebellin D Centaurea bella H HO HO Cl O OH H O O O Centaurea imperialis Centaurea marshalliana Centaurea scoparia Nowak et al. (1989a, 1996), Nowak (1992) Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Rustaiyan et al. (1984) Nowak et al. (1989a, 1996), Nowak (1992) Youssef and Frahm (1994a), Helal et al. (1997) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 39 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 230 Name Taxa Ref. Centaurea solstitialis Chartolepis glastifolia Chartolepis pterocaula Centaurea scoparia Nowak (1992), Nowak et al. (1996); Tešević et al. (1998b) Nowak et al. (1986c, 1996), Nowak (1992) Nowak (1992), Nowak et al. (1996) Youssef and Frahm (1994a) Centaurea scoparia Youssef (1998) 4b-(chloromethyl)-3b,4aCentaurea scoparia dihydroxy-8a- (sarracenoyloxy)1aH,5aH,6bH,7aH-guai10(14),11(13)-dien-6,12-olide Youssef (1998) repensolide; cebellin E chloroscoparin H HO O HO Cl OAc H O O O 231 H HO O HO Cl CHO H O O 4b-(chloromethyl)-3b,4adihydroxy-8a- (30 -formyl-20 methyl-propenoyloxy)1aH,5aH,6bH, 7aH-guai10(14),11(13)-dien-6,12-olide O 232 H OH HO O HO Cl H O O O 233 HO H HO chlororepdiolide Acroptilon repens Jakupovic et al. (1986) Nowak et al. (1989a, 1996), Nowak (1992) Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Cis et al. (2006), Zhang et al. (2010) Nowak et al. (1988, 1996), Nowak (1992), Kokoska and Janovska (2009) Stevens and Wong (1986) diain Centaurea scoparia Youssef and Frahm (1994b) 15-deschloro-15-hydroxychlorohysssopifolin B Amberboa ramosa Khan et al. (2005a, 2010) hermanoid 2; 15-deschloro-15hydroperoxychlorohysssopifolin B Centaurea hermannii Öksük et al. (1994) pterocaulin; repdiolide triol Centaurea incana Chartolepis biebersteinii Chartolepis glastifolia Chartolepis pterocaula Massiot et al. (1986) Nowak et al. (1986c, 1996), Nowak (1992) Öksük and Topçu (1994) Nowak et al. (1986c, 1996), Nowak (1990, 1992) Rhaserolide Rhaponticum serratuloides Berdin et al. (1999), Zhang et al. (2010) O HO Cl H Rhaponticum pulchrum Stemmamarca carthamoides O O Acroptilon repens Centaurea adjarica Centaurea bella O 234 HO H HO HO Cl O H O O O 235 H HO HO Cl O H OH O O O 236 H HO HO HO OH H O O 237 H HO HO HOO OH H O O 238 H HO HO HO O H O O O 239 H HO HO AcO O H O O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 40 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 240 H HO O HO HO H Name Taxa Ref. 15-deschloro-15hydroxychlorojanerin Amberboa ramosa Khan et al. (2005a, 2010) Centaurea conifera (=Leuzea conifera) Centaurea hololeuca Centaurea scoparia Rhaponticum pulchrum Bruno et al. (1998) Rosselli et al. (2006a) Dawidar et al., 1989 Cis et al. (2006), Zhang et al. (2010) Centaurea hermannii Öksük et al. (1994) Chartolepis glastifolia Öksük and Topçu (1994) 15-deschloro-3b-acetyl-15hydroxy-chlorojanerin Centaurea hermannii Öksük et al. (1994) cebellin G; 15-deschloro-15acetoxy-chlorojanerin Centaurea adjarica Centaurea bella Nowak et al. (1986d) Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Öksük et al. (1994) Rosselli et al. (2006a) Dawidar et al., 1989 Cis et al. (2006), Zhang et al. (2010) OH O O O 241 Hermanoid 1 15-deschloro-15hydroperoxy-chlorojanerin H HO HO HOO O H OH O O O 242 H AcO HO HO O H OH O O O 243 H HO O HO AcO H OH Centaurea hermannii Centaurea hololeuca Centaurea scoparia Rhaponticum pulchrum O O O 244 H HO O HO HO H babylin B Centaurea babylonica Bruno et al. (2005a) Centaurea conifera (=Leuzea conifera) or Bruno et al. (1998) 245 Centaurea hololeuca Rosselli et al. (2006a) 15-deschloro-15-hydroxyepisolstiolide Chartolepis glastifolia Öksük and Topçu (1994) cebellin J; desacyllinochlorin C; 15-deacetylrhaposerin Centaurea adjarica Centaurea babylonica Centaurea bella Nowak et al. (1996) Bruno et al. (2005a) Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) Rosselli et al. (2006a) Gonzalez et al. (1977a), Nowak et al. (1986a) Öksük and Topçu (1994) Berdin et al. (2001), Zhang et al. (2010) Gonzalez et al. (1977a, 1978b), Nowak et al. (1986a) O O O O 245 H HO O O HO HO H O O O 246 H Cl HO OH O HO HO H linochlorin C Centaurea hololeuca Centaurea linifolia Chartolepis glastifolia Rhaponticum serratuloides Centaurea linifolia rhaposerin Rhaponticum serratuloides Berdin et al. (1999), Zhang et al. (2010) Epicebellin J Chartolepis glastifolia Ö ksü k and Topç u (1994) O O O 247 H Cl AcO HO HO OH O H O O O 248 H Cl HO HO AcO OH O H O O O 249 H Cl HO HO HO OH O H O O O Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 41 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 250 H OH HO HO H Taxa Ref. Sinicin A Centaurea pseudosinaica Amer et al. (2001) Sinicin B Centaurea pseudosinaica Amer et al. (2001) 13-deschloro-15-hydroxy-8desacylcentaurepensin-8-O-(40 hydroxy)- tiglate Centaurea imperialis Rustaiyan et al. (1984) Cebellin H Centaurea bella Nowak et al. (1986d, 1996), Nowak (1990, 1992, 1993a,b) 19-desoxypicrolide A Chartolepis glastifolia Öksük and Topçu (1994) Picrolide A Acroptilon repens Stevens et al. (1991) Hololeucin Centaurea hololeuca Rosselli et al. (2006b) Rhaserin Rhaponticum serratuloides Berdin et al. (2001), Zhang et al. (2010) 3-oxo-4a-hydroxy-15-hydroxy1aH,5aH, 6bH,7aH,11bH-guai10(14)-ene-6,12-olide Centaurea musimomum Medjroubi et al. (1997) 3-oxo-4a-acetoxy-15-hydroxy1aH,5aH, 6bH,7aH,11bH-guai10(14)-ene-6,12-olide Centaurea musimomum Medjroubi et al. (1997) OH O HO Name O O O 251 H OH HO OH O HO H HO O O O 252 H HO O OH HO H HO O O O 253 H HO O OH HO H AcO O O O 254 H HO O HO O H O O O O HO 255 H HO O HO O H O OH O O O HO 256 H O O H O O O O HO OH O 257 HO H HO HO HO O H O O O 258 H O HO HO H O O 259 H O AcO HO H O O 13 (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 42 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 260 H HO Name Taxa Ref. Saussureolide Amberboa ramosa Khan et al. (2005b, 2010) ramosine; 15-dechloro-15hydroxychlorojanerin Amberboa ramosa Khan et al. (2004b, 2010) ludartin Amberboa ramosa Khan et al. (2004c) Grosheiminol Grossheimia macrocephala Daniewski et al. (1982), Barbetti et al. (1985) Grosshemin; grosheimin Amberboa lippii Gonzalez et al. (1967), Gonzalez et al., 1970, Gonzalez et al., 1977a, Gonzalez et al., 1978a, Breton et al. (1968), Bermejo et al. (1969), Rybalko et al. (1975), Khan et al. (2010) Rustaiyan et al. (1981a), Öksüz et al. (1982), Nowak et al. (1986a), Gürkan et al. (1998) Yayli et al. (2006) Gonzalez et al. (1977a) Adekenov et al. (1986b), Adekenov (1995) Krasnov et al. (2006), Kaminskii et al. (2010b,c) Nowak et al. (1986a) Mukhametzhanov et al. (1969d), Rybalko et al. (1975), Nowak et al. (1986a,c, 1996), Adekenov et al. (1986b, 1991), Nowak (1992), Adekenov (1995) Nowak et al. (1986c, 1996), Nowak (1990, 1992) Rybalko et al. (1964), Rybalko et al., 1975, Rybalko and Sheichenko (1965), Sheichenko and Rybalko (1970, 1972), Bialecki et al. (1973), Gonzalez et al. (1977a, 1978a), Daniewski et al. (1982), Barbetti et al. (1985), Nowak et al. (1986a), Monea (1986), Piacentini et al. (1986, 1987), Adekenov (1995) Bialecki et al. (1973), Popova et al. (1974) Gonzalez et al. (1973b, 1977a), Nowak et al. (1986a), Khan et al. (2010) OH HO H HO O O 261 H HO O HO OH H HO O O O 262 O H O O 263 H HO OH H O O 264 H O OH H Centaurea behen O Centaurea Centaurea Centaurea Centaurea O helenioides ornata ruthenica scabiosa Chartolepis glastifolia Chartolepis intermedia Chartolepis pterocaula Grossheimia macrocephala 265 Muricatin H HO O H Grossheimia ossica Amberboa muricata OH O O O 266 H grosheimin-20 S,30 -dihydroxyisobutyrate OH O OH O H Centaurea ornata Navarro et al. (1990)a, Bastos et al. (1994) O O O H HO 267 HO O H OH O O a Stereochemistry of the side chain not assigned in the original paper. Acrorepiolide Acroptilon repens Rustaiyan et al. (1981b), Rustaiyan and Nazarians (1984) O Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 43 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 268 H O O H HOH2C OH Name Taxa Ref. 15-hydroxy-8-(40 hydroxymethacroyloxy)10(14),11(13)-guaiadien-6,12olide Centaurea tweediei Fortuna et al. (2001) Isolipidiol Amberboa lippii Gonzalez et al. (1970, 1977a), Rybalko et al. (1975), Khan et al. (2010) Gonzalez et al. (1973b, 1977a), Nowak et al. (1986a), Khan et al. (2010) Gonzalez Collado et al. (1986a) Daniewski et al. (1982), Nowak et al. (1986a) O O O 269 H HO Amberboa muricata OH H Centaurea clementei Grossheimia macrocephala O O 270 H tetrahydro-dehydrozaluzanin C; Centaurea webbiana dihydroestafiatone Gonzalez et al. (1972b, 1977a, 1978a) 8a,9a-dihydroxy-4b,15,11b,13tetrahydro-dehydrozaluzanin C Amberboa tubuliflora Ahmed et al. (1990), Khan et al. (2010) Amberbin A; dihydrocumambrin A Amberboa ramosa Ibrahim et al. (2010) Amberbin B Amberboa ramosa Ibrahim et al. (2010) Lipidiol Amberboa lippii Gonzalez et al. (1970, 1977a, 1978a), Rybalko et al. (1975), Khan et al. (2010) Amberboin Amberboa lippii Centaurea sinaica Gonzalez et al. (1967), Gonzalez et al., 1970, Gonzalez et al., 1977a, Gonzalez et al., 1978a, Bermejo et al. (1969), Rybalko et al. (1975), Khan et al. (2010) Al-Easa et al. (1990) cynaratriol Centaurea musimomum Lopes-Rodriguez et al. (2009) 4b,15-dihydro-3-dehydro-13acetylsolstitialin A Centaurea behen Centaurea musimomum Centaurea solstitialis ssp. shouwii Öksüz et al. (1982, 1993) Nowak, 1990, Medjroubi et al. (2005) Bruno et al. (1991b), Ö ksü z et al. (1993) O H O O 271 OH H O OH H O O 272 OH H OAc H O O 273 O-β-D-glucose H OAc H O O 274 H HO OH H O O 275 H O OH H O O 276 H HO OH H O OH O 277 H O OAc H O OH O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 44 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 9 (continued) No Structure 278 H Name Taxa Ref. 4b,15-dihydro-3dehydrosolstitialin A Centaurea behen Centaurea musimomum Centaurea ptosimopappa Rustaiyan et al. (1981a) Gonzalez-Platas et al. (1999), Medjroubi et al. (2003b) Çelik et al. (2006) Clementein C Centaurea clementei Gonzalez Collado et al. (1986b,a) Pseudoivalin Serratula latifolia Rustaiyan and Feramarzi (1988) 4a-hydroxy-10bhydroperoxyguaia-1,11(13)dien-12, 8b-olide Serratula latifolia Rustaiyan and Feramarzi (1988) 4a-hydroxy-10ahydroperoxyguaia-1,11(13)dien-12, 8b-olide Serratula latifolia Rustaiyan and Feramarzi (1988) 4a-hydroxy-1bhydroperoxyguaia10(14),11(13)-dien-12, 8b-olide Serratula latifolia Rustaiyan and Feramarzi (1988) (3a,3aR,4S,6aR,9aS,9bR)-4hydroxy-3-methyl-6methyleneoctahydroazuleno[4,5-b]furan-2,8(3H,9bH)dione Centaurea deflexa Chicca et al. (2011) O OH H O OH O 279 O H HO OH O H O O O 280 O H OH O 281 OOH O H OH O 282 OOH O H OH 283 O HOO O H OH 284 O H O OH H O O against six bacteria and eight fungal species. All compounds showed greater antibacterial and antifungal activities than the positive control used, streptomicyn and miconazole, respectively (Djeddi et al., 2007, 2008b). On the other hand compounds 34 and 35, epoxygermacranes isolated from Stizolophus balsamita, exhibited only moderate antimicrobial activity against three bacterial strains and antifungal activity toward Candida candicans (Suleimenov et al., 2005a), and 8-hydroxyzaluzanin C (149) against S. aureus, and E. coli (Ndom et al., 2006). Antimicrobial properties against S. aureus and Micrococcus luteus were determined, by disc diffusion method, for compounds 142 and 143, structurally similar to 149 (Negrete et al., 1984). Santamarin (99), alantolactone (121), pseudoivalin (280), 9ahydroxypartenolide (28) and grosshemin (264) were shown to have antibiotic activity against five bacteria, the best compound being 9a-hydroxypartenolide (28) (Picman, 1983a). This germacrane at concentrations of 50 and 100 lg/disc, inhibited the growth of several microorganism showing the most relevant antibacterial activity against E. coli (El Hassany et al., 2004). In radio-respirometric bioassays against Mycobacterium tuberculosis and Mycobacterium avium, dehydrocostus lactone (142) exhibited MIC of 2 and 16 lg/mL, respectively (Cantrell et al., 1998), whereas costunolide (1), santamarine (99), reynosin (100) (Fischer et al., 1998) and alantolactone (121) (Cantrell et al., 1999) are moderately active against M. tuberculosis with MIC around 32–64 lg/mL. Costunolide (1) and dehydrocostus lactone (142), were the compounds responsible for the antimycobacterial activity against M. tuberculosis H37Rv with MICs of 6.3 and 12.5 mg/L, respectively. Antimycobacterial activity against drug-resistant (rifampicinresistant) M. tuberculosis clinic isolates appeared to be better for the mixture than for pure compounds because of a synergistic effect (Luna-Herrera et al., 2007). Costunolide (1), isolated from Chrysanthemum boreale, also showed antibacterial activity against Vibrio parahaemolyticus, B. subtilis, B. cereus and S. aureus (Jang et al., 1998a). The antibacterial activity of costunolide (1) against six plant pathogenic bacteria, Pseudomonas solanacearum, Sarcina lutea, Agrobacterium tumefaciens, Erwinia amylovolora, Erwinia cartovora and Corynebacterium fascians, was also evaluated using the agar dilution method. Costunolide was as effective as streptomycin against C. fascians with a MIC value of 10 mg/L (Abdelgaleil and Ahmed, 2005). Anti-Helicobacter pylori effect of costunolide (1) was also investigated using one commercial strain (H. pylori ATCC 43504) and three clinical strains (H. pylori 4, 43, 82548). Costunolide exhibited Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 C 142a;p 1 142a2 143a3 147a3 148a4 149a5 149b6 150a7 152a8 153a9 154a10 155a9 156a9 158a7 160a7 161a8 162a5 164a11 165a12 166n:r: 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 10 20 30 40 100 200 47.3 30.7 32.4 151.0 51.7 85.0 44.8 30.4 36.0 148.9 139.4 169.9 119.7 112.3 109.2 47.6 30.3 32.6 151.2 52.0 85.2 45.1 30.9 36.3 149.2 139.7 170.2j 120.2j 112.6k 109.6k 49.3 30.3 32.0 150.0 53.1 78.6 51.0 72.2 42.7 143.7 138.1 169.9 123.3 116.1 111.1 44.0 38.9 73.3 152.9 49.8 83.9 45.4 30.4 34.0 147.9 139.6 170.0 120.1 114.3 111.0 44.6 36.5 74.7 148.0 50.3 83.3 45.3 30.6 34.5 147.7 139.5 170.0 120.4 114.4 113.6 170.8 21.3 45.2 39.2 73.7 152.4 51.3 79.0 51.0 71.9 41.3 142.7 138.1 169.9 123.2 117.1 113.2 46.0 40.0 73.1 154.3 51.9 80.9 51.7 74.1 42.9 144.7 140.6 172.0 122.9 117.0 112.1 45.6 36.5 74.7 147.3 51.7 78.1 51.1 72.0 41.4 142.3 138.0 169.5 123.2 117.5 115.8 170.7 21.3 45.1 34.4 71.8 146.7j 52.0 76.6 50.5 74.3 36.3 58.4 138.3j 170.7 123.2 55.7 116.6 169.3 21.2 48.8⁄ 38.1 73.6 152.0 48.3⁄ 78.8 40.9 75.2 81.0 143.8 136.3 170.0 125.1 113.6 111.9 169.6 21.1 44.8 33.8 75.6 149.9 50.0 85.0 46.0 24.0 37.8 74.9 139.2 169.3 120.0 53.1 114.5 169.3 21.2 48.8⁄ 36.0 74.5 147.4 47.8⁄ 78.8 41.1 75.2 81.0 143.7 135.9 170.6 125.5 113.8 113.1 170.6 21.1 48.7⁄ 36.1 74.6 146.9 47.0⁄ 79.4 40.9 77.6 79.7 147.7 136.1 171.1 125.3 112.5 112.4 170.4 20.9 45.4 39.0 73.7 152.3 51.4 78.7 47.7 73.9 37.0 141.9 137.7 169.6 122.2 117.9 113.2 176.4 34.2 18.9 18.6 45.3 39.1 73.8 152.4 51.4 78.6 47.7 74.1 37.2 141.9 137.5 169.2 122.6 118.1 113.5 166.4 136.1 126.6 18.3 45.3 39.1j 73.8 152.2k 51.4 78.3l 47.7 75.2l 36.9j 141.3k 137.4k 169.8 122.3 118.8 113.7 168.8 53.8 52.8 17.4 45.3 39.1 73.7 152.2 51.4 78.6 47.6 74.3 37.0 141.8 137.4 169.2 122.7 118.2 113.5 165.4 139.4 126.6 62.1 45.6j 39.1 73.7 152.0 51.7j 78.1 47.3 75.9 35.8 141.4 137.5 168.8 122.1 118.7 114.1 171.7 74.7 51.1 23.4 45.3 39.0 73.5 152.1 51.4 78.6 47.2 73.9 36.5 141.9 137.3 169.6 123.0 118.1 113.6 171.1 42.4 64.4 13.5 45.3 38.3 73.2 151.8 51.5 78.1 46.9 75.2 35.6 141.6 136.8 169.5 123.6 118.1 113.8 174.8 76.0 68.1 21.6 C 168a14 169a14 171a14 176a;p 16 176i16 180a17 181e18 181i16 182e18 183a18 184e19 186e20 188a21 189d21 190a5 191a7 192a3 193a3 194a3 195n:r: 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 10 20 30 40 50 100 200 300 400 500 45.3 39.1 73.7 152.3 51.3 78.4n 47.8 73.8 37.2 141.9 137.4 169.2 122.6 118.0 113.5 166.9 128.3 136.6 14.6 12.0 45.1 38.9 73.6 152.1 51.2 78.6 47.5 74.1 36.9 141.7 137.3 169.2 122.7 118.1 113.4 166.2 127.7 141.9 59.7 12.7 45.5 36.3 75.0 152.2 51.4 77.4n 47.7 74.1 37.5 141.6 137.2 169.1 122.9 118.4 116.0 167.2 128.4 141.3 59.9 12.8 166.4 128.0 140.6 59.8 12.8 51.4 77.3 78.9 147.2 46.5 78.8 47.9 73.8 35.8 139.4 137.2 169.1 n.r. n.r. n.r. 166.5 135.9 n.r. n.r. 46.8 78.9 79.8 151.3 52.9 78.5 48.4 74.5 36.8 141.5 138.9 169.2 121.3 119.2 111.9 166.5 136.7 124.6 18.3 47.3 30.1 32.3 149.6 52.1 85.0 47.5 25.2 36.0 132.0 77.2 180.0 64.6 112.4j 109.8j 42.8 38.0 72.7 152.3 52.2 82.1 49.9 26.2 35.6 148.7 n.r. 179.0 62.9 113.1 110.4 43.5 39.4 73.2 155.4 53.4 83.2 50.7 27.7 37.6 150.5 78.6 180.5 64.9 112.9 108.7 44.1 36.6 75.4 149.1 52.4 82.8 51.1 26.7 36.3 148.6 n.r. 179.7 63.5 113.6 113.6 42.9 38.3 73.3 154.6 52.5 82.0 49.6 26.9 35.9 148.6 75.5 176.5 64.1 113.6 111.3 44.5* 30.5 30.2 151.6 53.3 79.7 55.5 68.0 32.3 145.1 76.5 178.9 44.1* 115.0 110.4 44.9 39.1 73.3 153.5 51.7 79.0 51.0 70.3 30.0 143.0 75.5 178.1 43.1 117.1 112.5 165.5 140.9 125.0 61.1 47.2 30.1j 32.3j 151.1 52.5 80.2 55.4 75.1 47.0 144.5 41.6 179.1 16.1 114.3k 109.7k 43.6 41.3 75.0 155.7 50.4 80.3 55.7 73.7 48.4 145.8 39.8 178.5 15.4 113.4j 110.9j 44.2 39.0 73.6 153.0 50.7 79.1 56.0 74.9 44.8 143.2 42.0 178.6 15.9 116.2 112.0 44.3 38.9 73.6 152.8 50.7 79.0 53.2 75.7 40.5 142.3 41.3 177.8 15.6 117.2 112.4 176.2 34.2 19.1 18.7 44.3 38.8 73.6 152.7 50.7 78.9 53.1 76.1 40.3 142.1 41.4 177.8 15.5 117.4 112.5 174.9 42.1 64.4 13.5 44.0 38.6 73.4 152.6 50.3 78.9 53.2 76.0 40.3 142.1 41.2 177.8 15.4 117.1 112.1 166.3 135.9 126.4 18.2 44.1 38.6 73.5 152.5 50.4 78.8 53.3 76.2 40.3 142.0 41.2 177.7 15.4 117.3 112.4 165.2 139.1 126.4 62.1 44.5 38.7 73.3 152.4 51.0 78.7 52.2 77.7 39.0 141.8 41.3 178.4 15.2 117.5 112.8 175.0 75.9 68.0 21.8 66.4 24.7 64.3 24.1 C 196a;o 22 199a24 201a25 208i27 209a28 210a28 211a29 212i27 213a14 214i16 215g30 217b31 45.8 38.8 75.2 69.1 45.6 37.5 75.0 68.3 45.4 37.4 75.7 68.2 46.2 38.0j 76.5 68.2 46.1 38.9 75.3 69.1 45.6 37.5 76.1 68.2 47.2 78.3 79.5 66.6 49.2 73.1 77.2 65.4 48.9 40.0 77.1 85.8 1 2 3 4 169.9 21.0 44.6 36.6 74.9 148.2 198a23 48.4 29.7 33.6 150.3 43.6 38.6 73.7 152.7 43.7 38.6 73.7 152.6 202a25 43.8 38.6 73.8 152.5 203e25 44.4 46.6 75.6 150.1 204a25 44.3 46.7 75.9 150.3 205d26 44.0 38.9 73.0 154.3 206a14 45.2 37.3 75.0 68.4 207a7 208a7 j j 45.7 37.7 76.1 68.3 45.7 37.7 76.1 68.2 ⁄ M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx 45 Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 Table 10 C NMR data of guaianes. 13 46 C 196a;o 22 198a23 199a24 201a25 202a25 203e25 204a25 205d26 206a14 207a7 208a7 208i27 209a28 210a28 211a29 212i27 213a14 214i16 215g30 217b31 5 6 7 8 9 10 11 12 13 14 15 10 20 30 40 50 60 51.1 79.2 54.1 85.3 42.8 142.8 41.9 178.3 16.3 117.1 114.5 101.5 72.1 73.3 68.6 72.1 62.1 52.9 79.4 50.7 70.0 36.2 144.4 42.6 178.2 16.1 116.0 110.7 49.9 78.9 53.4 69.9 45.0 143.1 38.1 179.1 11.2 115.9 112.6 49.8 79.0 50.7 72.0 40.4 142.2 38.1 178.3 11.3 117.0 112.7 166.4 136.2 126.1 18.2 49.9 78.8 50.7 72.2 40.3 142.3 38.1 177.3 11.3 117.3 113.1 166.8 144.3 126.3 62.3 50.2 79.1 53.6 70.8 36.5 142.2 39.1 179.2 11.2 115.0 113.6 165.8 145.4 123.2 61.3 50.6 79.5 53.5 70.4 36.5 145.4 39.1 179.2 11.2 115.0 113.5 167.2 137.6 126.2 18.4 49.7 79.3 57.6 73.3 42.7 145.0 46.5 175.8 56.5 110.3 114.9 53.7 23.6 23.6 53.7 52.4 77.4 51.1 71.5 40.8 142.2 137.8 170.3 123.1 117.3 48.4 53.1 77.0 47.9j 74.0 36.5 141.6 137.2 169.2 122.6 118.4 48.5 166.5 136.0 126.7 18.2 53.1 76.8 47.9j 74.2 36.5 141.4 137.0 169.0 122.7 118.6 48.5 165.3 139.3 126.7 62.2 52.8 77.5 47.8 74.3 36.8 142.2 138.6 169.0 121.4 117.7 48.5 165.7 143.1 127.7 60.9 53.0 76.7 47.9 76.0 36.1 140.9 137.0 168.9 122.3 118.8 48.5 169.9 53.8 52.8 17.3 52.7 76.6 47.6 75.1 36.5 141.3 136.4 169.2 123.5 118.6 48.4 170.1 53.7 52.9 17.2 53.7 76.6 47.5 75.8 35.3j 140.9 137.3 168.7 122.2 119.3 48.5 175.0 75.8 68.5 21.6 53.2 77.3 47.6 75.2 36.1 142.8 138.5 169.0 121.3 118.0 48.9 173.3 75.3 52.1 24.2 52.9 76.9 48.0 74.0 36.5 141.3 137.0 169.1 122.7 118.6 48.5 166.5 127.9 141.7 59.8 12.7 53.1 78.0 49.4 74.4 37.0 141.0 138.4 169.0 121.4 119.4 47.8 165.5 136.6 126.5 18.3 47.1 77.4 51.7 78.9 36.7 135.2 136.9 168.4 121.9 119.4 47.3 166.5 128.1 138.2 11.9 14.4 59.8 79.0 50.6 72.5 40.0 145.2 140.3 171.6 122.6 116.9 50.1 C 218a7 219a7 219b23 219i32 220b33 221b33 222a38 223a28 224a28 224i27 225a28 226d34 229h31 230b31 231b35 232b35 234i36 235b6 236b23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 10 20 30 40 50 100 200 300 400 500 600 700 800 47.1 37.8 77.3 84.5 57.6 76.4 46.6 73.9 35.2 142.3 137.0 168.8 122.7 117.9 49.9 166.5 136.0 126.6 18.2 47.1 37.8 77.2 84.5 57.5 76.3 46.5 74.1 35.2 142.2 136.8 168.7 122.8 117.9 49.8 166.4 139.3 126.8 62.3 48.9 39.6 77.0 85.5 59.1 78.7 47.9 75.6 36.1 144.4 139.2 171.0 122.3 117.4 50.2 166.5 141.5 126.2 61.6 46.6 40.3 76.5 85.4 59.6 77.6 48.7 74.5 35.4 144.8 139.0 169.2 121.1 116.9 51.3 165.9 142.4 124.9 61.1 50.0 40.1 77.0 85.9 59.4 78.4 47.7 75.4 35.9 144.9 139.9 170.9 122.4 117.7 50.2 174.5 42.2 63.9 14.9 50.0 40.0 77.1 85.9 59.5 78.5 47.5 75.5 35.9 144.9 139.9 170.9 122.5 117.7 50.2 169.7 45.9 180.2 15.2 46.4 37.7 77.2 84.5 57.5 77.2 47.1 75.0 34.8 141.6 136.8 168.5 122.5 118.3 49.9 169.9 53.8 52.8 17.4 46.2 37.6 76.0 84.4 57.4 77.2 46.9 75.0 35.1 142.1 136.2 168.7 123.7 118.0 49.8 170.1 53.7 52.9 17.3 46.4 37.9 76.0 84.6 57.5 77.2 47.3 75.9 34.6 141.8 136.9 168.3 122.4 118.5 50.0 173.1 74.7 51.2 23.4 48.6 40.3 76.3 85.3 59.4 77.5 46.5 75.4 35.1 144.6 138.9 169.0 121.1 117.1 51.2 173.5 75.2 52.2 24.3 46.6 38.0 76.1 84.7 57.5 77.4 47.1 76.0 34.7 142.0 136.4 168.3 123.3 118.3 50.0 173.0 75.1 50.9 23.9 48.6 40.0 76.6 85.2 59.2 77.3 46.9 76.1 35.2 144.6 139.0 169.4 121.5 117.5 50.4 173.9 79.3 51.8 24.0 47.6 39.1 76.1 84.4 58.5 77.1 46.4 74.1 35.1 143.9 138.0 169.0 121.6 116.8 50.1 166.8 126.9 143.7 59.2 12.5 49.0 40.0 77.0 85.8 59.8 78.5 47.6 75.6 35.9 145.1 139.5 170.8 122.1 117.5 50.1 168.2 128.9 143.5 59.7 12.6 176.4 22.1 47.8 39.7 76.2 84.6 58.3 77.2 46.5 74.3 35.0 143.8 138.2 169.7 122.3 116.5 50.0 166.6 130.2 132.7 193.1 13.2 48.3 40.2 77.0 85.2 59.2 77.3 46.9 75.0 35.6 145.0 139.3 170.8 122.1 117.2 50.1 167.4 132.1 141.9 14.3 55.7 58.4 83.3 84.1 83.9 60.1 77.6 47.2 74.4 36.7 142.8 138.8 169.0 120.9 118.0 50.9 166.5 136.7 126.3 18.3 48.6 39.9 77.0 85.9 60.0 78.5 49.9 76.8 36.7 145.2 44.7 180.1 40.1 116.7 49.9 166.4 142.1 125.3 61.5 48.3 37.8 77.9 85.8 55.5 79.4 51.6 70.7 36.8 144.7 139.5 173.2 122.7 116.3 64.5 C 238a7 239i27 240b23 241a37 24337 244a29 246a38 246i39 24827 249a38 254a38 255d32 255i32 256d40 257i39 258a41 259a41 260a;q 11 261b42 262a43 1 2 3 4 5 6 43.6 38.6 77.4 83.5 54.9 77.3 47.5 40.0 77.1 84.2 58.3 77.5 48.1 38.0 77.2 85.5 56.5 79.0 43.6 38.5 75.9 83.5 58.1 78.3 43.5 37.2 76.2 83.9 56.7 74.0 43.9 38.0j 77.0 83.5 55.3 78.0 44.1 38.1⁄ 77.9 84.5 56.1 77.5 47.1 39.8 77.1 85.8 57.7 77.9 47.6 40.4 77.0 84.3 58.3 77.5 44.2 38.1⁄ 77.9 84.5 56.1 77.5 47.9 38.4 77.1 83.9 57.9 77.6 47.6 39.5 77.0 84.7 58.3 77.5 46.6 40.1 77.1 84.7 58.6 77.7 47.1 37.9 85.1 95.7 52.7 77.3 52.5 78.4 84.5 81.0 54.8 77.7 39.6 43.9 219.7 77.2 51.4 87.2 39.7 43.9 219.0 75.6 51.4 86.9 41.5 32.8 78.2 81.4 55.0 76.9 48.3 37.5 77.9 85.8 55.5 79.4 133.9⁄ 33.6 63.8 67.1 52.5 80.7 71.5 36.4 131.0 116.2 130.9 156.2 130.9 116.2 a=d ⁄ M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 Table 10 (continued) 26.6 23.7 21.9 47.7 74.1 36.4 141.8 136.7 169.7 123.2 117.2 63.5 166.3 136.0 126.5 18.2 46.7 74.6 35.8 144.6 139.1 169.2 120.7 116.6 67.5 166.5 136.8 126.3 18.3 171.1 20.9 50.6 75.7 36.4 144.5 139.1 172.7 122.4 116.2 64.4 165.7 141.0 125.1 61.8 46.5 74.3 37.6 142.1 134.8 168.0 122.4 117.5 63.1 162.2? 136.3 126.6 62.4 46.1 76.4 35.3 142.0 139.2 172.0 121.4 116.5 65.7 165.0 135.6 124.8 60.7 165.0 20.2 47.5 75.2 36.9j 141.3 136.6 168.9 123.2 117.7 63.8 169.8 53.9 52.8 14.4 47.6 76.2 37.8⁄ 141.8 136.8 169.7 123.5 118.4 63.8 173.5 75.1 51.7 23.4 47.0 75.6 36.2 144.6 138.9 169.4 121.1 116.7 63.9 173.5 75.4 52.2 23.3 46.8 75.4 35.5 144.5 138.9 169.1 121.0 117.0 67.5 173.4 75.4 52.2 24.3 171.1 20.9 47.7 76.5 37.8⁄ 141.8 137.1 169.9 124.2 118.5 63.8 173.5 75.4 51.8 23.8 46.0 74.1 35.8 143.7 139.1 169.2 124.5 115.6 66.9 165.6 142.2 126.1 27.1 167.5 123.7 132.1 115.1 162.3 115.1 132.1 46.9 74.7 35.8 144.8 139.2 169.3 121.2 117.0 67.3 165.8 141.9 124.7 61.0 167.1 122.4 132.7 115.7 162.6 115.7 132.7 47.7 74.5 35.7 144.8 139.1 169.3 120.9 116.9 67.6 165.9 142.4 124.7 61.0 167.2 122.1 132.6 115.9 163.4 115.9 132.6 47.5 75.5 44.5 144.7 138.5 169.9 124.4 118.0 65.4 166.1 142.6 125.6 61.9 153.4 47.8 74.5 39.6 141.4 138.2 169.3 121.0 116.8 63.6 166.0 136.3 124.0 17.9 49.3 26.9 38.6 149.0 47.1 178.9 13.9 112.5 63.1 C 263i11 264a44 265e20 266a45 269b46 270a47 271a48 272a50 272b50 273b50 276a;q 51 277a52 278a52 279e20 284a53 287a54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 10 20 30 40 50 60 100 200 43.3 38.5 87.4 44.9 51.4 81.6 49.9 67.8 41.6 143.5 136.3 169.3 121.2 116.8 18.3 40.1 43.2 219.1 46.9 51.0 82.3 49.1 73.1 47.9 143.1 136.3 169.9 125.8 115.6 14.9 43.4 40.7 78.1 46.7 51.7 81.9 50.4 75.2 n.r. 142.2 137.8 170.5 123.0 116.9 18.4 165.5 140.2 126.0 61.1 40.7 42.3 218.2 46.7 51.5 80.6 46.5 75.9 40.7 141.5 135.6 168.9j 125.2 117.3 15.1 174.7j 75.5 67.9 21.9 43.6 35.5 79.1 48.2 52.3 83.9 60.0 77.1 48.9 146.3 43.5 181.9 16.8 115.1 18.8 39.7 44.0 219.2 47.2 50.9 88.5 48.6 32.9 39.0 149.1 41.7 178.2 13.3 112.5 14.0 38.4 43.1 219.3 30.5 50.9 77.4 44.4 72.3 83.2 147.5 47.5 179.5 11.1 114.9 14.3 53.5 33.6 125.6 143.4 54.5 80.5 51.2 74.3 41.7 73.3 41.9 178.1j 15.3 31.5 17.5 55.5 34.0 127.1 143.8 52.7 82.1 54.4 75.5 44.2 73.4 46.6 180.8j 15.8 29.5 17.4k 42.6 36.8⁄ 84.4 43.6 50.8 79.9 48.6 27.5 35.3⁄ 148.7 79.7 171.7 62.7 113.1 18.0 39.5 43.7 219.1 47.1 51.2 86.8 49.5 27.1 38.3 148.7 75.5 176.2 64.0 112.7 14.0 169.2 20.5 39.6 43.9 219.7 47.1 51.4 87.2 49.4 26.9 38.6 148.9 77.2 178.8 63.1 112.5 13.9 42.9 41.3 78.2 47.1 54.6 81.4 51.2 71.9 38.5 142.8 75.9 178.2 43.2 115.9 18.6 165.5 140.9 125.0 61.1 40.3 44.1 219.0 44.1 52.2 82.9 55.6 70.5 49.2 143.5 47.9 175.9 15.2 116.3 22.9 23.3 43.6 208.5 34.3 30.7 37.8 75.6 37.3 17.2 139.0 170.4 122.5 18.2 30.0 170.1j 21.3 172.1j 21.2k 53.0 34.0 126.8 144.0 55.0 82.3 52.3 75.4 42.8 81.1 42.1 181.0j 15.7 26.1 17.7 98.4 78.2 71.8 75.5 77.7 62.9 172.1j 21.3 49.6 27.2 38.5 148.8 47.2 176.2 14.1 112.9 64.1 170.4 20.7 53.7 75.4 42.0 140.5 40.5 176.8 15.7 117.2 64.1 57.6 75.7 36.8 144.7 43.1 180.5 16.1 116.1 64.3 165.3 141.9 125.9 62.4 54.5 25.8 34.0 134.9⁄ 139.4 169.5 117.8 22.7 19.0 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx 64.4 24.2 a In CDCl3. b In MeOD. c In DMSO-d6. d In acetone-d6. e In CDCl3/MeOD. f In CDCl3/pyridine-d5. g In CDCl3/DMSO-d6 9:1. h In CD2Cl2/DMSO-d6 7:1. i In pyridine-d5. j,k,,l,m Inverted with respect to the original paper. n Amended with respect to the original paper. o As penta-acetate. p Not assigned in the original paper. q As tri-acetate. ⁄, ,# These values may be interchanged. 1 Negrete et al. (1984); 2Hsu HF et al. (2009); 3Marco et al. (1994); 4Hibasami et al. (2003); 5Choi et al. (2005); 6Youssef and Frahm (1994b); 7Marco et al. (1993); 8Daniewski et al. (1993); 9Vajs et al. (1999); 10Bentamane et al. (2005); 11Buděšinský and Šaman (1995); 12Marco et al. (1992); 13Fernandez et al. (1989); 14Helal et al. (1997); 15Stevens (1982); 16Stevens and Merrill (1985); 17Meragelman et al. (1998); 18Wang et al. (1991); 19Collado et al. (1987); 20Gonzalez Collado et al. (1986b); 21Li and Jia (1989); 22Negrete et al. (1988b); 23Khan et al. (2005a); 24Li et al. (2008); 25Santos et al. (1988); 26Zha and Hou (2008); 27Berdin et al. (1999); 28Hamburger et al. (1993); 29Bruno et al. (2005a); 30Appendino et al. (1986); 31Youssef and Frahm (1994a); 32Stevens et al. (1991); 33Khan et al. (2004a); 34Dai et al. (2001); 35Youssef (1998); 36Stevens and Wong (1986); 37Öksük et al. (1994); 38Öksük and Topçu (1994); 39Berdin et al. (2001); 40Rosselli et al. (2006b); 41Medjroubi et al. (1997); 42Khan et al. (2004b); 43Sosa et al. (1989); 44Yayli et al. (2006); 45Navarro et al. (1990); 46Jang et al. (2000); 47Krishna Kumari et al. (2003); 48Ahmed et al. (1990); 49Lee et al. (2003); 50Ibrahim et al. (2010); 51Bernhard et al. (1979); 52Medjroubi et al. (2003b); 53Chicca et al. (2011); 54Fontana et al. (2007). 47 Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 7 8 9 10 11 12 13 14 15 10 20 30 40 100 200 300 400 500 600 700 48 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 11 H1 NMR diagnostic signals of guaionolides with epimeric side chains. Ha 14 Hb X 3' H13b H14b H30 a H30 b H40 solv. Ref. 5.58 4.97 3.17 2.82 1.62 CDCl3 Daniewski et al. (1993) 5.57 4.98 3.17 2.83 1.62 CDCl3 Bruno et al. (2005a) 5.59 5.56 5.71 4.96 4.96 4.92 3.01 3.15 3.16 2.85 2.81 2.82 1.57 1.60 1.60 acetone-d6 CDCl3 CDCl3 Bruno et al. (2005a) Hamburger et al. (1993) Hamburger et al. (1993) 5.57 4.84 3.17 2.81 1.61 CDCl3 Hamburger et al. (1993) 5.74 4.79 3.17 2.82 1.60 CDCl3 Hamburger et al. (1993) 5.64 4.98 3.17 2.83 1.62 CDCl3 Bruno et al. (2005a) 5.86 4.97 3.19 2.82 1.62 CDCl3 Öksük and Topçu (1994) 5.60 5.10 3.90 3.65 1.50 CDCl3 Gonzalez et al. (1978b) 3.88 3.91 4.18 3.96 3.65 3.73 4.06 3.77 1.56 1.54 1.55 1.55 CDCl3 CDCD3 Pyridine-d5 acetone-d6 Bruno Bruno Bruno Bruno 3.87 4.10 3.63 4.00 1.55 1.70 CDCl3 pyridine-d5 Hamburger et al. (1993) Berdin et al. (1999) OR H 4' O O H 13 O O 161 Hb Ha 15-Desoxyrepin H O HO O H O O O 209 Repin H O HO O O H O O O 210 Subteolide H O HO O O H O O O 222 Solstiziolide H HO O O HO Cl H O O O 223 Episolstiziolide H HO O O HO Cl H O O O 244 Babylin B H O HO O HO HO H O O O 245 15-Deschloro-15-hydroxy-episolstiolide H O HO O HO HO H O O O 164 Linochlorin B Cl H OH HO O H O O O 212 Acroptilin Cl H OH HO O O H 5.57 5.71 5.85 5.66 et et et et al. al. al. al. (2005a) (2005a) (2005a) (2005a) O O O 224 Centaurepensin Cl H HO HO Cl OH O H 5.57 5.75 5.00 5.07 O O O Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 49 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 11 (continued) Ha 14 Hb X 3' H13b H14b H30 a H30 b H40 solv. Ref. 5.83 4.81 3.87 3.63 1.55 CDCl3 Hamburger et al. (1993) 5.64 5.04 3.87 3.65 1.56 CDCl3 Bruno et al. (2005a) 5.87 4.91 3.87 3.64 1.55 n.r. Öksük and Topçu (1994) 5.60 5.02 3.90 3.65 1.55 CDCl3 Gonzalez et al. (1978b) 5.74 5.04 4.07 3.97 1.67 pyridine-d5 Berdin et al. (1999) 5.60 5.12 3.88 3.64 1.42 CDCl3 Bruno et al. (2005a) 5.60 5.09 3.87 3.64 1.40 CDCl3 Öksüz and Putun (1983) 5.90 5.91 3.86 3.78 3.61 3.57 1.34 1.34 CDCl3 n.r. Navarro et al. (1990) Fernandez et al. (1987) 6.07 3.82 3.61 1.34 CDCl3 Navarro et al. (1990) 3.76 3.44 1.40 Acetone-d6 Gonzalez et al. (1974b) OR H 4' O O H 13 O O 225 Hb Ha 17-epi-centaurepensin Cl H HO OH O HO Cl H O O O 246 Cebellin J Cl H OH HO O HO HO H O O O 249 Epicebellin J Cl H OH HO O HO HO H O O O 247 Linochlorin C Cl H OH AcO O HO H HO O O O 248 Rhaposerine Cl H HO OH O HO H AcO O O O 211 Babylin A OH H OH HO O O H O O O 167 17,18-dihydroxy-aguerin A OH H OH HO O H O O O 166 (20 S)-17,18-dihydroxy-aguerin A OH H OH HO O H O O O 266 Grosheimin-20 ,30 -dihydroxy-isobutyrate OH H O OH O H O O O 228 Chlorohyssopifolin D HO HO Cl 5.73 OH H OCH CH 2 O H 4.90 3 O O O (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 50 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 11 (continued) Ha 14 Hb X 3' H13b H14b H30 a H30 b H40 solv. Ref. 5.70 5.01 3.86 3.56 1.39 Acetone-d6 Gonzalez et al. (1974b) OR H 4' O O H 13 O O 227 Hb Ha Chlorohyssopifolin E OH H HO HO Cl OH O H O O O Table 12 Other sesquiterpenes isolated from taxa of the Subtribe Centaureinae. No Structure 285 Name Taxa Ref. 4,9-Dioxo-bisabol-2,7(14),10-triene Centaurea calcitrapa Jakupovic et al. (1986) 4,9-Dioxo-bisabol-2,7E,10-triene Centaurea calcitrapa Jakupovic et al. (1986) Carabrone Serratula latifolia Rustaiyan and Feramarzi (1988) O O 286 O O 287 O O O H potent anti-H. pylori activity, and the MIC was around 100–200 lg/ mL. However, costunolide had no inhibitory effect of H. pylori urease activity at the concentation used for the growth inhibition assay. The most used drugs for the treatment of H. pylori infection, i.e. proton pump inhibitors (omeprazole, lansoprazole), affect the inhibtion of H. pylori urease activity or the inhibition of H. pylori survival by urease-independent mechanisms. Costunolide, apparently exploits the latter type mechanism (Park et al., 1997). Antimicrobial tests on costunolide (1), isolated from Cosmos caudatus, indicated a complete inhibitory activity against S. aureus and Saccharomyces cerevisiae, partial inhibitory activity against B. subtilis, slight inhibitory activity against C. albicans and negative inhibitory activity against E. coli and P. aeruginosa at concentrations of 100 lg/mL and 1 mg/mL, respectively (Ragasa et al., 1997). Antimicrobial properties of 13-acetyl solstitialin A (183), chlorojanerin (219) and centaurepensin (224) were screened against both standard and the isolated strain of E. coli, P. aeruginosa, Enterococcus faecalis, S. aureus, C. albicans and Candida parapsilosis. All lactones displayed moderate antibacterial activity (Gürbuz et al., 2006;Ozcelik et al., 2009). The antimicrobial activities of chloroform extracts from the weeds C. tweediei and Centaurea diffusa, and the main SLs isolated from these species, onopordopicrin (8) and cnicin (19), respectively, were assayed. Results show that the chloroform extracts from both Centaurea species possess antibacterial activities against a panel of Gram+ and Gram bacteria. Remarkable antibacterial activity against methicillin-resistant S. aureus was also measured (Bach et al., 2011). Santamarin (99), alantolactone (121), pseudoivalin (280) were shown to have good antifungal activity against Trichophyton mentagrophytes and Microsporum cookei; 9a-hydroxypartenolide (28) only against T. mentagrophytes (Picman, 1984). Compounds 129, 155 and 156 revealed good inhibitory activity against Aspergillus niger, Aspergillus ochraceus, Cladosporium cladosporioides and Phomopsis helianthi (Vajs et al., 1999). The in vitro antifungal activity of compounds 8, 14, 15, 19, 20, 22, 24, 36, 75, 80–82, 94, 103, 107–109, 111, 137, 138 was tested against nine fungal species, using the micro-dilution method. All the compounds tested showed great antifungal activity comparable and sometimes better than miconazole used as control (Skaltsa et al., 2000a; 2000b). The activity against the fungus Cunninghamella echinulata of compounds 1, 4, 19 and 142 has been evaluated. Compounds 4 and 19 were inactive whereas 1 and 142 showed the same noticeable EC50 values (6 lg/mL) close to that of ketokonazole (1.5 lg/ mL) used as reference drug (Barrero et al., 2000). Costunolide (1), dehydrocostus lactone (142), zaluzanin C (147) and 3-desoxysolstitialin A (180) were tested for their fungicidal activity against the phytopathogenic fungi Colletotrichum acutum, Colletotrichum fragariae, Colletotrichum gloesporioides,Fusarium oxysporum,Botrytis cinerea and Phomopsis ssp. Active compounds in decreasing order of activity were 142, 1 and 147, whereas 180 was not active (Wedge et al., 2000). The in vitro antifungal activity of four of the 10 sesquiterpenes isolated from Centaurea deusta was tested against nine fungal species (Aspergillus ssp., Penicillum ssp., Trichoderma viride, C. cladosporioides, Alternaria alternata). Compounds 24, 81, 95, and 112 showed greater antifungal potential than miconazole except against C. cladosporioides. The antibacterial bioassays showed an activity only for compound 19 (Karioti et al., 2002). Nevertheless, this germacrane has also been proved to be active against the same previous nine fungi with a fungicidal potential higher Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 51 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 13 Occurrence of sesquiterpenoids in taxa of the Subtribe Centaureinae. Taxa Only germacranes Aegialophila pumila (syn. Centaurea aegialophila Sect. Aegialophila) Centaurea affinis C. aggregata C. alba C. alba ssp. caliacrae C. alba ssp. deusta C. alexandrina C. aplopea C. aplopea ssp lunensis C. araneosa (a.n. C. procurrens) C. arenaria C. arenaria ssp. majorowii C. arenaria ssp. odessana C. aspera ssp. scorpiurifolia C. attica ssp. drakiensis C. attica ssp. ossaea C. bombycina C. calolepis C. calvescens C. cineraria C. cineraria var. circae C. coronopifolia C. crithmifolia C. crocodylium C. cuneifolia ssp. pallida C. derventana C. diffusa ssp. brevispina = C. bovina C. eriophora C. friderici C. gigantea C. glaberima C. glomerata C. granatensis C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. C. grisebachi ssp. confusa iberica kartschiana leucophaea lusitanica maculosa mantoudii mariolensis maroccana (a.c.C. sulphurea) micranthos monticala ovina pallescens pallidior paniculata pelia polyacantha pontica pseudomaculosa raphanina ssp. mixta C. C. C. C. C. rhenana ssp. savranica rocheliana rothmalerana seridis sonchifolia C. splendens C. squarrosa C. sulphurea Section or Subgenus Germacanes Gr. 6 4, 19 Egypt Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Phalolepis Gr. 7, Phalolepis Gr. 7, Phalolepis Gr. 7, Calcitrapa Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7,Calcitrapa Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7,Seridia Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 1, Stizolphus Gr. 7, Acrolophus Gr. 6, Crocodylium Gr. 7, Acrolophus Unresolved classification Gr. 7, Acrolophus Gr. 7, Seridia 4, 19 19 4, 19, 21, 24, 36 4 4 19 19 19 19 19 19 19 4, 5, 19, 21 19 19 4, 19, 24 19 19 19 19 31, 32, 34, 35 4 4, 19 19 4, 19, 21, 24 Serbia Polonia ?? Spain Bulgaria Italy Egypt Italy Italy Egypt Hungary Ukraine Germany Spain Greece Greece Spain Turkey Germany Italy Italy Turkey Italy Poland Greece Serbia 19 4, 19 Gr. 7, Acrolophus Cynaroides Unresolved classification Unresolved classification Gr. 7, Acrocentron, syn. Colymbada Gr. 7,Acrolophus Gr. 7, Calcitrapa Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Seridia Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Calcitrapa Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Acrolophus Gr. 7, Seridia Gr. 7, Calcitrapa Gr. 7, Acrolophus Gr. 7, Acrocentron, syn. Colymbada Gr. 7, Acrolophus Gr. 7, Jacea Gr. 7, Acrolophus Gr. 7, Seridia Gr. 7, Seridia 4 9, 13 19 Greece Poland, France Italy Turkey Montenegro 15, 17, 39, 43 Egypt 19 Spain 19 4, 19 19 19 3, 5, 19 19 19 19, 21 4, 19, 21, 36 19 19, 21 19 19 19 4 19 53, 54 4 4, 19 19 Greece Uzbekistan Italy Italy Portugal USA Greece Spain Morocco ?’ Spain Poland Egypt Greece France Greece ?? Romania Kazakhstan Greece 19 19 19 53, 54, 57 8, 53, 54 Greece Rep. Czeka Portugal Spain Spain, Greece Montenegro Uzbekistan Spain, Morocco Algeria Gr. 7, Phalolepis Gr. 7, Acrolophus Gr. 7,Solstitiaria 19 19 19 19, 64, 66 Elemanes Eudesmane Guaianes Other Collection place (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 52 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 13 (continued) Taxa Section or Subgenus Germacanes C. transiens C. tymphaea C. thymphaea ssp. brevispina C. vallesiaca C. weldeniana Stizolophus balsamita Zoegea baldshuanica Gr. Gr. Gr. Gr. Gr. Gr. Gr. 19 19 19 19 4 27, 29, 32, 33, 34, 35, 47, 56 28 7, 7, 7, 7, 7, 1 1 Acrolophus Acrolophus Acrolophus Acrolophus Jacea Elemanes Eudesmane Guaianes Other Collection place Greece Greece Greece Italy Italy Kazakhstan Poland Germacranes and elemanes Centaurea aegialophila (a.n. Aegialophila pumila) C. amara C. aspera Gr. 6 19 69, 80 Cyprus Gr. 7, Jacea Gr. 7, Seridia 10, 40 69, 84 4, 5, 8, 19, 21, 24, 36, 37, 38 94 C. aspera ssp. stenophylla Gr. 7, Seridia 69, 84, 97 71 80, 84 Spain Spain, France Spain C. brugueriana C. calcitrapa 4, 5, 8, 11, 16, 18, 19, 21, 24, 38, 58 Gr. 7, Tetramorphaea 19 Gr. 7, Calcitrapa 4, 19, 21, 36, 49 285, 286 C. C. C. C. castellana cineraria ssp. busambarensis cineraria ssp. umbrosa cuneifolia Gr. Gr. Gr. Gr. 7, 7, 7, 7, Acrolophus Acrolophus Acrolophus Acrolophus 19, 53 19 19, 21 19 19 19, 21 8, 9, 19 69, 87 69, 80 80 69, 80 C. melitensis C. napifolia Gr. 7, Acrolophus Gr. 7, Acrocentron, syn. Colymbada Gr. 7, Seridia Gr. 7, Seridia 4, 8, 9 19, 21 C. nicaensis Gr. 7, Seridia 8, 10, 19, 36, 40, 45 76, 84, 90 69, 80, 81, 84 84, 91 C. paniculata ssp. castellana C. phrygia Gr. 7, Acrolophus Gr. 7, Jacea, Lepteranthus Gr. 7, Seridia Gr.1 Gr. 7 19, 21 16 80 79 19, 21, 30, 53, 54 4, 6, 7, 8, 15 4, 16, 19, 21, 53 69, 81 75, 94 80 C. diffusa C. eryngioides C. sphaerocephala Cheirolophus intybaceus Cnicus benedictus Germacranes, eudesmanes Centaurea kurdica C. stoebe Gr. 7, Cynaroides Gr. 7, Acrolophus Phonus arborescens (a.n. Carthamus arb.) Gr. 5 Germacranes, elemanes, eudesmanes Centaurea achaia Spain Sicily Sicily Turkey Serbia Argentina Egypt 81, 83 75 1, 2, 48 19 4, 19, 24 51, 52 Spain Sicily Sicily, Algeria Spain Bulgaria Sicily Spain 100 102 139, 140, 141 C. aspera ssp. subinermis Gr. 7, Acrocentron, syn. Colymbada Gr. 7, Seridia C. attica Gr. 7, Acrolophus 4, 7, 8, 13, 14, 15, 22, 36, 42 75, 94 5, 38 69, 92, 19, 21 80, C. deusta Gr. 7, Phalolepis 19, 20, 21, 24 C. grisebachi Gr. 7, Acrolophus 4, 19, 24 80, 81, 95, 96 69, 80 C. malacitana C. moesiaca C. orphanidea Gr. 7, Seridia Gr. 7, Lepteranthus Gr. 7, Acrolophus 4, 5, 10, 18, 19, 21 8, 16, 19, 20, 21, 24, 25, 26 4, 19, 21 69 80 80 C. paui Gr. 7, Acrolophus 4, 19, 21, 24, 36, 59, 60, 61, 62, 64, 65, 67, 68 C. pullata Gr. 7, Melanoloma 44, 45, 36, 46 C. spinosa Gr. 7, Acrolophus 19, 21, 23 C. thessala ssp. drakiensis C. zuccariniana Neither germacranes nor guaianes Centaurea. cadmea C. granata C. hierapolitana Gr. 7, Acrolophus Gr. 7, Acrolophus 19, 21, 24 19, 21 69, 70, 83, 85, 95 69, 84, 115, 117, 89 118, 119 80, 83, 95 109, 110, 111, 113 80, 81 103, 109 80 104 Gr. 7, Phalolepis Gr. 7, Jacea Gr. 7, Phalolepis 82, 84, 93 95 74, 77 Iran Spain, Egypt Argentina Turkey Serbia Germany ?? Spain 107, 137 114, 135 109, 138 111, 108, Greece 116, Spain 111, Greece 112 Greece 103, 110, 112 109 109, 103, 111 102 109, 111, Greece 111 109, 122 115 130, 131 Spain Bulgaria Greece Spain Algeria Greece Greece Greece Turkey Algeria Turkey Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 53 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx C. phyllocephala Unresolved classification Gr. 7, Tetramorphaea Only guaianes Acroptilon repens (syn. Centaurea repens) Gr. 3 C. pamphilica Amberboa divaricata A. muricata (syn. Volutaria m., Centaurea m.) A. ramosa Gr. 2 Gr. 2 A. tubuliflora Centaurea adjarica (a.n. Psephellus simplicicaulis) Gr. 2 Gr. 1, Psephellus C. aegyptiaca Gr. 7, Calcitrapa C. ainetensis (a.n. C. eryngioides) Gr. 7, Acrocentron, syn. Colymbada Gr. 1, Plectocephalus Gr. 7 or 1, Microlophus, aff. Sect. Centaurium Gr. 7 or 1, Microlophus, aff. Sect. Centaurium Gr. 1, Cheirolophus C. americana C. babylonica, (a.n. Centaurea behen) C. behen (syn. Centaurium behen) C. canariensis (a.n. Cheirolophus canariensis) C. clementei C. collina C. C. C. C. C. debeauxii ssp. thuillieri deflexa depressa floccose helenoides C. hermannii C. hololeuca C. hyrcanica C. imperialis C. isaurica C. janeri C. kandavanensis C. kotschyi C. marshalliana (a.n. Psephellus marshallianus) C. musimomum C. nicolai C. nigra C. pabotii C. phaeopappoides (a.n. Psephellus phaeopapp.) C. pseudosiniaca (a.n. C. sinaica) Gr. 2 Gr. 7, Acrocentron, syn. Colymbada Gr. 7, Acrocentron, syn. Colymbada Gr. 7, Lepteranthus Cheirolepis Gr. 7, Cyanus Gr. 7, Cyanus Unresolved classification Unresolved classification Unresolved classification Gr. 7, Jacea Gr. 7, Cynaroides Unresolved classification Gr. 7,Jacea Gr. 7, Acrocentron, syn. Colymbada Cheirolepis Gr. 1, Psephellus Unresolved classification Gr. 7, Acrocentron, syn. Colymbada Gr. 7, Jacea, sect. Lepteranthus Unresolved classification Gr. 1, Psephellus Gr. 7, Calcitrapa 80, 81 133 Turkey 109 Iraq 149, 163, 208, 218, 234, 162 149, 151, 176, 209, 219, 255, 162, 198, 221, 261, 149, 162, 208, 216, 224, 246 149, 208, 218, 227 156 188, 217, 236, 262, 160, 169, 209, 218, 229, 160, 177, 212, 224, 267 162, 205, 214, 233, 162, 265, 269 189, 219, 240, 272, 162, 176, 212, 219, 233, 190, 220, 260, 273 271 207, 213, 222, 243, 162, 199, 206, 209, 214, 217, 219, 222, 224, Caucasus Argentina India Spain?? Pakistan Egypt Poland Sinai Lebanon 162 208, 209, 211, 212, 244, 246 Mexico Lebanon 149, 160, 162, 183, 264, 277, 278 Iran 149, 158, 160, 162 Canary Is. 149, 162, 186, 187, 269, 279 149, 166, 190, 195 Spain 162 149, 181, 144, 162, France Turkey Turkey ?? Turkey 162, 237, 162, 243, 209, 180, 229, 208 160, 162, 284 183 149 264 208, 241, 208, 244, 212, 181, 252 218, 242, 209, 246, 224 183, 219, 243 240, 256 224, Spain Turkey Lebanon Russia?? Iran?? Turkey 208, 219 150, 156 Spain Iran 149, 162, 164, 167 208, 212, 219, 229 Turkey Russia 160, 208, 224, 276, 150, 156 224 207, 219, 259, Algeria 155, Montenegro 162, 209, 225, 277, 152, 164, 218, 258, 278 153, Spain 158, 165, 190 Iran 162, 208, 219 Armenia 250, 251 S. Arabia (continued on next page) Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 54 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Table 13 (continued) Taxa Section or Subgenus C. ptosimopappa Gr. 7, Ptosimopappus C. ptosimopappoides C. ragusina Gr. 7, Ptosimopappus Gr. 7, Acrocentron, syn. Colymbada Gr. 1, Rhaponticoides C. ruthenica (a.n. Rhaponticoides ruthenicus) C. sinaica Gr. 7, Calcitrapa C. solstitialis ssp. shouwii C. sventenii (a.n. Cheirolophus sventenii) C. thracica C. webbiana (a.n. Cheirolophus webbianus) Centaurothamnus maximus Chartolepis biebersteinii (a.n. Centaurea pterocaula) C. glastifolia (a.n. Centaurea glastifolia) Gr. 7, Chartolepis C. intermedia (a.n. Centaurea chartolepis) C. pterocaula (a.n. Centaurea pterocaula) Gr. 7, Chartolepis Gr. 7, Chartolepis Cheirolophus junoniaus C. metlesicsii Gr.1 Gr.1 C. teydis C. uliginosus Gr.1 Gr.1 Grossheimia macrocephala (a.n. Centaurea m.) G. ossica (a.n. Centaurea polyphylla) Leuzea longifolia L. rhapontica ssp. helenipholia L. rhaponticoides Psephellus carthalinicus Gr. 7 P. colchicus Gr. 1 P. daghestanicus Gr. 1 P. dealbatus Gr. 1 P. declinatus P. hypoleucus P. karabaghensis Gr. 1 Gr. 1 Gr. 1 P. leucophyllus P. nogmovii Gr. 1 Gr. 1 P. somcheticus Gr. 1 P. taochius Gr. 1 P. zangezuri Gr. 1 Rhaponticum pulchrum Gr. 3 R. serratuloides Gr. 3 Serratula strangulata Stemmamarca carthamoides Gr. 4 Unresolved classification Unresolved classification Unresolved classification S. rhapontica Tricholepis glaberrima Germacanes Gr. Gr. Gr. Gr. Gr. Gr. Gr. Gr. Gr. Gr. Gr. 7, Solstitiaria 1, Cheirolophus 7, Microlophus 1, Cheirolophus 6 Rhaponticum 7, Chartolepis 7 3 3 3 1 Guaianes, germacranes Amberboa lippii Gr. 2 19 Centaurea africana (a. n. Rhaponticoides a.) Gr. 1, Rhaponticoides 19 Elemanes Eudesmane Guaianes 147, 190, 278 162, 149, Other Collection place 148, 149, 162, 199, 208, 219, Turkey 190 160, 162 Turkey Egypt 264 Caucasus 200, 208, 219, 224, 275 160, 162, 277 149, 160, 162 162, 208, 219 270 162, 208, 219 162, 208, 209, 212, 219, 224, 238 160, 162, 169, 207, 208, 209, 212, 218, 219, 223, 224, 225, 229, 238, 241, 245, 246, 249, 254, 264 162, 264 162, 208, 209, 212, 219, 224, 229, 238, 264 149, 158, 162, 190 158, 159, 190, 191, 199 158, 160, 162, 190 149, 160, 162, 190, 193, 194 149, 157, 160, 162, 263, 264, 269 264 201, 202, 203, 204 162, 208, 219 162, 208, 219 161,162, 164, 208, 209, 212, 224 161,162, 164, 208, 209, 212, 224 161,162, 164, 208, 209, 212, 224 161,162, 164, 208, 209, 212, 224 161, 162, 164 161, 162, 164 161,162, 164, 208, 209, 212, 224 161, 162, 164 161,162, 164, 208, 209, 212, 224 161,162, 164, 208, 209, 212, 224 161, 164, 208, 209, 212, 224 161,162, 164, 208, 209, 212, 224 160, 162, 176, 207, 208, 219, 233, 240, 243 162, 176, 212, 224, 239, 246, 248, 257 224, 226 162, 176, 208, 219, 233 162, 208, 219 Qatar Sicily Canary Is?? Bulgaria Canary Is. S. Arabia Caucasus Caucasus, Turkey Caucasus Caucasus Canary Is. Spain Canary Is. Spain Russia Georgia Portugal Poland?? Poland?? Romania Germania France Italy Bielorussia Romania Armenia Romania ????? Hungary Hungary Belgium Biolorussia Kazakhstan China Poland?? ?? 162, 190 North India 264, 269, 275 162 Canary Is. Algeria Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 55 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx C. bella (a.n. Psephellus bellus) Gr. 1, Psephellus syn. 50 Sect. Hyalinella C. exarata C. incana Gr. 7,Acrolophus Gr. 7,Acrolophus 161, 173, 178, 209, 218, 229, 253 162 19 8 162, 174, 179, 212, 219, 233, 169, 175, 207, 213, 222, 243, Germany 172, 176, 208, 216, 224, 246, Spain Morocco Algeria 207, 208, 210, 212, 223, 238 C. scabiosa Gr. 7, Acrocentron, syn. Colymbada C. scoparia Gr. 7, 8 Pseudophaeopappus C. solstitialis Gr. 7, Solstitiaria Guaianes, eudesmanes Centaurea arguta (a.n. Cheirolophus teydis) C. canariensis var. subexpinnata (a.n. Cheirolophus canariensis var. subexpinnata) C. conifera (a.n. Leuzea conifera) 55 Rep Czeka Gr. 1 Cheirolophus Gr. 1, Cheirolophus 127, 129 128 Gr. 3, Leuzea 132 Gr. 7, Jacea 106 C. linifolia Gr. 7, Jacea 106 C. ornata 99, 120 Cheirolophus sempervirens Gr. 7, Acrocentron, syn. Colymbada Gr. 7, Jacea, sect. Lepteranthus Gr.1 Raponticum uniflorum Serratula latifolia Gr. 3 Gr. 4 Guaianes, germacrane, eudesmanes Centaurea acaulis 99, 100 101, 126, 128 134 121, 122, 124 C. tweediei (a.n. Plectocephalus tweediei) Cheirolophus x hortigenus 1 Gr. 7, Acrocentron, syn. Colymbada Gr. 1, Plectocephalu s 8, 63 Gr.1 7, 8 C. mauritanicus Gr.1 6 Gr. 1 Cheirolophus 12, 41 Gr. 7, Acrocentron, syn. Colymbada 4, 57 Guaianes, germacrane, elemanes Centaurea. arbutifolia (a.n. Cheirolophus arb.) C. salonitana C. tagananensis (a.n. Cheirolophus tagananensis) Guaianes, elemanes C. chilensis (a.n. Plectocephalus chilensis) Gr. 1, Cheirolophus 209, 162, 171, 208, 219, 231, 243 264 168, 197, 213, 224, 232, 169, 199, 217, 229, 235, 149, 181, 206, 210, 222, 229, 161, 182, 207, 212, 223, 162, 183, 208, 218, 224, 164, 190, 209, 219, 225, 160, 143, 160, 188, 162 145, 146, 149, 162, 184, 185, 189, 190 Siberia Egypt 32, 55 C. hyssopifolia C. uniflora ssp. nervosa 162, 149, 170, 206, 218, 230, 240, 8 69, 86 75, 84 Gr. 1, Plectocephalus Spain Sicily 210, 219, 240, 217, 224, Spain 162, 218, 246, 166, Spain 164, 224, 247 264, Spain 215 Italy 143, 147, 158, 162 160, 162, 224 280, 281, 282, 283 Portugal 287 China Iran 148, 150, 154 Algeria 105, 136 108, 126 268 143, 147, 149, 160, 162 149, 158, 162, 165, 190, 191, 192 Argentina Spain 158 Canary Is. 150, 152, 156, 158, 161, 164, 190, 200 Bulgaria, Serbia Greece, Turkey Turkey Canary Is. 149, 162 142, 143, 144, 149, 196 72, 73 Canary Is. Canary Is. 98, 99 123, 124, 125 78, 88 208, 209, 224, 225, 244(245) 162, 212, 227, 228 149, 160, 212, 217, 227, 228, 149, 162, 266 208, 213, Georgia Argentina France, Bulgaria Morocco Chile Chile Gr. = group; a.n. = accepted name. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 56 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Fig. 3. Clusters based on presence/absence of single sesquiterpene in the Psephellus. than miconazole (Panagouleas et al., 2003) and to inhibit mycelia growth of B. cinerea and Fusarium moniliforme (Adekenov et al., 1986a). Alantolactone (121) was examined for activity against 16 species of fungi. At 10 lg/mL, the lactone strongly inhibited the growth of M. cookei, T. mentagrophytes, and Trichothecium roseum (Picman, 1983b). At the MIC of 1–5 ppm, it significantly inhibited growth of four isolates of Fusarium graminearum and two of each of Verticillium albo-atrum and Leptosphaeria maculans (Picman and Schneider, 1993). Furthermore, it completely inhibited the growth of T. mentagrophytes, Microsporum canis, Paecilomyces liacinus and Rhizotonia at 30, 40, 70, and 80 lg/mL, respectively. Complete inhibition of spore germination of Fusariumwas recorded at 400 lg/mL (Wahab et al., 1981). The antifungal activity of costunolide (1) was assessed using the mycelial radial growth inhibition technique against six plant pathogenic fungi (A. alternata, Helminthosporium spp., Nigrospora spp., F. oxysporum, F. culmorium and Rhizocotonia solani). Costunolide showed the strongest antifungal activity against three fungi, Nigrospora spp., R. solani, and Helminthosporium spp. with EC50 values of 0.48, 2.92, and 2.96 lg/mL, respectively (Ahmed and Abdelgaleil, 2005). Dehydrocostus lactone (142), isolated from a dichloromethane extract of the Portuguese liverwort Targionia lorbeeriana, presented antifungal activity against Cladosporium cucumerinum and C. albicans(Neves et al., 1999). The antifungal sesquiterpene acid, isocostic acid (123), was isolated from Inula viscosa leaves, exhibited antifungal activity against six species of dermatophytes, but was devoid of antibacterial activity. The mouse oral LD50 values for it were 1 g/kg, with a favorable therapeutic index of 100 (Shtacher and Kashman, 1970). Phytochemical investigation of Vernonia arborea resulted in the isolation of zaluzanin D (148). It showed 100% inhibition in mycelia growth of R. solani, the effect being ca. 75% with Curvularia lunata and B. cinerea at 200-ppm concentration (Kunari et al., 2003). 4.2. Antiprotozoal Cynaropicrin (162), isolated from Moquinia kingii was evaluated in vitro against Trypanosoma cruzi trypomastigotes and the IC50 values for trypanocidal activity was 93.5 lg/mL (Schinor et al., 2004). Stizolin (27), alantolactone (121), cynaropicrin (162), repin (209), acroptilin (212) and centaurepensin (224) showed strong protozoacidal activity in vitro (active at 0.24–7.8 lg/mL) against Entamoeba histolytica and Trichomonas vaginalis. The presence of an exocyclic methylene ring conjugated with the lactone carbonyl, the presence of an acetyl group on the ring, or oxidation of a hydroxyl group to a keto group generally increased the protozoacidal activity of the sesquiterpenes (Rubinchik et al., 1976). The AcOEt extract of the bark of Michelia alba D.C. (Magnoliaceae) exhibited killing activity against T. cruzi. A bioassay-guided purification afforded several trypanocidal constituents, among which costunolide (1) and santamarine (99). The minimum lethal concentrations of these compounds against epimastigotes of T. cruzi were 7 lM and 25 lM, respectively (Asaruddin et al., 2003). Also dehydrocostus lactone (142) and zaluzanin D (148) showed lethal activity against epimastigotes of T. cruzi at concentrations of 6.3 and 2.5 lM, respectively (Uchiyama et al., 2002). Costunolide (1), b-cyclocostunolide (98) and dehydrocostus lactone (142) showed significant antitrypanosomal activity against T. brucei with EC50 of 0.066, 0.18 and 0.21 lg/mL, respectively, several-fold more potent than the antitrypanosomal drugs eflornithine and suramin (Otoguro et al., 2011). The essential oil of Echinops kebericho, containing as major constituent dehydrocostus lactone (142), exerted strong antileishmanial activity activity against two Leishmania Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx 57 Fig. 4. Clusters of Acrolophus based on presence/absence of single sesquiterpene. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 58 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Fig. 5. Clusters based on presence/absence of structurally similar sesquiterpenes part A. strains ( Leishmania aethiopica and Leishmania donovani) that was even higher than that of amphotericin B (Tariku et al., 2011). Costunolide (1), isolated from the essential oils from heartwood and sapwood of Eremanthus elaeagnus, Vanillosmopsis erythropappa and Moquinea velutina was effective against infestation by Schisto- Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx 59 Fig. 6. Clusters based on presence/absence of structurally similar sesquiterpenes part B. soma mansoni when topically applied to the skin (Baker et al., 1973). In the course of searching for antiprotozoal agents from terrestrial plants, costunolide (1) was isolated from Magnolia sororum using bioassay-guided fractionation methods. It exhibited activity (IC50 = 9.4 lM) in vitro against the Leishmania mexicana parasite but not against T. cruzi and Monkey vero (Sanchez et al., 2007). Cnicin (19), reynosin (100), alantolactone (121), ivalin (122) and carabrone (287) were tested in vitroagainst four major protozoan pathogens, T. brucei rhodesiense, T. cruzi, L. donovani as well as Plasmodium falciparum. Cnicin displayed high anti-parasitic activity against T. brucei rhodesiense (IC50 = 1.3 lM), while alantolactone was moderately active against all the four pathogens (Schmidt et al., 2009). Extracts from C. scabiosa L. aerial parts revealed evident antiopisthorchiasis activity. The most effective was the extract contained greater amount of SLs (cynaropicrin (162), repin (209) and grosheimin (264) than other extracts (Kaminskii et al., 2010a,b). 12-Carboxy-3,11(13)-eudesmadiene (123), isolated from the above-ground portions of I. viscosa, showed anthelmintic activity against Hymenolepis nana var. fraterna and Syphacia obvelata in vitro. However, its activity against these parasites in mice was poor, due to considerable absorption in the digestive tract before reaching the intestinal site of parasitization (Azoulay et al., 1986). 4.3. Anti-inflammatory SLs are known to possess a considerable anti-inflammatory activity in different inflammation models. They inhibit the transcription factor NF-jB, involved in the synthesis of inflammatory mediators, such as cytokines and chemokines, probably by alkylating cysteine in the DNA binding domain of the p65 subunit. Cynaropicrin (162), santamarine (99) and reynosin (100) showed potent dose-dependent inhibitory effect on the production of tumor necrosis factor-a (TNF-a) with an IC50 of TNF-a production were 2.86 lg/mL (8.24 lM), 26.2 lg/mL (105 lM), and 21.7 lg/mL (87.4 lM), respectively. In the case of cynaropicrin (162) the result was better than dbcAMP and prednisolone used as controls. Treatment with sulfydryl (SH) compounds such as L-cysteine, dithiothreitol, and 2-mercaptoethanol abrogated the inhibitory effect of cynaropicrin on TNF-a production showing that Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 60 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx the bioactive moiety is the unsaturated lactone (Cho et al., 2000, 1998). Cynaropicrin (162), aguerin B (160) and grosheimin (264) showed a remarkable inhibitory effect on inducible nitric oxide synthase with IC50 values in the range 1.5–9.5 lg/mL (Blunder et al., 2008). Cynaropicrin (162) displayed immunomodulatory effects on the production of cytokine and nitric oxide from macrophages/monocytes. It has been demonstrated that cynaropicrin may be a potent functional regulator of CD29 and CD98 via interrupting extracellular signal-regulated kinase (ERK) activation which may be linked to cytoskeleton rearrangement, suggesting further application to CD29- and CD98-mediated diseases such as virus-induced chronic inflammation, and invasion, migration, and metastasis of leukocyte (Cho et al., 2004a). An investigation on a set of 103 different SLs representing six structural groups (44 germacranolides, 16 heliangolides, 22 guaianolides, 9 pseudoguaianolides, 2 hypocretenolides, 10 eudesmanolides) for their NF-jB inhibiting properties was carried out and the resulting IC100-values were submitted to a QSAR study. These studies indicated that the SLs more active possessed a rigid skeleton (furanoheliangolides and guaianolides), whereas in the case of flexible skeletons (germacranolides, such as germacrolides and melampolides), inhibition might be mostly determined by the number and type of a, b-unsaturated carbonyl structural elements (Siedle et al., 2004). A review on the roles of NF-jB in inflammation, photoaging, and other diseases, on the inhibition of NF-jB by artichoke extract, the identification of cynaropicrin (162) as an active ingredient of artichoke extract and the prevention of pigmentation and photoaging, and decrease of open pores of the skin by lotions containing artichoke extracts in humans has been reported (Banno, 2011). Investigation of Podachaenium eminens afforded several SLs from which costunolide (1) and santamarin (99) are new for this plant. The isolated compounds were studied for their anti-inflammatory activity using NF-jB as a molecular target. NF-jB is involved in the synthesis of inflammatory mediators, such as cytokines and chemokines. The compounds completely inhibited NF-jB DNA binding in an electrophoretic mobility shift assay at concentrations of 50 and 200 lM, respectively, without showing any cytotoxic effects (Castro et al., 2000). Nitric oxide (NO), derived from L-arginine, is produced by two types (constitutive and inducible) of nitric oxide synthase (NOS: cNOS and iNOS). The NO produced in large amount by the iNOS is known to be responsible for inflammation, the vasodilation, and hypotension observed in septic shock, and cancer metastasis. Inhibitors of the overproduction of NO may thus be useful candidates for the treatment of inflammatory diseases. Dehydrocostuslactone (142) showed significant inhibitory activities on the production of NO and release of TNF-a with IC50 values lower than 1 lM (Zhao et al., 2008). Costunolide (1), santamarine (99), reynosin (100), dehydrocostus lactone (142) and zaluzanin C (147) were found to inhibit NO production in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages (IC50 = 1.2–3.8 lM). Furthermore, costunolide and dehydrocostus lactone inhibited iNOS in accordance with induction of heat shock protein 72 (HSP 72) (Matsuda et al., 2000a, 2003; De Marino et al., 2005). Costunolide (1), isolated from Magnolia grandiflora, was found to inhibit NO production by down-regulating iNOS expression, at least, in part through the inhibition of IjBs0 phosphorylation and degradation, which are essential for the activation of NF-jB (Koo et al., 2001). Furthermore, costunolide (1) showed an ability to inhibit expression of multiple neuroinflammatory mediators of NFjB and MAPK activation. Further investigation of this novel role of costunolide may aid in developing better therapeutic strategies for treatment of neuroinflammatory diseases (Rayan et al., 2011). The antipyretic and anti-inflammatory effects of costunolide (1) were investigated. The oral administration of costunolide inhibited carrageenan (Cg)-induced paw edema (ID50 0.18 (0.12–0.27) mg/ kg) and was effective in abolishing lipopolysaccharide (LPS)-induced fever (0.15 mg/kg) (Kassuya et al., 2009). It was shown that the suppression of NO production by dehydrocostus lactone (142) is mediated by the inhibitory action on the i-NOS gene expression through the inactivation of NF-jB and this sesquiterpene lactone can act as a pharmacological inhibitor of the NF-jB activation (3.0 lM better than pyrrolidine dithiocarbamate used as control) (Jin et al., 2000). In order to elucidate the mechanism for the anti-inflammatory activity of santamarin (99), its ability to interfere with the activation of the transcription factor NF-jB was studied. Santamarin (99) showed a moderate inhibitory activity (Lyss et al., 2000). Alantolactone (121), isolated from the roots of Inula racemosa (Asteraceae), was screened for its inflammatory activity against carrageenan induced paw edema and hepatoprotective activity in vitro against galactosamine and thioacetamide and in vivo against carbon tetrachloride, paracetamol and rifampicin induced hepatotoxicities in albino rats. It showed significant anti-inflammatory and hepatoprotective activities similar to that of silymarin (Kurma and Mishra, 1997). Cynaropicrin (162) and 13-acetyl solstitialin A (183), both present in the aerial parts of the yellow star thistle (C. solstitialis) have toxic potential in cell cultures of substantia nigra of the rat. The specificity of action towards cells of the substantia nigra remains to be proved, and a toxic action in the midbrain may contribute to the nigro-pallidal encephalomalacia, caused by the ingestion of the yellow star thistle by horses (Wang et al., 1991;Cheng et al., 1992). The mixture of elemanolides 72 and 73 from C. chilensis showed anti-inflammatory activity when tested against carrageenan-induced edema in the guinea pig hindpaw (Negrete et al., 1993) and desacylcynaropicrin (149) isolated from the aerial parts of Cyclolepis genistoides produced a significant inhibition of carrageenan-induced inflammation at doses of 75 and 100 mg/kg, respectively (Sosa et al., 2011). Cnicin (19) showed an anti-inflammatory activity in the rat paw edema screen which was nearly equivalent to that of indomethacin (Schneider and Lachner, 1987). Compounds 196 and 199 were evaluated for their inhibitory effects against cyclooxygenases-1 and 2 in vitro. Compound 199showed moderate COX-1-inhibiting activity with IC50 value of 78.8 lM, comparable to that of representative anti-inflammatory drug aspirin with an IC50 value of 77.2 lM. Both compounds displayed potent COX-2 inhibitory activities with IC50 values of 28.7 and 57.9 lM, respectively, in comparison with that of aspirin with an IC50 value of 87.6 lM (Wang et al., 2009). 4.4. Antitumor and cytotoxic Several guianolides have been the object of many antitumor and cytotoxic studies. For example, cynaropicrin (162) has been shown to have cytotoxic effect against several types of cell lines such as macrophages, eosinophils, fibroblasts and lymphocytes. Cynaropicrin potently inhibited the proliferation of leukocyte cancer cell lines, such as U937, Eol-1 and Jurkat T cells, but some other cells such as Chang liver cells and human fibroblast cell lines were not strongly suppressed by cynaropicrin treatment. The cytotoxic effect of cynaropicrin was due to inducing apoptosis and cell cycle arrest at G1/S phase, according to flow-cytometric, DNA fragmentation and morphological analyses using U937 cells (Cho et al., 2004b). The same compound (162) along with desacylcynaropicrin (149) and aguerin B (160) a were evaluated in vitro for cytotoxic activity against human cancer cell lines, comprising SK-OV-3, Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx LOX-IMVI, A549, MCF-7, PC-3 and HCT-15 by the sulforhodamine B (SRB) assay method. Compounds 160 and cynaropicrin (162) showed the most potent cytotoxic activity against MCF-7 (IC50: 1.1 lg/mL) and HCT-15 cells (IC50: 0.9 lg/mL and 1.4 lg/mL, respectively), whereas compound 149 showed a moderate activity (IC50: 17.1 lg/mL) only against the HCT-15 cell line (Ha et al., 2003). The biological investigation on the anti-proliferative activity of aguerin B (160) and the nor-guaianolide 284 was carried out against human pancreatic and colon cancer cells. Of the two compounds, only aguerin B (160) was shown to induce apoptotic cell death, confirming the role as pro-apoptotic moiety of the a-methylene-c-lactone ring present in 160 but not in 284 (Chicca et al., 2011). Desacylcynaropicrin (149), cynaropicrin (162), chlorojanerin (219), chlorohyssopifolin A (224) and chlorohyssopifolin E (227) have been tested for cytotoxic activities against human cervix epitheloid carcinoma cell lines (HeLa) and human hepatoma cell lines (SMMC-7721). The best activity was found for compound 162 with IC50 of 13.0 and 8.7 lg/mL, respectively (Ren et al., 2007). The cytotoxicity of some of the above compounds (149, 160, 162) along with 169 and 190 was tested by SRB bioassay method against five cultured human tumor cells (A549, SK-OV-3, SKMEL-2, XF-498, HCT-15). 160 and 162 showed non-specific significant cytotoxicity against these human tumor cell lines (160: 0.23– 1.72 lg/mL and 162: 0.29–1.37 lg/mL) comparable and sometimes better than etoposide and doxorubicin used as comparison drugs (Choi et al., 2005). Cytotoxic studies with VERO cell cultures treated with deacylcynaropicrin (149), cynaropicrin (162), and grossheimin (264) indicated that the IC50 values for the last two compounds were 5.5 and 4.2 lg/L, respectively (Piacentini et al., 1986, 1987). Compounds 149 and 162 showed very potent cytotoxic activity against tumor cell line P388 (murine leukemia), more than the natural anticancer agent pseudolaric acid B used as positive control, at the IC50 levels of 0.36 and 0.01 lM, respectively (Zha and Hou, 2008). They were also tested against human cancer cell lines of malignant melanoma (SK-MEL), epidermoid (KB), ductal (BT-549) and ovarian (SK-OV-3) carcinomas for cynaropicrin (162), janerin (208) and chlorojanerin (219), showing in vitro cytotoxic activity with IC50 values of 2–6 lg/mL (Muhammad et al., 2003). Grosshemin (264) and the germacranolide cnicin (19) had cytostatic action on HeLa cells with ID50 of 2.5 lg/mL and 0.1 lg/mL, respectively. Dihydroestafiatone (270), on the other hand, showed poor cytostatic action (Gonzalez et al., 1978a). Compounds 224, 217, 212, 228, 227, 162, and 149 were also tested for cytostatic action on HeLa cells: the first four exhibited an ID50 in the range 0.25–0.5 lg/mL (Gonzalez et al., 1980b). Furthermore, grosshemin (264) inhibited the growth of malignant HeLa cultures. The effect of the compound on an in vitro lymphocyte culture showed that it inhibited cell division at the metaphase stage (Bialecki et al., 1973). Grosshemin (264) also inhibited sarcoma 180, Pliss’s lymphosarcoma and Ehrlich solid tumor (Adekenov et al., 1986b). The cytotoxic activity of the guaianolides 208, 209, 211, 212, 224, 244 and 246 against tumor cell replication (A549, MCF-7, 1A9, KB, KB-V, HCT-8, SK-MEL-2) was reported. Repin (209), chlorohyssopifolin C (212) and chlorohyssopifolin A (224) showed significant antitumor potency (Bruno et al., 2005c). Repin (209) showed also significant activity toward chick embryo sensory neurons and a causal relationship between repin and the necrosis of the neural cells in substantia nigra of horses leading to equine nigrostriatal encephalomalacia (ENE) disease has been suggested (Stevens et al., 1990). To understand the mechanism whereby ingestion of Centaurea repens induces ENE and a Parkinson’s disease (PD)-like disorder, repin cytotoxicity was examined. Repin was found to be highly cytotoxic to both Pc12 cells and mouse 61 astrocytes in a dose- and time-dependent way. The cytotoxic effects were accompanied by depletion of glutathione, a rise in the level of reactive oxygen species and damage to cellular membranes (Robles et al., 1997). Both A- an B-ring modifications of the electrophilic exocyclic methylene group and the epoxy-ester moiety were performed, further demonstrating the importance of these functional group contributions to toxicity (Anand et al., 2003; Tukov et al., 2004). Zaluzanin C (147) showed a significant cytotoxicity against several tumor cell lines A549, SK-OV-3, SK-MEL-2, XF498, HCT15 (Choi et al., 2006), GTB, HL60 (Zidorn et al., 2004) and P-388 lymphocytic leukemia (Jolad et al., 1974), a moderate cytotoxicity against three tumor cell lines (HepG2, HeLa, OVACAR-3) (Sun et al., 2003), and revealed relatively high cytotoxicities on human colon carcinoma cell lines and lung adenocarcinoma cell lines (Ahn et al., 2006). Furthermore, it showed significant cell growth inhibitory activity against murine lymphocytic leukemia (P388) in vitro (Ando et al., 1982), and a capacity to inhibit protein synthesis in intact HeLa cells preferentially to DNA and RNA synthesis. On the other hand dihydroestafiatone (270) showed poor cytostatic action on HeLa cells (Gonzalez et al., 1978a). Zaluzanin C (147) inhibits the proliferation of T and B lymphocytes of mice in vitroexhibiting cytotoxicity at concentration of 10 lM or lower (Chen et al., 2006). Compounds 142, 147 and 190 isolated from Ainsliaea macrocephala were tested for inhibitory activity against the production of nitric oxide in RAW 264.7 cells stimulated by LPS, as well as for cytotoxicity against RAW 264.7 macrophages. Zaluzanin C (147) strongly inhibited the production of nitric oxide with an IC50 value of 2.5 lM, and simultaneously showed low cytotoxicity against RAW 264.7 macrophages. The other two compounds had moderate activity (Wu et al., 2011). The molecular mechanism underlying the suppression of lipopolysaccharide (LPS)/interferon-c (IFN-c)-induced nitric oxide (NO) and prostaglandin (PGE2) production was investigated in RAW 264.7 macrophages treated with sesquiterpene lactone, zaluzanin-C (147). It decreased NO production in LPS/IFN-c-stimulated RAW 264.7 macrophages with an IC50 of about 6.6 lM and 3.8 lM, respectively. In addition, these compounds inhibited the synthesis of PGE2 in LPS/IFN-c-treated RAW 264.7 macrophages. Furthermore, treatment with zaluzanin C (147) resulted in a decrease in inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and mRNA expression levels (Shin et al., 2005). Salograviolide A (156) was found reduced the growth of colon cancer cell lines (El-Najjar et al., 2008) and to exert significant growth inhibitory effects on neoplastic cells. At concentrations that were not cytotoxic to primary keratinocytes, it preferentially inhibited the proliferation of papilloma and squamous cell carcinoma (SCC) cell lines without significantly affecting the growth of normal cells (Ghantous et al., 2008). Furthermore it was shown to reverse the effects observed by interleukin-I on cyclooxygenase-2 levels in NF-kB translocation in intestinal epithelial cells. It reduces the level of inflammatory cytokines and the level of inflammation in the animal model (Al-Saghir et al., 2009). Also several sesquiterpenoids with a different skeleton rather than guaiane have been studied for their cytotoxic and antitumor activities. Cnicin (19) showed cytotoxic activity against KB with ED50 = 3.4 lg/mL (Vanhaelen-Fastre, 1972), against TXL-5 mice lymphoma cells with ID50 = 6 lg/mL (El-Marsy et al., 1984) and showed moderate antiproliferative effects against HeLa, and A431 human tumor cell lines (Csapi et al., 2010). The cytotoxic activities of some cnicin (19) and salonitenolide (4) derivatives were determined against A549 and MCF-7 tumor cell lines. Cnicin was selectively cytotoxic against the MCF-7 breast cancer cell line with IC50 = 4.2 lM (Rosselli et al., 2010). Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 62 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx The cytotoxic activities of chloroform extracts from the weeds C. tweediei and C. diffusa, and the main SLs isolated from these species, onopordopicrin (8) and cnicin (19), respectively, were assayed. Both the extracts and the purified SLs show high cytotoxicity against human-derived macrophages (Bach et al., 2011). Onopordopicrin (8) also showed cytotoxic activity against KB cell line (Lonergan et al., 1992). The in vitro cytotoxic activity of germacranes 4, 5, 8, 19, 20 and elemanes 69, 75 was investigated against P388, A549 (human non small lung cancer) and HT29 (human colon cancer). As expected for compounds with an a-methylene-c-lactone group, they have cytotoxic activity with IC50 values ranging from 2 to 10 lg/mL. The additional a, b-unsaturated ester group present in 8, 19, 20 and 75 increases the activity two or three times (Barrero et al., 1995). Also germacranes 19, 20, elemanes 75, 80, 94, and eudesmanes 103, 104, 111, 112 were examined for their in vitro cytotoxic/cytostatic activity against five human cell lines (i.e. DLD1, SF268, MCF7, H460, OVCAR3). Compounds 75 and 80 were found to be the most active and exhibited a considerable growth-inhibiting activity against most of the cell lines tested (Koukoulitsa et al., 2002). Cnicin (19), salitenolide (4) and the elemanes 66, 70, 80, 83 were tested against nine cancer cell lines. 19 was active against 1A9, KB and KB-VIN. 83 showed good activity for all the lines except A549, and 66 and 70 were shown to be the best with IC50 < 1 lM (Bruno et al., 2005b). Cnicin (19) showed inhibition of NF-jB and inhibition of iNOS activity with IC50 values of 1.8 and 6.5 lM, respectively. Cytotoxic activity of cnicin (19) was observed toward pig epithelial (LLC-PK11), human malignant melanoma (SK-MEL) and human ductal carcinoma (BT-549) (Baykan Erel et al., 2011). It has been suggested that deregulation of activin signaling contributes to tumor formation. Data suggested that alantolactone (121) induced activin/SMAD3 signaling in human colon adenocarcinoma HCT-8 cells and that it performs its antitumor effect by interrupting the interaction between Cripto-1 and the activin receptor type IIA in the activin signaling pathway (Shi et al., 2011). Furthermore, it showed antiproliferative activities against MK-1, HeLa, and B16F10 cell lines with GI50 in the range 4.7– 6.9 lM (Konishi et al., 2002). Alantolactone (121) was also identified from the roots of Inula helenium L. and its inhibitory effects on human non-small cell lung cancer (NSCLC) A549 cells was examinated. The antiproliferative effect of alantolactone on A549 cells was investigated via MTT [30 -(4,5dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay and its apoptosis-inducing effect was determined by Hoechst staining and flow cytometry. Alantolactone was found to significantly inhibit the proliferation of A549 cells and to induce morphological changes typical for apoptosis (Zong et al., 2011). 9-a-Hydroxyparthenolide (28), isolated from Anvillea garcini, has shown activity in both the 9 KB cell culture and P388 mouse leukemia test systems (Tyson et al., 1981). Compound 28 was evaluated by an in vitro disease-oriented antitumor screen, which determinates cytotoxic effects against a panel of approximately 60 human tumor cell lines. The best results were obtained for NCI-H522 (non-small cell lung) and CCRF-CEM (leukemia) with ED50 of 0.5 lg/mL and 0.84 lg/mL, respectively (Sattar et al., 1996). Other authors tested the same compound against five other human cancer lines showing an IC50 of 2 lg/mL for A549, H116 and PSN1 (El Hassany et al., 2004). The in vitro cytotoxic activities of 8a-(40 acetoxy-angeloyl)-salonitenolide (18) and malacitanolide (109) were assayed towards P388 and Schabel mouse lymphomas and toward the A549 (lung carcinoma), HT-29 (colon carcinoma) and MEL-28 (melanoma) human cell lines. Compound 18 showed an IC50 = 2.5 lg/mL against both mouse lymphomas and an IC50 = 5 lg/mL towards the three human cell lines whereas 109 showed an IC50 = 0.12 lg/mL in all cases (Barrero et al., 1997a). Stizolicin (32), solstitialin A (181) and xanthinin (288) demonstrated a limited antitumor action in vivo on two types of tumor: L-1210 leukemia and P388 leukemia (Naidenova et al., 1988). A moderate cytotoxic activity of compound 83 was also shown against SF268 and OVCAR3 tumor cell lines (Saroglou et al., 2005). Compounds 9 and 13 were shown to have a good cytotoxic activity against colon cancer cell line CaCo-2 with IC50 values of 8.5 and 26.4 lM, respectively (Shoeb et al., 2007a). Ivalin (122) showed cytotoxic activity (ED50 < 10 lM) against A549, SK-OV-3, SK-MEL-2 XF-498 and HCT-15 tumor cell lines comparable to that of cisplatin. Carabrone (287) was less active (Lee et al., 2002). A very good cytotoxic activity was observed for ivalin (122) against P388, KB-3 and KB-V1 with ED50 in the range 0.14–1.8 lg/mL (Topçu et al., 1993). A large number of papers have been published on the biological properties of costunolide (1) and dehydrocostuslactone (142). Costunolide (1), isolated from the root of Saussurea lappa, was investigated for its effects of on the induction of apoptosis in HL60 human leukemia cells (Kim et al., 2010) and its putative pathways of action. Using apoptosis analysis, measurement of reactive oxygen species (ROS), and assessment of mitochondrial membrane potentials, it was shown that costunolide is a potent inducer of apoptosis, and facilitates its activity via ROS generation, thereby inducing mitochondrial permeability transition (MPT) and cytochrome c release to the cytosol. ROS production, mitochondrial alteration, and subsequent apoptotic cell death in costunolidetreated cells were blocked by the antioxidant N-acetylcysteine (NAC) (Lee et al., 2001). Furthermore costunolide (1) was found to induce apoptotic cell death in a dose-dependent manner by nucleosomal DNA ladder and flow cytometric analysis. Immunoblot analysis showed that the level of the anti-apoptotic protein, Bcl-2, was decreased, whereas the cleavage of poly-(ADP-ribose) polymerase was activated. Furthermore, the N-acetyl-L-cysteine antioxidant effectively prevented costunolide-induced cytotoxicity. These results suggested that costunolide-induced cell death is mediated by reactive oxygen species (Park HJ et al., 2001). Other results indicate that costunolide-induced c-Jun N-terminal kinase (JNK) activation acts downstream of ROS but upstream of Bcl-2, and suggest that ROS-mediated JNK activation plays a key role in costunolide-induced apoptosis. Moreover, the administration of costunolide (i.p. once a day for 7 d) significantly suppressed tumor growth and increased survival in 3LLLewis lung carcinoma-bearing model (Choi and Lee, 2009). Costunolide (1), isolated from the stem bark of Magnolia sieboldii, demonstrated a significant inhibition upon the farnesylation process of human lamin-B by farnesyl-proteintransferase (FPTase), in a dose dependent manner in vitro (IC50 value was calculated as 20 lM). It was also found to exhibit an inhibition upon the proliferation of human tumor cell cultures, i.e., A549 (non small cell lung), SK-OV-3 (ovary), SK-MEL-2 (melanoma), XF498 (central nerve system) and HCT-15 (colon), in vitro (Park SH et al., 2001). Costunolide (1) also inhibits the killing activity of cytotoxic T lymphocytes through preventing the increase in tyrosine phosphorylation in response to the crosslinking of T-cell receptors (Taniguchi et al., 1995). Costunolide (1) demonstrated inhibitory effect on the protein and mRNA expression of interleukin-1 b (IL-1 b) in LPS-stimulated RAW 264.7 cells. Costunolide was also shown to suppress the transcriptional activity of the IL-1 b promoter. Moreover, costunolide inhibited the activity of AP-1 transcription factor, and the phosphorylation of MAPKs, including SAPK/JNK and p38 MAP kinase. The inhibitory effect of costunolide on AP-1 activity was also confirmed by an electrophoretic mobility shift assay. These results demonstrated that costunolide inhibits IL-1 b gene expression by Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx blocking the activation of MAPKs and DNA binding of AP-1 in LPSstimulated RAW 264.7 cells (Kang et al., 2004). It has been also suggested that costunolide (1) induces apoptosis in human promonocytic leukemia U937 cells by depleting the intracellular thiols. Costunolide treatment rapidly depleted the intracellular reduced glutathione (GSH) and protein thiols, and this preceded the occurrence of apoptosis. Pretreatment with sulfhydryl compounds such as GSH, N-acetyl-L-cysteine, dithiothreitol and 2-mercaptoethanol almost completely blocked the costunolide-induced apoptosis, highlighting the significance of the intracellular thiol level in the process. Furthermore, overexpression of Bcl-2 also significantly attenuated the effects of costunolide. The apoptosis-inducing activity of costunolide is likely to depend on the exomethylene moiety because derivatives, in which this group was reduced, such as dihydrocostunolide and saussurea lactone, did not deplete the cellular thiols and showed no apoptotic activity. In this study it has been demonstrated that the costunolide-induced apoptosis depends on intracellular thiols contents, which are modulated by Bcl-2 (Choi et al., 2002a). Other studies were carried out on the induction mechanism of apoptosis by costunolide in a human B cell leukemia NALM-6 cell culture system and the data suggested that one of the costunolide-induced apoptotic mechanisms is that the receptor-mediated pathway precedes the mitochondria-dependent pathway, caused by the inhibition of telomerase activity via suppression of telomerase reverse transcriptase (hTERT) in NALM-6 cells (Kanno et al., 2008). Also, in the case of MCF-7 and MDA-MB-231 cells, their growth inhibition seem to be mediated at least in part by a significant reduction in telomerase activity (Choi et al., 2005). In the cell adhesion inhibitory activity test against B16-F1 mouse melanoma cell, costunolide (1) showed significant activities, with IC50 of 0.9 lg/mL. In the cytotoxicity test against several human tumor cells, costunolide had an IC50 values of below 0.3 lg/ mL against all the tested cell lines except for UACC62. It exhibited a stronger activity against HCT15 and UO-31 cell lines than a positive control, adriamycin (Jang et al., 1998b). Costunolide (1) showed effective antiproliferative activity against hormone dependent (LNCaP) and independent (PC-3 and DU-145) prostate cancer cells (ATCC) by SRB assay, clonogenic test and flow cytometric analalysis of carboxyfluorescein succinimidyl ester labeling. In PC-3 cells, data showed that costunolide induced a rapid overload of nuclear Ca2+, DNA damage response and ATR phosphorylation (Hsu et al., 2011). It also had cytotoxic properties against MCF-7, NCI-H460, and SF-268 cancer cell lines in vitro (Chang et al., 2010), P-388, L-1210 leukemia and SNU-5 stomach cancer cells (Kim et al., 1999) and against human A549, SK-OV-3, SK-MEL-2, and HCT15 tumor cells (Park et al., 2010). Costunolide (1) and the guainolide zaluzanin D (147) displayed strong growth inhibitory effect against human promyelotic leukemia HL-60 cells by induction of chromatin condensation in the HL-60 cells (Hibasami et al., 2003). Costunolide (1) has been reported to exhibit potent chemopreventive effects on carcinogenesis. Modifying effects of costunolide on intestinal carcinogenesis were examined in a rat model using azoxymethane (AOM). The results suggest that the natural sesquiterpene could be a promising chemopreventive agent for human intestinal neoplasia (Mori et al., 1994). Effects of costunolide on cellular activation induced by a tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) were investigated: iNOS promoter-dependent reporter gene activity was significantly increased by TPA, and the TPA-induced increase of the reporter gene activity was efficiently reduced by costunolide, with an IC50 of approximatively 2 lM (Fukuda et al., 2001). It was found that costunolide (1) selectively inhibits angiogenic factors including basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF)-induced endothelial cells prolif- 63 eration and migration. From these results, it has been suggested that costunolide would inhibit angiogenesis by blockade of angiogenic factors signaling pathway (Jeong et al., 2001, 2002). Costunolide (1) could reduce the viability and arrest cell cycling at mitosis in hepatoma cells. Logical exploration of this mitosisarresting activity for cancer therapeutics shows costunolide enhanced the killing effect of radiotherapy against human hepatocellular carcinoma (HCC) cells (Liu et al., 2011). Investigations on the effect of costunolide (1) on cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system were carried out. Costunolide markedly increased the degree of HL-60 leukemia cell differentiation when simultaneously combined with 5 nM 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). The results indicate that PKC, PI3-K, ERK and NF-jB may be involved in 1,25-(OH)2D3-mediated cell differentiation enhanced by costunolide (Choi et al., 2002b; Kim et al., 2002). Investigations of the anticancer effect of dehydrocostus lactone (142) on human breast cancer cells (MCF7) (Kuo et al., 2009), human ovarian cancer cells (SK-OV-3) (Choi and Ahn, 2009), human prostate cancer cells (DU145) (Kim et al., 2008), human non-small cell lung cancer cell lines (A549, NCI-H460 and NCI-H520) (Hung et al., 2010), HeLa, T-98, HLE and HMV-1 cells (Chen et al., 2011) and HepG2 and PLC/PRF/5 cells (hepatocellular carcinoma) (Hsu YL et al., 2009) were carried out. Compound 142 was shown to inhibit cell proliferation by inducing cells to undergo cell cycle arrest and apoptosis. Dehydrocostus lactone (142) inhibited the proliferation of human lung cancer A549 cells in a time- and dose-dependent manner. The cytometric analysis showed that the A549 cells were arrested at the sub-G1 phase by the treatment of dehydrocostus lactone. The evidence of the activation of caspase-9 and -3 verified that the death of A549 cells was through the apoptosis pathway. Dehydrocostus lactone also exhibited strong cytotoxicity on MDA-MB-231 (breast cancer) and HepG2 (hepatoma) cells (Hsu HF et al., 2009). Dehydrocostus lactone (142), isolated from the medicinal plant, Saussurea lappa, inhibited the production of NO in lipopolysaccharide (LPS)-activated RAW 264.7 cells by suppressing inducible NO synthase enzyme expression (Lee et al., 1999). The anti-proliferative activity of dehydrocostus lactone (142) was investigated in human breast cancer (MDA-MB-231, MDAMB-453 and SK-BR-3) and ovarian cancer (SK-OV-3 and OVCAR3) cell lines using the MTT assay. In the cells, exposure to dehydrocostus lactone resulted in a dose-dependent decline in cell proliferation. The IC50 value was found to be 21.5, 43.2, 25.6, 15.9 and 10.8 lM in MDA-MB-231, MDA-MB-453, SK-BR-3, SK-OV-3 and OVCAR3 cells, respectively. Dehydrocostus lactone exerted its antiproliferative effects by inducing cell cycle arrest and apoptosis. Cell cycle distribution and apoptosis were analyzed using flow cytometry in cell lines exposed to 10 lM dehydrocostus lactone for 48 h (Choi and Kim, 2010). It was demonstrated that dehydrocostus lactone (142), the major sesquiterpene lactone isolated from the roots of Saussurea lappa, inhibits NF-jB activation by preventing TNF-a-induced degradation and phosphorylation of its inhibitory protein I-jBa in human leukemia HL-60 cells and that 142 renders HL-60 cells susceptible to TNF-a-induced apoptosis by enhancing caspase-8 and caspase-3 activities (Oh et al., 2004). Costunolide (1) and dehydrocostus lactone (142) both showed strong suppressive effect on the expression of the hepatitis B surface antigen (HBsAg) in human hepatoma Hep3B cells, but had little effect on the viability of the cells. Both costunolide and dehydrocostus lactone suppressed the HBsAg production by Hep3B cells in a dose-dependent manner with IC50 of 1.0 and 2.0 lM, respectively (Chen et al., 1995). Dehydrocostus lactone (142) and costunolide (1) exhibited potent dose- and time-dependent cytotoxicity with CD50 values in Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 64 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx the range 1.6–3.5 lg/mL against HepG2, OVCAR-3 and HeLa human cancer cell lines whereas zaluzanin C (147), santamarin (99) and reynosin (100) which are less lipophilic due to the presence of an hydroxyl group, showed lower cytotoxicity (Sun et al., 2003). Costunolide (1), santamarine (99), reynosin (100) obtained through bioactivity-directed isolation from a methanol extract of the fruits of Laurus nobilis were found to be highly cytotoxic against the A2780 ovarian cancer cell line (Barla et al., 2007). Furthermore, cytotoxicity testing of the sesquiterpene lactone reynosin (100) against the KB cancer cell line (ATCC CCL17) revealed IC50 values of 2.7 lg/mL (Hilmi et al., 2003). Dehydrocostus lactone (142), santamarine (99) and b-cyclocostunolide (98) showed effects on inhibited proliferation of human stomach cancer cells MGC-803, human pharyngeal cancer cells KB, human lung cancer cells NCI-H460, and human colon cancer cells HT-29 cultured for 72 h (IC50 < 10.0 mg/mL), and had weak effect on inhibiting proliferation of human liver cancer cells HepG-2 cultured for 72 h (IC50 = 16.3, 48.7, and 16.1 mg/mL, respectively) (Tang et al., 2010). Cyathocline purpurea has been traditionally used to treat various diseases including cancers for many years and santamarine (99), one of its main constituents, inhibited the growth of L1210 murine leukemia, CCRF-CEM human leukemia, KB human nasopharyngeal carcinoma, LS174T human colon adenocarcinoma and MCF 7 human breast adenocarcinoma cells in vitro, with IC50 in the range of 0.16–1.3 lg/mL. In the L1210 model, santamarine inhibited cell growth, colony formation and [3H]-thymidine incorporation in time- and concentration-dependent manners. The mechanism of the cytotoxicity of santamarine towards L1210 cells could be related to alkylation of the sulfhydryl enzymes involved in nucleic acids and protein synthesis, as previously found for other SLs with the a-methylene-c-lactone moiety. Santamarine (99) induced apoptosis of L1210 cells via activation of caspase 3 (Ma et al., 2009) and had moderate inhibitory effect on topoisomerases (Zhang et al., 2007). Santamarine (99) has been used as cytotoxic anticancer agent that is selective to mouse leucocythemia cell (L1210), human leucocythemia cell (CCRF-CEM), human nasopharyngeal carcinoma cell (KB), human mammary gland cancer cell (MCF-7), and human colon cancer cell (LS174T). The IC50 is 0.41, 0.59, 0.16, 0.92 and 0.53 lg/mL to the above tumor cells respectively, and the anticancer activity is in direct proportion to santamarine concentration and action time. The anticancer mechanism of santamarine relates to the inhibition of tubulin. Santamarine leads to tumor cell necrosis, not apoptosis (Li, 2005). Santamarin (99) and reynosin (100) have been reported to exhibit cytotoxic activity against the human lung carcinoma cell line GLC4 and the colorectal cancer cell line COLO 320 with IC50 in the range 7.4–10.7 lM (Goren et al., 1996). 4.5. Antiviral Chlorohyssopifol A (224) and rhaposerin (248) suppressed reproduction of influenza virus by more than 50% at 5 lM concentration. Compound 224 decreased the infecting ability of virus of Newcastle disease (Berdin et al., 1999). Antiviral properties of 13-acetyl solstitialin A (183), chlorojanerin (219) and centaurepensin (224) were screened against Herpes simplex type-1 (representative of DNA virus) and Parainfluenza (representative of RNA virus) were employed for the determination of antiviral activity. 13-acetyl solstitialin A (183) had significant activity against DNA virus over a wide range of concentration (16 lg/mL–6 10 5 lg/mL) (Gürbuz et al., 2006;Ozcelik et al., 2009). 4.6. Effects on insects Grosheimin (264), and repin (209), administered in 0.1 mg/g doses to Tenebrio molitor larvae, inhibited its growth and showed antifeedant activity. Growth inhibition was due not only to reduced food intake but also to decreased absorption of digested food constituents and metabolic disorders (Rosinski et al., 1988). Also stizolin (27), 9a-hydroxypartenolide (28), stizolicin (32), aguerin B (160) and chlorojanerin (219) showed good antifeedant properties against Sitophilus granaries, Trogoderma granarium and Tribolium confusum, while janerin (208) and cynaropicrin (162) inhibited feeding of the latter species only (Cis et al., 2006;Bloszyk, 1988). Cynaropicrin (162) was proved to be a potent feeding deterrent on testing against 4th instar larvae of Bihar hairy caterpillar, Diacrisia obliqua and the eri-silkworm Philosamia ricini (Bhattacharyya et al., 1996). The antifeedant activity of compounds, 162, 208, 209, 212, 219,222,224, 240, 243, 244 and 246 were tested against larvae of Spodoptera littoralis. The chlorine-containing guaianes, 217, 219 and 246 showed significant activity at 100 ppm (Rosselli et al., 2006a). Shiromool (52) showed significant antifeedant activity against the larvae of S. littoralis whereas compound 51 was inactive (Barrero et al., 1999). Cnicin (19) exhibited significant mortality against the Formosan subterranean termite, Coptotermes formosanus, one of the most devastating termite pests (Meepagala et al., 2006) and was shown to be a disrupter of insect metamorphosis and modifier of reduced glutathione synthesis (Maymò et al., 1999). Furthermore, the effects of cnicin (19) on the ovopositional response and larval development of generalist and specialist insect herbivores were investigated as well as the toxicity on the larvae of S. littoralis (Landau et al., 1994). Compounds 64 and 83 produce altering effects on the metamorphosis of the grasshopper Locusta migratoria when topically applied to the nymphs (Castillo et al., 1998). Several SLs were examined for their nematocidal activity against root-knot nematode as a function of their structure. Maximum nematocidal activity was associated with an a-methylene-clactone moiety, e.g., alantolactone (121) (97% mortality) (Mahajan et al., 1986). HPLC-bioactivity-guided fractionations led to the isolation of costic acid (124) showing repellent activity against subterranean termite C. formosanus (Watanabe et al., 2005). Furthermore costic acid (124) had selective cytotoxic effects toward insect-derived Sf9 cells (Gonzalez-Coloma et al., 2005). The larvicidal activities of alantolactone (121), isolated from the roots of I. helenium, against 3rd and 4th instars of Aedes albopictus (Diptera: Culicidae) and Paratanytarsus grimmii (Diptera: Chironomidae), were examined. It showed LC50 values of 2.7 lg/mL for A. albopictus and 5.1 lg/mL for P. grimmii, respectively (Konishi et al., 2008). It also had larvicidal activity against Aedes aegypti (Cantrell et al., 2010) and insect feeding deterrent properties (Picman et al., 1978). Also dehydrocostus lactone (142), isolated from the dichloromethane extract of the Portuguese liverwort T. lorbeeriana, presented larvicidal activity against A. aegypti (Gonzalez-Coloma et al., 2005). Costunolide (1), isolated from the fruits of Magnolia salicifolia exhibited 100% mortality on 4th instar A. aegypti at 15 ppm, in 24 h (Kelm et al., 1997). Studies showed the insect repellent activity found in Saussurea lappa rhizomes to be due to dehydrocostus lactone (142) (Malik and Naqvi, 1984). Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx 4.7. Effects on plants The SLs repin (209), acroptilin (212), solstitiolide (222), and centaurepensin (224) caused increased lettuce root elongation at 10 ppm and inhibited it at higher concentrations (Stevens and Merrill, 1985). Cnicin (19) and onopordopicrin (8) drastically reduced the germination of lettuce and honey weed. Furthermore cnicin (19) at 0.1 mg/g concentration selectively inhibited some soil microorganisms (Cabral et al., 2008) and was shown to have germination and growth inhibitor properties (Kelsey and Locken, 1987; Locken and Kelsey, 1987). Stizolin (27) has been tested on inhibition of seed germination of wheat and showed an excellent phytotoxic activity (Starykh and Konovalov, 1997). Costunolide (1) and dehydrocostus lactone (142) caused inhibition of radicle growth of seedlings of Amaranthus hypochondriacus (Mata et al., 2002). A structure–activity study to evaluate the effect of the trans,trans-germacranolide sesquiterpene lactone, costunolide (1), and some derivatives (in a range of 100–0.001 lM) on the growth and germination of several mono- and dicotyledon target species, was accomplished. These compounds appeared to have a selective effect on the radicle growth of monocotyledons at levels comparable to those of Logran (Macias et al., 1999a). Zaluzanin C (147) was shown to inhibit root and shoot growth in lettuce, tomatoes and cress (Macias et al., 1999b, 2010). 4.8. Other activities In the nitric oxide release inhibitory experiments, costunolide (1) exhibited strong inhibition with an IC50 value of 0.2 lg/mL (0.86 lM). In the ACAT (acyl CoA: cholesterol acyltransferase) inhibitory assay, costunolide exhibited strong inhibition, with an IC50 value of 17 lg/mL (73.3 lM) (Jang et al., 1999). A study demonstrated that dehydrocostus lactone (142) can protect osteoblasts against H2O2-induced cellular dysfunction. The results also suggest that 142 may be valuable as a protective agent against oxidative damage in osteoblasts (Choi et al., 2009) and, furthermore, it protects osteoblastic MC3T3-E1 cells from antimycin A induced cell damage through the improved mitochondrial function (Choi, 2011). The effect of costunolide (1) on the function of osteoblastic MC3T3-E1 cells was studied. Costunolide significantly increased the growth of MC3T3-E1 cells and caused a significant elevation of alkyl phosphatase (ALP) activity, collagen content, and mineralization in the cells (P < 0.05). These data indicate that the enhancement of osteoblast function by costunolide may result in the prevention for osteoporosis (Lee and Choi, 2011). The molecular mechanism of inhibitory action of dehydrocostus lactone (142) and costunolide (1) towards the activation of signal transducer and activator of transcription 3 (STAT3) was studied. In human THP-1 cell line, they inhibit IL-6-elicited tyrosine phosphorylation of STAT3 and its DNA binding activity with EC50 of 10 lM with concomitant down-regulation of the phosphorylation of the tyrosine Janus kinases JAK1, JAK2 and Tyk2. Furthermore, these compounds that contain an a b-unsaturated carbonyl moiety and function as potent Michael reaction acceptor, induced a rapid drop in intracellular glutathione (GSH) concentration by direct interaction with it, thereby triggering S-glutathionylation of STAT3. It was concluded that SLs 142 and 1 are able to induce redox-dependent post-translational modification of cysteine residues of STAT3 protein in order to regulate its function (Butturini et al., 2011). Costunolide (1) and dehydrocostus lactone (142), the active principle from the leaves of Laurus nobilis, were shown to inhibit selectively ethanol absorption rather than glucose absorption and to have a gastroprotective effect on acidified ethanol-induced gastric mucosal (Yoshikawa et al., 2000) lesions in rats (Matsuda et al., 2000b). The inhibitory mechanism of costunolide was investigated 65 (Matsuda et al., 2002). In other studies through bioassay-guided separation from methanolic extract of the leaves of Laurus nobilis, costunolide (1), dehydrocostus lactone (142), and santamarine (99) were isolated as the active constituents that inhibited the elevation of blood ethanol level in ethanol-loaded rat; the a-methylene-c-butyrolactone moiety was found to be essential for the preventive effect on ethanol absorption (Matsuda et al., 1999). Costunolide (1) and dehydrocostus lactone (142) showed strong cholagogic effect (Wang et al., 2001). It has been shown that artichoke leaf extract is effective against acute gastritis and its beneficial effect is due to that of cynaropicrin (162) (Ishida et al., 2010). A study of the cytoprotective activity of several guaianolides was undertaken. Ludartin (262) was found to exhibit good protection (Giordano et al., 1990). The structural activity relationship of the antiulcerogenic activity and the mechanism of action were investigated. It has been ascertained that a sterically unhindered Michael acceptor is an essential requirement for the activity, interacting with the thiol containing compounds of the gastric mucosa (Giordano et al., 1992). The main components of C. solstitialis ssp. solstitialis responsible for its significant anti-ulcerogenic activity were determined as solstitialin A (181), 13-acetyl solstitialin A (183) and chlorojanerin (219) (Yesilada et al., 2004;Gürbüz and Yesilada, 2007). Saussurea root has been used in Oriental medicine as sedative, as well as in incense. Dehydrocostus lactone (142) and costunolide (1) were isolated from this root and found to have sedative and analgesic effects on the central nervous system. The sedative effects of these two compounds were found to be caused by antidopaminergic and partly anti-serotonergic effects (Okukawa et al., 2000): they also increased hexobarbital sleeping time and decreased body temperature, nociception, and spontaneous locomotor activity (Okugawa et al., 1996). The analgesic effect of 8a-(30 -hydroxy-40 -acetoxy-20 -methylene-butanoyloxy)-4-epi-sonchucarpolide (111), isolated from C. grisebachi, and of 8a-O-(40 -hydroxy-20 -methylenebutanoyloxy)11b,13-dihydrosonchucarpolide (118), isolated from C. pullata, was studied in mice. The results showed significant decreasing in pain at 30 min post treatment with a dose of 10 mg/kg (Djeddi et al., 2008c). Solstitialin A (181) and 13-acetyl solstitialin A (183) were defined as the active components responsible of the antinociceptive and antipyretic properties C. solstitialis and C. depressa (Akkol et al., 2009). It has been demonstrated that the a-methylene-c-butyrolactone structural unit of dehydrocostus lactone (142) is the moiety responsible for increasing cellular resistance to oxidant injury in HepG2 cells, presumably through Nrf2/ARE-dependent HO-1 expression (Jeong et al., 2007). The hexane fraction of I. helenium showed the potential to induce detoxifying enzymes such as quinine reductase (QR) and glutathione S-transferase in a dose-dependent manner. Its potential to induce the reported activity, suggested an antioxidant response element-mediated mechanism of action in the induction of phase II detoxifying enzymes. Alantolactone (121) isolated from this fraction significantly induced QR activity in both Hepa1c1c7 and BPRc1 cells (Im et al., 2007) and was shown to be a more effective antioxidant than a-tocopherol or ubiquinone (Mir-Babaev and Sereda, 1987). Alantolactone (121) caused a dose-dependent induction of antioxidant enzymes including QR, GST, c-glutamylcysteine synthase, glutathione reductase, and heme oxygenase 1 in hepa1c1c7 mouse hepatoma cells. The compound increased the luciferase activity of HepG2–19 cells, transfectants carrying antioxidant response element (ARE)-luciferase gene, in a dose-dependent manner, suggesting ARE-mediated transcriptional activation of antioxidant enzymes. Alantolactone also stimulated the nuclear accumulation Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 66 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx of Nrf2 that was inhibited by phosphatidylinositol 3-kinase (PI3K) inhibitors. In conclusion, alantolactone appears to induce detoxifying enzymes via activation of PI3K and JNK signaling pathways, leading to translocation of Nrf2, and subsequent interaction between Nrf2 and ARE in the encoding genes (Seo et al., 2008). Grosheimin (264), isolated from the medicinal plants of Youngia japonica, exhibited strong antiallergic and antioxidant activities (Yae et al., 2009). Costunolide (1) and reynosin (100), isolated from Saussureae Radix, showed potent inhibitory effects on the IBMX-induced melanogenesis, in dose-dependent manners, with IC50 values of 3 and 2.5 lg/mL, respectively (Choi et al., 2008). Costunolide (1) inhibited contractions of the aorta induced by KCl but exerted less effect on those induced by norepinephrine, indicating the possible Ca antagonistic action of costunolide. Dehydrocostus lactone (142) caused similar inhibitor effects but its specificity of KCl-induced contraction was less than costunolide (Shoji et al., 1984). The oxygen functional groups at the 3- and 8-positions and exomethylene moiety in a-methylene-c-butyrolactone ring were found to be essential for the anti-hyperlipidemic activity of guaiane-type sesquiterpene. In fact cynaropicrin (162), aguerin B (160) and grosheimin (264) significantly suppressed serum TG elevation at 50 and 100 mg/kg during the early stage (2 h after olive oil administration), whereas dehydrocostus lactone (142) and 11b, 13-dihydro-deacylcynaropicrin (190) had a weaker activity (Shimoda et al., 2003). In vitro protein synthesis was blocked by zaluzanin C (147) and the study of the effects of the drug on resolved model systems indicates that it inhibits enzymic translocation of peptidyl-tRNA specifically (Santamaria et al., 1984). The Acyl-CoA cholesterol acyltransferase (ACAT), diacylglycerol acyltransferase (DGAT) and farnesyl-protein transferase (FPTase) inhibitory effects of the roots of Ixeris dentata forma albida were investigated and one of the active compounds was identified as zaluzanin C (147) (Bang et al., 2004). The inhibition of ATP synthesis, proton uptake, and electron transport (basal, phosphorylating, and uncoupled) from water to methylviologen by zaluzanin C (147) indicates that it acts as an electron transport inhibitor. The studies concluded that the site of inhibition by zaluzanin C is located at the oxygen evolution level (Lotina-Hennsen et al., 1992). An inhibitor of CINC-1 (cytokine-induced neutrophil chemoattractant-1) induction in LPS-stimulated rat kidney epithelioid NRK-52E cells was purified from the roots of Sassurea lappa, a herbal medicine used in Korean traditional prescriptions for gastric intestinal diseases by a variety of column chromatography procedures. The inhibitor was identified as reynosin (100). It exhibited a dose-dependent inhibition on CINC-1 induction in LPS-stimulated NRK-52E cells, where 50% of inhibitory effect was shown at the concentration of about 1 lM (Jung et al., 1998). Furthermore, reynosin (100) displayed considerable inhibition against platelet aggregation induced by AA, ADP, or PAF (Wang et al., 2000). A study describing the antispasmodic activity of some fractions and cynaropicrin (162), a sesquiterpene lactone from Cynara scolymus, cultivated in Brazil, against guinea-pig ileum contracted by acetylcholine was carried out. The dichloromethane fraction showed the most promising biological effects, with an IC50 of 0.93 (0.49–1.77) lg/mL. Its main active component, the sesquiterpene lactone cynaropicrin, exhibited potent activity, with IC50 of 0.065 (0.049–0.086) lg/mL, being about 14-fold more active than dichloromethane fraction and having similar potency to that of papaverine, a well-known antispasmodic agent (Emendoerfer et al., 2005). A characteristic smooth muscle inhibitory profile is demonstrated by the a-methylenebutyrolactone cynaropicrin (162), but not by a compound lacking this functional group (solstitialin 13-acetate, 183) (Hay et al., 1994). Repin (209), on intraperitoneal injection, produces a dosedependent and highly significant hypothermia in naive rats (Akbar et al., 1995). Several SLs isolated from different Asteraceae species from north-western Argentina were investigated for their inhibitory action on the estrogen biosynthesis. Ludartin (262) was found to inhibit the aromatase enzyme activity in human placental microsomes and it was competitive inhibitor with an apparent Ki of 23 lM (Blanco et al., 1997). Compounds 220 and 221 displayed promising inhibitory potential against enzyme urease in a concentration-dependent fashion (Khan et al., 2004a). Compounds 190, 198, 217, 219, 236 and 240 showed inhibitory potential against butyrylcholinoesterase, the best one being chlorojanerin (219) with IC50 values of 15 lg/mL (Khan et al., 2005a). 5. Conclusions This subtribe Centaureinae appears taxonomically very complex. It is worth to keep in mind that, in the numerous papers reviewed, the correct botanic identification plays a pivotal role. Moreover, the correct assessment of the taxa in their sections is a further problem in order to draw any chemotaxonomic classification. The elaboration of the collected data allows to define groups of taxa with a consistent chemical composition reflecting a botanic relationship, i.e. Psephellus and Acrolophus sections. Other similarities or differences can be found, i.e. Cheirolophus intybaceus showing a complete different profile with respect to the other species of genus Cheirolophus or C. calcitrapa, C. incana, C. salonitana and C. solstitialis that have a very different composition depending on the collection place. Clearly, all the information arising from the statistical approach of the qualitative content of sesquiterpenes in the taxa, both single product and structural similarity products methods, should be evaluated for any botanical consistency. As it is possible to observe, the main biological properties ascribed to sesquiterpenes are the antibacterial, anti-inflammatory and antitumor activities. In this context, a lot of publications regarding custonolide (1) and cynaropicrin (162), have shown a high potential towards these activities. Acknowledgment This work was supported by Italian Government fund MIUR PRIN 2009 ‘‘Composti naturali da piante mediterranee e loro derivati sintetici con attivita’ antitumorale’’. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.phytochem.2013. 07.002. References Abdelgaleil, S.A., Ahmed, S.M., 2005. In vitro activity of extracts and sesquiterpene lactones of Magnolia grandiflora L. against six plant pathogenic bacteria. Alexandria Sci. Exch. J. 26, 158–163. Aboul-Ela, M.A., 1994. A new aromatic dimer and an elemanolide from Centaurea calcitrapa. Alexandria J. Pharm. Sci. 8, 133–136 (C.A. 122, 51328h). Adekenov, S.M., Turmukhambetov, A.Zh., Mukhametzhanov, N.M., Abdrakhmanov, O.A., 1979. Chemical study of Centaurea pseudomaculosa. VINITI Dep Doc 9pp. Adekenov, S.M., Kadirberlina, G.M., Sadykova, V.I., Kupriyanova, T.I., Kagarlitskii, A.D., 1986a. Biologically-active compounds of Centaurea pseudomaculosa. Izv. Akad. Nauk Kaz. SSR, Ser. Khim., 65–69. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Adekenov, S.M., Aituganov, K.A., Kagarliskii, A.D., Rakhimov, K.D., Vermenichev, S.M., 1986b. Grosshemin from Chartolepis intermedia and Centaurea ruthenica. Khim.-Farm. Zh. 20, 938–942. Adekenov, S.M., Kupriyanov, A.N., Aituganov, K.A., 1991. Resources of Chartolepis intermedia Boiss, its cultivation and dynamics of localization of the sesquiterpene lactone grosshemin. Rastit. Resur. 27, 67–73. Adekenov, S.M., 1995. Sesquiterpene lactones from plants of the family Asteraceae in the Kazakhstan flora and their biological activity. Khim. Prir. Soedin. 31, 29– 36. Ahmed, A.A., Abou El-Ela, M., Jakupovic, J., Seif El-Din, A.A., El-Ghazouly, M., 1990. A guaianolide from Amberboa tubuliflora. Phytochemistry 29, 3946–3947. Ahmed, S.M., Abdelgaleil, S.A.M., 2005. Antifungal activity of extracts and sesquiterpene lactones from Magnolia grandiflora L. (Magnoliaceae). Int. J. Agric. Biol. 7, 638–642. Ahn, E.M., Bang, M.H., Song, M.C., Park, M.H., Kim, H.Y., Kwon, B.M., Baek, N.I., 2006. Cytotoxic and ACAT-inhibitory sesquiterpene lactones from the root of Ixeris dentata forma albiflora. Arch. Pharm. Res. 29, 937–941. Akkol, E.K., Arif, R., Ergun, F., Yesilada, E., 2009. Sesquiterpene lactones with antinociceptive and antipyretic activity from two Centaurea species. J. Ethnopharmacol. 122, 210–215. Ali, Y.E., Omar, A.A., Sarg, T.M., Slatkin, D.J., 1987. Chemical constituents of Centaurea pallescens. Planta Med. 53, 503–504. Al-Easa, H.S., Mann, J., Rizk, A.F., 1990. Guaianolides from Centaurea sinaica. Phytochemistry 29, 1324–1325. Al-Saghir, J., Al-Ashi, R., Salloum, R., Saliba, N.A., Talhouk, R.S., Homaidan, F.R., 2009. Anti-inflammatory properties of Salograviolide A purified from Lebanese plant Centaurea ainetensis. BMC Complementary Altern. Med. 9, 1–10. Al-Sheddi, E.S., Mossa, J.S., Muhammad, I., El-Sayeda, A.E., Farouk, F.S., 2002. Sesquiterpenes from Tarchonanthus camphorates: an alternative natural source of parthenolide and of feverfew. Saudi Pharm. J. 10, 30–35. Akbar, S., Freis, D.S., Malone, M.H., 1995. Effect of various pretreatments on the hypothermic activity of repin in native rats. J. Ethnopharmacol. 49, 91–99. Amer, M.E., Abdel Kader, M.S., Hassan, M.A., Mossa, J.S., El-Masry, S., 2001. Two novel guaianolides from Centaurea pseudosinaica. Alexandria J. Pharm. Sci. 15, 65–67. Amigo, J.M., Debaerdemaeker, T., Seoane, E., Tartajada, A., Picher, M.T., 1984. Structure and stereochemistry of stenophyllolide A a germacranolide from Centaurea aspera subsp. stenophylla. Phytochemistry 23, 1999–2001. Anand, S., Rimoldi, J.M., Tukov, F.F., Matthews, J.C., 2003. Structure–activity/toxicity relationship studies of the sesquiterpene lactone repin. 225th ACS National Meeting (AN 2003, 184066). Ando, M., Yamaoka, H., Takase, K., 1982. Total syntheses of zaluzanin C, zaluzanin D, and 3-epizaluzanin C. Chem. Lett., 501–504. Appendino, G., Gariboldi, P., Belliardo, F., 1986. Sesquiterpene lactones from Centaurea uniflora subsp. nervosa. Phytochemistry 25, 2163–2165. Appendino, G., Özen, H.Ç., 1993. Sesquiterpene lactones of Centaurea kurdica. Gaz. Chim. Ital. 123, 93–94. Asaruddin, M.R., Honda, G., Tsubouchi, A., Nakajima-Shimada, J., Aoki, T., Kiuchi, F., 2003. Trypanocidal constituents from Michelia alba. Nat. Med. (Tokyo, Jpn.) 57, 61–63. Azoulay, P., Reynier, J.P., Balansard, G., Gasquet, M., Timon-David, P., 1986. Biogalenic and pharmacological study on three sesquiterpenes with antiparasitic actions: helenin, santonin, and 12-carboxy-3,11(13)eudesmadiene. Pharm. Acta Helv. 61, 345–352. Bach, S.M., Fortuna, M.A., Attarian, R., De Trimarco, J.T., Catalan, C.A.N., Av-Gay, Y., Bach, H., 2011. Antibacterial and cytotoxic activities of the sesquiterpene lactones cnicin and onopordopicrin. Nat. Prod. Commun. 6, 163–166. Bachelier, A., Mayer, R., Klein, C.D., 2006. Sesquiterpene lactones are potent and irreversible inhibitors of the antibacterial target enzyme MurA. Bioorg. Med. Chem. Lett. 16, 5605–5609. Baker, P.M., Fortes, C.C., Gazzinelli, G., Gilbert, B., Lopes, J.N.C., Pellegrino, J., Tomassini, T.C.B., Vichnewski, W., 1973. Eremathin, costunolide, acyclocostunolide, and bisabolol. Chemoprophylactic agents for schistosomiasis. Cienc. Cult. (Sao Paulo, Braz.) 25, 627–631. Bang, M.H., Jang, T.O., Song, M.C., Kim, D.H., Kwon, By.M., Kim, Y.K., Lee, H.S., Chung, I.S., Kim, D.K., Kim, S.H., Park, M.H., Baek, N.I., 2004. Screening of biologically active compound from edible plant sources. IX. Isolation and identification of sesquiterpene lactones isolated from the root of Ixeris dentata forma albiflora; inhibition effects on ACAT, DGAT and FPTase activity. Han’guk Eungyong Sangmyong Hwahakhoeji 47, 251–257. Banno, N., 2011. NF-jB-targeting anti-aging effect of artichoke extract. Aromatopia 107, 82–86. Barbetti, P., Fardella, G., Chiappini, I., Scarcia, V., Furlani Candiani, A., 1985. New cytotoxic guaianolides and derivatives from Grossheimia macrocephala. Farmaco 40, 755–769. Barla, A., Topçu, G., Oeksuez, S., Tuemen, G., Kingston, D.G.I., 2007. Identification of cytotoxic sesquiterpenes from Laurus nobilis L.. Food Chem. 104, 1478–1484. Barrero, A.F., Sancez, J.F., Rodriguez, I., Soria Sanz, C., 1988. Germacranolidas de Centaurea malacitana. An. Quim. 84, 344–347. Barrero, A.F., Sanchez, J.F., Rodriguez, I., 1989. Germacranolides from Centaurea melitensis. Phytochemistry 28, 1975–1976. Barrero, A.F., Oltra, J.E., Rodriguez, I., Barragan, A., Gravalos, D.G., Ruiz, P., 1995. Lactones from species of Centaurea. Cytotoxic and antimicrobial activities. Fitoterapia 66, 227–230. 67 Barrero, A.F., Oltra, J.E., Morales, V., Alvarez, M., 1997a. Biomimetic cyclization of cnicin to malacitanolide, a cytotoxic eudesmanolide from Centaurea malacitana. J. Nat. Prod. 60, 1034–1035. Barrero, A.F., Arteaga, P., Quilez, J.F., Rodriguez, I., Herrador, M.M., 1997b. Sesquiterpene glycosides and phenylpropanoid esters from Phonus arborescens. J. Nat. Prod. 60, 1026–1030. Barrero, A.F., Herrador, M.M., Quilez, J.F., Alvarez-Manzaneda, R., Portal, D., Gavin, J.A., Gravalos, D.G., Simmonds, M.S.J., Blaney, W.M., 1999. Bioactive sesquiterpenes from Santolina rosmarinifolia subsp. canescens. A conformational analysis of the germacrane ring. Phytochemistry 51, 529–541. Barrero, A.F., Oltra, J.E., Raslan, D.S., Alvarez, M., Saude, D.A., Akssira, M., 2000. New sources and antifungal activity of sesquiterpene lactones. Fitoterapia 71, 60–64. Bastos, M.M.S.M., Kijjoa, A., Pinto, M.M.M., 1994. Constitents of Centaurea ornata ssp. ornata. Fitoterapia 65, 191. Baykan Erel, S., Karaalp, C., Bedir, E., Kaehlig, H., Glasl, S., Khan, S., Krenn, L., 2011. Secondary metabolites of Centaurea calolepis and evaluation of cnicin for antiinflammatory, antioxidant and cytotoxic activities. Pharm. Biol. 49, 840–849. Benayache, F., Benayache, S., Medjroubi, K., Massiot, G., Aclinou, P., Droźdź, B., Nowak, G., 1992. Sesquiterpene lactones from Centaurea pullata. Phytochemistry 31, 4359–4360. Bentamane, A., Benayache, S., Crèche, J., Petit, G., Bermejo-Barrera, J., Leon, F., Benayache, F., 2005. A new guaianolide and other sesquiterpene lactones from Centaurea acaulis. Biochem. Syst. Ecol. 33, 1061–1065. Bentamene, A., Benayache, S., Creche, J., Bermejo, J., Benayache, F., 2007. Sesquiterpene lactones and phenolic compounds from Centaurea maroccana. Chem. Nat. Comp. 43, 749–750. Berdin, A.G., Adekenov, S.M., Ralgudin, V.A., Shakirov, M.M., Druganov, A.G., Kalyyasov, A.T., Tolstikov, G.A., 1999. Chemistry of natural compounds and bioorganic chemistry: rhaposerine and rhaserolide, new sesquiterpene lactones from Rhaponticum serratuloides. Russ. Chem. Bull. 48, 1987–1991. Berdin, A.G., Ralgugin, V.A., Shakirov, M.M., Bargyanskaya, Yu., Gatilov, Yu.V., Druganiv, A.G., Kulyyasov, A.T., Adekenov, S.M., Habdolda, G., Tolstikov, G.A., 2001. 15-O-deacetylrhaposerin and rhaserin – new components of a lactone mixture from Rhaponticum serrutaloides. Russ. Chem. Bull. 50, 537–542. Bermejo, J., Betancor, C., Breton, J.L., Gonzalez, A.G., 1969. Sesquiterpene lactones of Amberboa lippii. An. Quim. 65, 285–295. Bernhard, H.O., Thiele, K., Pretsch, E., 1979. Cynaratriol, a new guajanolide from the thistle Cynara cardunculus L. and the artichoke C. scolymus L.. Helv. Chim. Acta 62, 1288–1297. Bhattacharyya, P.R., Barua, N.C., Ghosh, A.C., 1996. Cynaropicrin from Trichlorepis glaberrima: a potential insect feeding deterrent compound. Ind. Crops Prod. 4, 291–294. Bialecki, M., Bloszyk, E., Drozdz, B., Hladon, B., Szwemin, S., 1973. Sesquiterpene lactones. Cytostatic activity of grosheimin. Polish J. Parmacol. Pharm. 25, 195– 199. Blanco, J.G., Gil, R.R., Alvarez, C.I., Patrito, L.C., Genti-Raimondi, S., Flury, A., 1997. A novel activity for a group of sesquiterpene lactones: inhibition of aromatase. FEBS Lett. 409, 396–400. Bloszyk, E., 1988. Plant extracts and sesquiterpene lactones with antifeeding activity on some stored product insects. Prace. Nauk. Inst. Chem. Org. Fiz. Politecn. Wrocl. 33, 109–112. Blunder, M., Kunert, O., Bauer, R., 2008. Inhibitory activity of Cynara scolimus L. on inducible nitric oxide synthase (iNOS). Planta Med. 74, 974. Bohlmann, F., Gupta, R.K., 1981. Guaianolides from Centaurea canariensis. Phytochemistry 20, 2773–2775. Breton, J.L., Marrero, B.G., Gonzalez, A.G., 1968. Sesquiterpene lactones of Amberboa lippii. Structure of grosshemine. An. Quim. 64, 1015–1016. Bruno, M., Herz, W., 1988. Sesquiterpene lactones and flavones from Centaurea cineraria subsp. umbrosa. Phytochemistry 27, 1873–1875. Bruno, M., Diaz, J.G., Herz, W., 1991a. Germacranolides from Anthemis cupaniana. Phytochemistry 30, 3458–3460. Bruno, M., Diaz, J.G., Herz, W., 1991b. Guaianolides and lignans from Centaurea solstitialis subsp. schouwii. Phytochemistry 30, 4165–4166. Bruno, M., Fazio, C., Passannanti, S., Paternostro, M.P., Diaz, J.G., Herz, W., 1994. Sesquiterpene lactones from Centaurea sphaerocphala subsp. spaerocephala. Phytochemistry 35, 1371–1372. Bruno, M., Fazio, C., Paternostro, M.P., Diaz, J.G., Herz, W., 1995. Sesquiterpene lactones and other constituents of Centaurea napifolia. Planta Med. 61, 374–375. Bruno, M., Paternostro, M.P., Gedris, T.G., Herz, W., 1996. Sesquiterpene lactones and other constituents of Centaurea nicaensis. Phytochemistry 41, 335–336. Bruno, M., Vassallo, N., Fazio, C., Gedris, T.E., Herz, W., 1998. Sesquiterpene lactones of two Centaurea species from Sicily. Biochem. Syst. Ecol. 26, 801–803. Bruno, M., Maggio, A., Paternostro, M.P., Rosselli, S., Arnold, N.A., Herz, W., 2001. Sesquiterpene lactones and other constituents of three Cardueae from Cyprus. Biochem. Syst. Ecol. 29, 433–435. Bruno, M., Maggio, A., Rosselli, S., Gedris, T.E., Herz, W., 2002. Sesquiterpene lactones and other constituents of Centaurea paniculata ssp. castellana. Biochem. Syst. Ecol. 30, 379–381. Bruno, M., Rosselli, S., Maggio, A., Raccuglia, R.A., Napolitano, F., Senatore, F., 2003. Antibacterial evaluation of cnicin and some natural and semisynthetic analogues. Planta Med. 69, 277–281. Bruno, M., Rosselli, S., Maggio, A., Raccuglia, R.A., Arnold, N.A., 2005a. Guaianolides from Centaurea babylonica. Biochem. Syst. Ecol. 33, 817–825. Bruno, M., Rosselli, S., Maggio, A., Raccuglia, R.A., Bastow, K.F., Wu, C.C., Lee, K.H., 2005b. Cytotoxyc activity of some natura and synthetic sesquiterpene lactones. Planta Med. 71, 1176–1178. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 68 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Bruno, M., Rosselli, S., Maggio, A., Raccuglia, R.A., Bastow, K.F., Lee, K.H., 2005c. Cytotoxic activity of natural and synthetic guaianolides. J. Nat. Prod. 68, 1042– 1046. Bruno, M., Maggio, A., Rosselli, S., Safder, M., Bancheva, S., 2011. The metabolites of the genus Onopordum (Asteraceae): chemistry and biological properties. Curr. Org. Chem. 15, 888–927. Buděšinský, M., Šaman, D., Droźdź, B., Holub, M., 1984. 9a-hydroxyparthenolide from Zoegea baldshuanica. Coll. Czech. Chem. Commun. 49, 637–641. Buděšinský, M., Šaman, D., 1995. Carbon-13 NMR spectra of sesquiterpene lactones. Annu. Rep. NMR Spectrosc. 30, 231–475. Butturini, E., Cavalieri, E., Carcereri de Prati, A., Darra, E., Rigo, A., Shoji, K., Murayama, N., Yamazaki, H., Watanabe, Y., Suzuki, H., 2011. Two naturally occurring terpenes, dehydrocostuslactone and costunolide, decrease intracellular GSH content and inhibit STAT3 activation. PLoS One 6, e20174. Cabral, M.E.S., Fortuna, A.M., De Riscala, E.C., Catalan, C.A.N., Sigstad, E.E., 2008. Allelopathic activity of Centaurea diffusa and Centaurea tweediei: effect of cnicin and onopordopicrin on seed germination phytopathogenic bacteria and soil. Allelopathy J. 21, 183–190. Cantrell, C.L., Nunez, I.S., Castaneda-Acosta, J., Foroozesh, M., Fronczek, F.R., Fischer, N.H., Franzblau, G., 1998. Antimycobacterial activities of dehydrocostus lactone and its oxidation products. J. Nat. Prod. 61, 1181–1186. Cantrell, C.L., Abate, L., Fronczek, F.R., Franzblau, S.G., Quijano, L., Fischer, N.H., 1999. Antimycobacterial eudesmanolides from Inula helenium and Rudbeckia subtomentosa. Planta Med. 65, 351–355. Cantrell, C.L., Pridgeon, J.W., Fronczek, F.R., Becnel, J.J., 2010. Structure–activity relationship studies on derivatives of eudesmanolides from Inula helenium as toxicants against Aedes aegypti larvae and adults. Chem. Biodivers. 7, 1681– 1697. Cardona, L., Garcia, B., Pedro, J.R., Sinisterra, J.F., 1989. Sesquiterpene lactones and elemane derivative from Onopordum corymbosum. Phytochemistry 28, 1264– 1267. Cardona, L., Frernandez, I., Pedro, J.R., Perez, B., 1991. Sesquiterpene lactones and flavonoids from Centaurea aspera. Phytochemistry 30, 2331–2333. Cardona, L., Fernandez, I., Pedro, J.R., Vidal, R., 1992. Polyoxygenated terpenes and cyanogenic glucosides from Centaurea aspera var. subinermis. Phytochemistry 31, 3507–3509. Cardona, L., Garcia, B., Navarro, F.I., Pedro, J.R., 1994. Sesquiterpene lactones from Centaurea paui. Nat. Prod. Lett. 5, 47–54. Cardona, L., Garcia, B., Muñoz, M.C., Navarro, F.I., Pedro, J.R., 1997. New sesquiterpene lactones and other constituents of Centaurea paui. Liebig. Ann., 527–532. Cassady, J.M., Abramson, D., Cowall, P., Chang, C.J., McLaughlin, J.I., 1979. Centaurepensin: a cytotoxic constituent of Centaurea solstitialis and C. repens. J. Nat. Prod. 42, 427–429. Cassady, J.M., Bean, M.Fz.K., McLaughlin, J.I., Aynehchi, Y., 1984. Structure revision and cytotoxicity of the germacranolide, stizolicin, from Stizolophus balsamitus. Experientia 40, 930–931. Castillo, M., Martinez-Pardo, R., Garcera, M.D., Couillaud, F., 1998. Biological activities of natural sesquiterpene lactones and effect of synthetic sesquiterpene derivatives on insect juvenile hormone biosynthesis. J. Agric. Food Chem. 46, 2030–2035. Castro, V., Murillo, R., Klaas, C.A., Meunier, C., Mora, G., Pahl, H.L., Merfort, I., 2000. Inhibition of the transcription factor NF-j B by sesquiterpene lactones from Podachaenium eminens. Planta Med. 66, 591–595. Chang, H.S., Lee, S.J., Yang, C.W., Chen, I.S., 2010. Cytotoxic sesquiterpenes from Magnolia kachirachirai. Chem. Biodivers. 7, 2737–2747. Chen, H.C., Chou, C.K., Lee, S.D., Wang, J.C., Yeh, S.F., 1995. Active compounds from Saussurea lappa Clarks that suppress hepatitis B virus surface antigen gene expression in human hepatoma cells. Antiviral Res. 27, 99–109. Chen, J., Wang, S., Li, C., Zhang, M., Dong, M., Shi, Q., 2011. Studies on the inhibitory effects of sesquiterpenoids from Artemisia frigida on the proliferation activity of human tumor cell lines and the structure–activity relationship. Zhongyao Yaoli Yu Linchuang 27, 24–26. Chen, W., Liu, Q., Wang, J., Zou, J., Meng, D., Zuo, J., Zhu, X., Zhao, W., 2006. New guaiane, megastigmane and eudesmane-type sesquiterpenoids and antiinflammatory constituents from Youngia japonica. Planta Med. 72, 143–150. Cheng, C.H.K., Costall, B., Hamburger, M., Hostettmann, K., Naylor, R.J., Wang, Y., Jenner, P., 1992. Toxic effects of solstitialin A 13-acetate and cynaropicrin from Centaurea solstitialis L. (Asteraceae) in cell cultures of fetal rat brain. Neuropharmacology 31, 271–277. Cheng, D.L., Han, H.X., Chen, J.K., 1995. A new eudesmane sesquiterpene from the root of Rhaponticum uniflorum. Chin. Chem. Lett. 6, 111–112. Chicca, A., Tebano, M., Adinolfi, B., Ertugul, K., Flamini, G., Neri, P., 2011. Antiprolilferative activity of aguerin B and a new rare nor-guaianolide lactone isolated from the aerial parts of Centaurea deflexa. Eur. J. Med. Chem. 46, 3066– 3070. Cho, J.Y., Park, J., Yoo, E.S., Baik, K.U., Jung, J.H., Lee, J., Park, M.H., 1998. Inhibitory effect of sesquiterpene lactones from Saussurea lappa on tumor necrosis factor-a production in murine macrophage-like cells. Planta Med. 64, 594–597. Cho, J.Y., Baik, K.U., Jung, J.H., Park, M.H., 2000. In vitro anti-inflammatory effects of cynaropicrin, a sesquiterpene lactone, from Saussurea lappa. Eur. J. Pharmacol. 398, 399–407. Cho, J.Y., Kim, A.R., Joo, H.G., Kim, B.H., Rhee, M.H., Yoo, E.S., Katz, D.R., Chain, B.M., Jung, J.H., 2004a. Cynaropicrin, a sesquiterpene lactone, as a new strong regulator of CD29 and CD98 functions. Biochem. Biophys. Res. Comm. 313, 954– 961. Cho, J.Y., Kim, A.R., Jung, J.H., Chun, T., Rhee, M.H., Yoo, E.S., 2004b. Cytotoxic and pro-apoptotic activities of cynaropicrin, a sesquiterpene lactone, on the viability of leukocyte cancer cell lines. Eur. J. Pharm. 492, 85–94. Choi, E.J., Ahn, W.S., 2009. Antiproliferative effects of dehydrocostuslactone through cell cycle arrest and apoptosis in human ovarian cancer SK-OV-3 cells. Int. J. Mol. Med. 23, 211–216. Choi, E.J., Kim, G.H., 2010. Evaluation of anticancer activity of dehydrocostuslactone in vitro. Mol. Med. Rep. 3, 185–188. Choi, E.M., Kim, G.H., Lee, Y.S., 2009. Protective effects of dehydrocostus lactone against hydrogen peroxide-induced dysfunction and oxidative stress in osteoblastic MC3T3-E1 cells. Toxicol. In Vitro 23, 862–867. Choi, E.M., 2011. Dehydrocostus lactone prevents mitochondrial dysfunction in osteoblastic MC3T3-E1 cells. Eur. J. Pharmacol. 664, 1–7. Choi, J.H., Ha, J., Park, J.H., Lee, J.Y., Lee, Y.S., Park, H.J., Choi, J.W., Masuda, Y., Nakaya, K., Lee, K.T., 2002a. Costunolide triggers apoptosis in human leukemia U937 cells by depleting intracellular thiols. Jpn. J. Cancer Res. 93, 1327–1333. Choi, J.H., Seo, B.R., Seo, S.H., Lee, K.T., Park, J.H., Park, H.J., Choi, J.W., Itoh, Y., 2002b. Costunolide induces differentiation of human leukemia HL-60 cells. Arch. Pharm. Res. 25, 480–484. Choi, J.H., Lee, K.T., 2009. Costunolide-induced apoptosis in human leukemia cells: involvement of c-Jun N-terminal kinase activation. Biol. Pharm. Bull. 32, 1803– 1808. Choi, J.Y., Choi, E.H., Jung, H.W., Oh, J.S., Lee, W.H., Lee, J.G., Son, J.K., Kim, Y., Lee, S.H., 2008. Melanogenesis inhibitory compounds from Saussureae radix. Arch. Pharm. Res. 31, 294–299. Choi, S.H., Im, E., Kang, H.K., Lee, J.H., Kwak, H.S., Bae, Y.T., Park, H.J., Kim, N.D., 2005. Inhibitory effects of costunolide on the telomerase activity in human breast carcinoma cells. Cancer Lett. 227, 153–162. Choi, S.Z., Choi, S.U., Lee, K.R., 2005. Cytotoxic sesquiterpene lactones from Saussurea calcicola. Arch. Pharm. Res. 28, 1142–1146. Choi, S.Z., Yang, M.C., Choi, S.U., Lee, K.R., 2006. Cytotoxic terpenes and lignans from the roots of Ainsliaea acerifolia. Arch. Pharm. Res. 29, 203–208. Cis, J., Nowak, G., Kisiel, W., 2006. Antifeedant properties and chemotaxonomic implications of sesquiterpene lactones and syringin from Rhaponticum pulchrum. Biochem. Syst. Ecol. 34, 862–867. Collado, L.G., Macias, F.A., Massanet, G.M., Molinillo, J.M.G., Luis, F.R., 1987. Chemical transformation of deacylsuexpinnatin into the natural oxetane lactone subexpinnatin C. J. Org. Chem. 52, 3323–3326. Csapi, B., Hajdù, Z., Zupkò, I., Berènyi, A., Forgo, P., Szabò, P., Hohmann, J., 2010. Bioactivity-guided isolation of antiproliferative compounds from Centaurea arenaria. Phytother. Res. 24, 1664–1669. Çelik, S., Rosselli, S., Maggio, A.M., Raccuglia, R.A., Uysal, I., Kisiel, W., Michalska, K., Bruno, M., 2006. Guaianolides and lignans from the aerial parts of Centaurea ptosimopappa. Biochem. Syst. Ecol. 34, 349–352. Clarke, K.R., Gorley, R.N., 2006. PRIMER v6: User Manual/Tutorial. PRIMER-E, Plymouth. Dai, J.Q., Hou, Z.F., Zhu, Q.X., Yang, L., Li, Y., 2001. Sesquiterpenes and flavonoids from Serratula strangulata. J. Chin. Chem. Soc. 48, 249–252. Daniewski, W., Wawrzuń, A., Błoszyk, E., Droźdź, B., Holub, M., 1982. Terpenes. CCLXVIII. Sesquiterpenic lactones from Grossheimia macrocephala. Structure of grossheiminol. Coll. Czech. Chem. Commum. 47, 3160–3163. Daniewski, W.M., Nowak, G., Routsi, E., Rychlewska, U., Szczepańska, B., Skibicki, P., 1992. Salograveolide A, a sesquiterpene from Centaurea salonitana. Phytochemistry 31, 2891–2893. Daniewski, W.M., Nowak, G., Pankowska, E., Georgiadis, T., Routsi, E., Rychlewska, U., Szczepańska, B., 1993. Sesquiterpene lactones of Centaurea salonitana. Phytochemistry 34, 445–447. Daniewski, W.M., Nowak, G., 1993. Further sesquiterpene lactones of Centaurea bella. Phytochemistry 32, 204–205. Dawidar, A.M., Metwally, M.A., Abou-Elzahab, M., Abdel-Mogib, M., 1989. Chemical constituents of two Centaurea species. Pharmazie 44, 735–736. De Marino, S., Borbone, N., Zollo, F., Ianaro, A., Di Meglio, P., Iorizzi, M., 2005. New sesquiterpene lactones from Laurus nobilis leaves as inhibitors of nitric oxide production. Planta Med. 71, 706–710. Djeddi, S., Karioti, A., Sokovic, M., Stojkovic, D., Serdi, R., Skaltsa, H., 2007. Minor sesquiterpene lactones from Centaurea pullata and their antimicrobial activity. J. Nat. Prod. 70, 1796–1799. Djeddi, S., Argyropoulou, C., Skaltsa, H., 2008a. Secondary metabolites from Centaurea grisebachii ssp. grisebachii. Biochem. Syst. Ecol. 36, 336–339. Djeddi, S., Karioti, A., Sokovic, M., Koukoulitsa, C., Skaltsa, H., 2008b. A novel sequiterpene lactone from Centaurea pullata: structure elucidation, antimicrobial activity and prediction of pharmacokinetic properties. Bioorg. Med. Chem. 16, 3725–3731. Djeddi, S., Chatter, R., Karioti, A., Argyropouklou, C., Karrat, R., Skaltsa, H., 2008c. Analgesic activity of secondary metabolites from two Centaurea species. Planta Med. 74, 947. Drozdz, B., 1966. Isolation of cnicin from the herbs of Centaurea diffusa Lam. Diss. Pharm. Pharmacol. 18, 281–283. Drozdz, B., 1967. Occurrence of cincin in the foliage of Centaurea calcitrapa, C. iberica, C. ovina. Diss. Pharm. Pharmacol. 19, 223–225. Drozdz, B., 1968. Sesquiterpene lactones. III. Bitter sesquiterpene lactones in species of the tribe Cynareae. Diss. Pharm. Pharmacol. 20, 93–103. El Dahmy, S., Bohlmann, F., Sarg, T.M., Ateya, A., Farrag, N., 1985. New guaianolides from Centaurea aegyptiaca. Planta Med. 51, 176–177. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx El Hassany, B., El Hanbali, F., Akssira, M., Mellouki, F., Haidour, A., Barrero, A.F., 2004. Germacranolides from Anvillea radiata. Fitoterapia 75, 573–576. El-Marsy, S., Vuilhorgne, M., Evans, F.J., 1984. Sesquiterpene lactones from Aegialophila pumila. Planta Med. 50, 115. El-Marsy, S., Darwish, F.A., Abou-Donia, A., Abou-Karam, M.A., Grenz, M., 1985. Sesquiterpene lactones from Centaurea glomerata. Phytochemistry 24, 999– 1001. El-Moghazy, S.A., Ahmed, A.A., Abdel-Ghani, H.F., El-Shanawany, M.A., 2002. A new eudesmane derivative from Onopordum ambiguum. Fitoterapia 73, 97–98. El-Najjar, N., Dardouki, S., Darwiche, N., El-Sabban, M., Saliba, N.A., Gali-Muhtasib, H., 2008. Anti-colon cancer effects of Salograviolide A isolated from Centaurea ainetensis. Oncology Rep. 19, 897–904. Emendoerfer, F., Emendoerfer, F., Bellato, F., Noldin, V.F., Cechinel-Filho, V., Yunes, R.A., Delle Monache, F., Cardozo, A.M., 2005. Antispasmodic activity of fractions and cynaropicrin from Cynara scolymus on guinea-pig ileum. Biol. Pharm. Bull. 28, 902–904. Evstratova, R.I., Rzazade, R.Ya., Rybalko, K.S., 1966. Repin a new sesquiterpene lactone from Acroptilon repens. Khim. Prir. Soedin. 2, 290. Evstratova, R.I., Rybalko, K.S., Rzazade, R.Ya., 1967. Acroptilin – a new sesquiterpene lactone from Acroptilon repens. Khim. Prir. Soedin. 3, 284. Evstratova, R.I., Mukhametzhanov, M.N., Sheichenko, V.I., Shreter, A.I., Pakaln, D.A., 1969. Isolation of repin from Centaurea hyrcanica. Khim. Prir. Soedin. 5, 186. Evstratova, R.I., Kiseleva, E.Ya., Sheichenko, V.I., Rybalko, K.S., 1971. The strutture of acroptilin – a sesquiterpene lactone from Acroptilon repens. Khim. Prir. Soedin. 6, 272–276. Evstratova, R.I., Rybalko, K.S., Sheichenko, V.I., 1972. The strutture of the sesquiterpene lactone repin. Khim. Prir. Soedin. 7, 451–461. Evstratova, R.I., Sheichenko, V.I., Rybalko, K.S., 1973. The strutture of acroptilin – a sesquiterpene lactone from Acroptilon repens. Khim. Prir. Soedin. 8, 161–167. Farrag, N.M., Abd El Aziz, E., El-Domiaty, M.M., El Shafea, A.M., 1993. Phytochemical investigation of Centaurea araneosa growing in Egypt. Zagazig J. Pharm. Sci. 2, 29–45, C.A. 120, 240145r. Fernandez, I., Garcia, B., Grancha, F.J., Pedro, J.R., 1987. Two guaianolides from Centaurea collina. Phytochemistry 26, 2403–2405. Fernandez, I., Garcia, B., Grancha, F.J., Pedro, J.R., 1989. Sesquiterpene lactones, flavones and coumarins from Centaurea collina. Phytochemistry 28, 2405–2407. Fernandez, I., Pedro, J.R., Polo, E., 1995. Sesquiterpene lactones of Centaurea alba and C. conifera. Phytochemistry 38, 655–657. Fischer, H.H., Lu, T., Cantrell, C.L., Castaneda-Acosta, J., Quijano, L., Franzblau, S.G., 1998. Antimycobacterial evaluation of germacranolides. Phytochemistry 49, 559–564. Flamini, G., Stoppelli, G., Morelli, I., Ertugul, K., Dural, H., Tugay, O., Demirelma, H., 2004. Secondary metabolites from Centaurea isaurica from Turkey and their chemotaxonomical significance. Biochem. Syst. Ecol. 32, 553–557. Fontana, G., La Rocca, S., Passannanti, S., Paternostro, M.P., 2007. Sesquiterpene compounds from Inula viscosa. Nat. Prod. Res. 21, 824–827. Forgacs, P., Desconclois, J.F., Dubec, J., 1981. Flavones and sesquiterpene lactones of Volturella divaricatica. Planta Med. 42, 284–287. Fortuna, A.M., de Riscala, E.C., Catalan, C.A.N., Gedris, T.E., Herz, W., 2001. Sesquiterpene lactones from Centaurea tweediei. Biochem. Syst. Ecol. 29, 967– 971. Fortuna, A.M., de Riscala, E.C., Catalan, C.A.N., Gedris, T.E., Herz, W., 2002. Sesquiterpene lactones and other constituents of Centaurea diffusa. Biochem. Syst. Ecol. 30, 805–808. Fukuda, K., Akao, S., Ohno, Y., Yamashita, K., Fujiwara, H., 2001. Inhibition by costunolide of phorbol ester-induced transcriptional activation of inducible nitric oxide synthase gene in a human monocyte cell line THP-1. Cancer Lett. 164, 7–13. Gadeschi, E., Jorge, Z.D., Massanet, G.M., Luis, F.R., 1989. Two derivatives of costic acid from Centaurea arguta. Phytochemistry 28, 2204–2206. Garcia, B., Skaltsa, H., Navarro, F.I., Pedro, J.R., Lazari, D., 1996. Sesquiterpene lactones and elemane derivatives from Onopordum myriacanthum. Phytochemistry 41, 1113–1117. Garcia-Jacas, N., Susanna, A., Mozaffarian, R., Ilarslan, R., 2000. The natural delimitation of Centaurea (Asteraceae: Cardueae): ITS sequence analysis of the Centaurea jacea group. Plant Syst. Evol. 223, 185–199. Garcia-Jacas, N., Uysal, T., Romashchenko, K., Suárez-Santiago, V.N., Ertuğrul, K., Susanna, A., 2006. Centaurea revisited: a molecular survey of the Jacea group. Ann. Bot. 98, 741–753. Georgiadou, E., Skaltsa, H., Lazari, D., Garcia, B., Harvala, C., 2000. A novel eudesmanolide from Centaurea thessala ssp. drakiensis. Nat. Prod. Lett. 14, 167–173. Geppert, B., Droźdź, B., Kiełczewskii, M., Holub, M., 1983. Sesquiterpene lactones. XXIII. Isolation of sesquiterpene lactones from Centaurea species. Acta Soc. Bot. Pol. 52, 23–34. Ghantous, A., Abou Tayyoun, A., Abou Lteif, G., Saliba, N.A., Gali-Muhtasib, H., ElSabban, M., Darwiche, N., 2008. Purified salograviolide A isolated from Centaurea ainetensis causes growth inhibition and apoptosis in neoplastic epidermal cells. Int. J. Oncol. 32, 841–849. Giordano, O.S., Guerreiro, E., Pestchanker, M.J., Guzman, J., Pastor, D., Guardia, T., 1990. The gastric cytoprotective effect of several sesquiterpene lactones. J. Nat. Prod. 53, 803–809. Giordano, O.S., Pestchanker, M.J., Guerreiro, E., Saad, J.R., Enriz, R.D., Rodriguez, A.M., Jauregui, E.A., Guzman, J., Maria, A.O.M., Wendel, G.H., 1992. Structure–activity 69 relationship in the gastric cytoprotective effect of several sesquiterpene lactones. J. Med. Chem. 35, 2452–2458. Gonzalez, A.G., Bermejo, J., Breton, J.L., Betancor, C., 1967. Amberboin, a new sesquiterpene lactone from Amberboa lippii D.C.. An. Quim. 63, 965–966. Gonzalez, A.G., Garcia Marrero, B., Breton, J.L., 1970. Terpenoides de las Compuestas. X. Estructura de la grosshemina, lipidiol, e isolipidiol. Lactonas de la Ambrerboa (Centaurea) lippii DC e su posible estereoquimica. An. Quim. 66, 799–813. Gonzalez, A.G., Arteaga, J.M., Bermejo, J., Breton, J.L., 1971. Quimica de las Compuestas. XIII. Melitensina, nueva lactona sesquiterpenica de la Centaurea melitensis L.. An. Quim. 67, 1243–1244. Gonzalez, A.G., Bermejo, J., Breton, J.L., Triana, J., 1972a. Constituents of compositae. XV. Chlorohyssopifolin A and B, two new sesquiterpene lactones isolated from Centaurea hyssopifolia. Tetrhedron Lett., 2017–2020. Gonzalez, A.G., Bermejo, J., Rodriguez Rincones, M., 1972b. Quimica de las Compuestas. XII. Dihidroestafiatna aislada de la Centaurea webbiana Sch. Bip. An. Quim. 68, 333–334. Gonzalez, A.G., Artega, J.M., Bretòn, J.L., 1973a. Germacranolides from Centaurea seridis. Phytochemistry 12, 2997–2999. Gonzalez, A.G., Bermejo, J., Massanet, G.M., Perez, J., 1973b. Muricatina, una nueva lactona sesquiterpenica aislada de la Amberboa muricata. An. Quim. 69, 1333– 1334. Gonzalez, A.G., Bermejo, J., Cabrera, J., Massanet, G.M., 1974a. Quimica de las compuestas. XX. 11,13Dehidromelitensina y chlorohyssopifolina A, lactonas sesquiterpenicas aisladas de las Centaurea pullata L. y C. nigra L.. An. Quim. 70, 74–75. Gonzalez, A.G., Bermejo, J., Breton, J.L., Triana, J., 1974b. Chlorohyssopifolin C, D, E and vahelin, four new sesquiterpene lactones from Centaurea hyssopifolia. Phytochemistry 13, 1193–1197. Gonzalez, A.G., Artega, J.M., Breton, J.L., 1975. Elemanolides from Centaurea melitensis. Phytochemistry 14, 2039–2041. Gonzalez, A.G., Bermejo, J., Massanet, G.M., 1977a. Aportacion al estudio quimiotaxonomico del genero Centaurea, determinacion estructurales de la lactona sesquiterpenicas presentes en Centaureas de Canarias y de la peninsula iberica. Rev. Latinoamer. Quim. 8, 176–180. Gonzalez, A.G., Bermejo, J., Cabrera, I., Galindo, A., Massanet, G.M., 1977b. Quimica de las compuestas. XXIX. Principios activos de la Centaurea janeri. An. Quim. 73, 86–87. Gonzalez, A.G., Darias, V., Alonso, G., Boada, J.N., Feria, M., 1978a. Cytostatic activity of sesquiterpene lactones from compositae of the Canary Islands. Planta Med. 33, 356–359. Gonzalez, A.G., Bermejo, J., Amaro, J.M., Massanet, G.M., Galindo, A., Cabrera, I., 1978b. Sesquiterpene lactones from Centaurea linifolia. Can. J. Chem. 56, 491– 494. Gonzalez, A.G., Bermejo, J., Cabrera, I., Massanet, G.M., Mansilla, H., Galindo, A., 1978c. Two sesquiterpene lactones from Centaurea canariensis. Phytochemistry 17, 955–956. Gonzalez, A.G., Bermejo, J., Zaragozza, T., Velasquez, R., 1980a. Quimica de las compuestas. XLIII. Lactonas sesquiterpenicas de la Centaurea amara. An. Quim. 76, 296–297. Gonzalez, A.G., Darias, V., Alanso, G., Estevez, E., 1980b. The cytostatic activity of chlorohyssopifolins, chlorinated sesquiterpene lactone from Centaurea. Planta Med. 40, 179–184. Gonzalez, A.G., Bermejo, J., Toledo, F., Daza, L.R., 1981. Sesquiterpene lactones from Centaurea arbutifolia. Phytochemistry 20, 1895–1897. Gonzalez, A.G., De Rosa, A.D., Massanet, G.M., 1982. Subexpinnatin, a new guaianolide from Centaurea canariensis. Phytochemistry 21, 895–897. Gonzalez, A.G., Velasquez, J.M., Breton, J.L., 1983. Lactonas sesquiterpenicas de la Centaurea solstitialis. Quimica de las compuestas XLVII. An. Quim. 79, 469–470. Gonzalez, A.G., Bermejo Barrera, J., Zaragoza Garcia, T., Estevez Rosas, F., 1984. Sesquiterpene lactones from Centaurea species. Phytochemistry 23, 2071–2072. Gonzalez, A.G., Castañeda Acosta, J., Bermejo Barrera, J., De Paz, P.P., 1993. Distibution of sesquiterpene lactones in Cheirolophus from Canary Islans. Biochem. Syst. Ecol. 21, 267–270. Gonzalez Collado, I., Macias, F.A., Massanet, G.M., Rodriguez Luis, F., 1985. Guaianolides from Centaurea canariensis. Phytochemistry 24, 2107–2109. Gonzalez Collado, I., Macias, F.A., Massanet, G.M., Rodriguez Luis, F., 1986a. Guayanolideas naturales con anillo oxetano. Rev. Latinoamer. Quim. 16, 128– 141. Gonzalez Collado, I., Macias, F.A., Massanet, G.M., Rodriguez Luis, F., 1986b. Structure, chemistry and stereochemistry of clementeins, sesquiterpene lactones from Centaurea clementei. Tetrahedron 42, 3611–3622. Gonzalez-Coloma, A., Guadano, A., Tonn, C.E., Sosa, M.E., 2005. Antifeedant/ Insecticidal terpene from Asteraceae and Labiatae species native to Argentinian semi-arid lands. Z. Naturforsch. C 60c, 855–861. Gonzalez-Platas, J., Ruiz-Perez, C., Gonzalez, A.G., Bermejo, J., Medjroubi, K., 1999. 4b,15-Dihydro-3-dehydrosolstitialin A. Acta Crystallogr. C Cryst. Struct. Commun. 55, 1837–1839. Goren, N., Woerdenbag, H.J., Bozok-Johansson, C., 1996. Cytotoxic and antibacterial activities of sesquiterpene lactones isolated from Tanacetum praeteritum. Planta Med. 62, 419–422. Gousiadou, C., Skaltsa, H., 2003. Secondary metabolites of Centaurea orphanidea. Biochem. Syst. Ecol. 31, 389–396. Gürbuz, I., Özçelik, B., Karaaoglu, T., Yesilada, E., 2006. Antiviral and antimicrobial activities of three sesquiterpene lactone from Centaurea solstitialis L. ssp. solstitialis. Planta Med. 72, 1004. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 70 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Gürbüz, I., Yesilada, E., 2007. Evaluation of the anti-ulcerogenic effect of sesquiterpene lactones from Centaurea solstitialis L. ssp. solstitialis by using various in vivo and biochemical techniques. J. Ethnopharmacol. 112, 284–291. _ Öksöz, S., 1998. Cytotoxicity assay of some plants from Gürkan, E., Sarioğlu, I., Asteraceae. Fitoterapia 69, 81–82. Ha, T.J., Jang, D.S., Lee, J.R., Lee, K.D., Lee, J., Hwang, S.W., Jung, H.J., Nam, S.H., Park, K.H., Yang, M.S., 2003. Cytotoxic effects of sesquiterpene lactones from the flowers of Hemisteptia lyrata. Arch. Pharm. Res. 26, 925–928. Hamburger, M., Wang, Y., Cheng, C.H.K., Costall, B., Naylor, R.J., Jenner, P., Hostettmann, K., 1991. Neurotoxic sesquiterpene lactones from the yellow starthistle Centaurea solsititialis, large scale isolation and biological activity. Planta Med. 57 (Sup.2), A8–A9. Hamburger, M., Wolfender, J.L., Hostettmann, K., 1993. Search for chlorinated sesquiterpene lactones in the neurotoxic thistle Centaurea solstitialis by liquid chromatography–mass spectrometry, and model studies on their possible artifactual formation. Nat. Toxins 1, 315–327. Harley-Mason, J., Hewson, A.T., Kennard, O., Pettersen, R.C., 1972. Isolation of centaurepensin, a guaianolide sesquiterpene lactone ester containing two chlorine atom; determination of structure and absolute configuration by X-ray crystallography. J. Chem. Soc. Chem. Commun., 460–461. Harraz, F.M., Kassem, F.F., El-Shaer, N.S., 1994. Sesquiterpene lactones and flavonoids from Centaurea bruguierana. Alexandria J. Pharm. Sci. 8, 219–222, C.A. 123, 193614t. Harrison, D.A., Kulshreshtha, D.K., 1984. Chemical constituentd of Amberboa ramosa. Fitoterapia 55, 189–192. Hay, A.J., Hamburger, M., Hostettmann, K., Hoult, J.R.S., 1994. Toxic inhibition of smooth muscle contractility by plant-derived sesquiterpenes caused by their chemically reactive alpha-melhylenebutyrolactone functions. Br. J. Pharmacol. 112, 9–12. Helal, A.M., Nakamura, N., Meselhy, M.R., El-Fishawy, A.M., Hattori, M., Mahran, G.H., 1997. Guaianolides of Centaurea scoparia. Phytochemistry 45, 551–554. Hibasami, H., Yamada, Y., Moteki, H., Katsuzaki, H., Imai, K., Yoshioka, K., Komiya, T., 2003. Sesquiterpenes (costunolide and zaluzanin D) isolated from laurel (Laurus nobilis L.) induce cell death and morphological change indicative of apoptotic chromatin condensation in leukemia HL-60 cells. Int. J. Mol. Med. 12, 147–151. Hidalgo, O., Garcia-Jacas, N., Garnatje, T., Susanna, A., 2006. Phylogeny of Rhaponticum and related genera inferred from nuclear and chloroplast DNA sequence data: taxonomic and biogeographic implications. Ann. Bot. 97, 705–714. Hilmi, F., Sticher, O., Heilmann, J., 2003. New cytotoxic sesquiterpene lactones from Warionia saharae. Planta Med. 69, 462–464. Horoszkiewicz-Hassan, M., Nowak, G., 2001. Germacranolides in Centaurea crocodylium. Herba Polonica 47, 122–124. Hsu, H.F., Wu, Y.C., Chen, L.C., Houng, J.Y., 2009. Induction of apoptosis of A549 lung cancer cell line by dehydrocostus lactone isolated from Glossogyne tenuifolia. J. Food Drug Anal. 17, 107–115. Hsu, J.L., Pan, S.L., Ho, Y.F., Hwang, T.L., Kung, F.L., Guh, J.H., 2011. Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer. J. Urol. 185, 1967–1974. Hsu, Y.L., Wu, L.Y., Kuo, P.L., 2009. Dehydrocostuslactone, a medicinal plant-derived sesquiterpene lactone, induces apoptosis coupled to endoplasmic reticulum stress in liver cancer cells. J. Pharmacol. Exp. Ther. 329, 808–819. Huneck, S., Jakupovic, J., Schuster, A., 1986a. Weitere Inhaltsstffe aus Centaurea stoebe. Planta Med. 52, 398–399. Huneck, S., Knapp, H.D., 1986. Components of further Compositae of Mongolia. Pharmazie 41, 673. Hung, J.Y., Hsu, Y.L., Ni, W.C., Tsai, Y.M., Yang, C.J., Kuo, P.L., Huang, M.S., 2010. Oxidative and endoplasmic reticulum stress signaling are involved in dehydrocostuslactone-mediated apoptosis in human non-small cell lung cancer cells. Lung Cancer 68, 355–365. Ibrahim, M., Khan, R., Malik, A., 2010. Two new guaianolides from Amberboa ramosa. Nat. Prod. Commun. 5, 1865–1868. Im, S.S., Kim, J.R., Lim, H.A., Jang, C.H., Kim, Y.K., Konishi, T., Kim, E.J., Park, J.H.Y., Kim, J.S., 2007. Induction of detoxifying enzyme by sesquiterpenes present in Inula helenium. J. Med. Food 10, 503–510. Isamukhamedova, Sh.Z., Dobronravova, E.K., Shakirov, T.T., 1977. Method for the quantitative determination of cnicin in Centaurea squarrosa. Khim. Prir. Soedin. 12, 418–419. Ishida, K., Kojima, R., Tsuboi, M., Tsuda, Y., Ito, M., 2010. Effects of artichoke leaf extract on acute gastric mucosal injury in rats. Biol. Pharm. Bull. 33, 223–229. Ismail, S.I., Hammouda, F.M., Rimpler, H., Abdallah, S.M., 1986. Flavonoids and sesquiterpene lactones. Constituents of Centaurea alexandrina. Planta Med. 52, 527. Jakupovic, J., Jia, Y., Pathak, V.P., Bohlmann, F., King, R.M., 1986. Bisabolene derivatives and sesquiterpene lactones from Centaurea species. Planta Med. 52, 399–401. Janaćković, P., Tešević, V., Milosavljević, S., Vajs, V., Marin, P.D., 2004. Sesquiterpene lactones, lignans and flavones of Centaurea affinis. Biochem. Syst. Ecol. 32, 355– 357. Jang, D.S., Park, K.H., Yang, M.S., 1998a. Germacranolides from flowers of Chrysanthemum boreale Makino. Saengyak Hakhoechi 29, 67–70. Jang, D.S., Park, K.H., Kim, H.M., Hong, D.H., Chun, H.K., Kho, Y.H., Yang, M.S., 1998b. Biological activities of sesquiterpene lactones isolated from several Compositae plants. Part 1. Cytotoxicity against cancer cell lines. Saengyak Hakhoechi 29, 243–247. Jang, D.S., Park, K.H., Ko, H.L., Lee, H.S., Kwon, B.M., Yang, M.S., 1999. Biological activities of sesquiterpene lactones isolated from several Compositae plants. Part 3. Inhibitory activity on nitric oxide release and ACAT. Saengyak Hakhoechi 30, 74–78. Jang, D.S., Ha, T.J., Choi, S.U., Nam, S.H., Park, K.H., Yang, M.S., 2000. Isolation of isoamberboin and isolipidiol from whole plants of Youngia japonica (L.) DC. Saengyak Hakhoechi 31, 306–309. Jimeno, M.L., Apreda-Rojas, M.C., Cano, F.H., Rogriguez, B., 2004. NMR and X-ray conformational study of artemisiifolin and three other related germacranolides. Magn. Res. Chem. 42, 474–483. Jeong, G.S., Pae, H.O., Jeong, S.O., Kim, Y.C., Kwon, T.O., Lee, H.S., Kim, N.S., Park, S.D., Chung, H.T., 2007. The a-methylene-c-butyrolactone moiety in dehydrocostus lactone is responsible for cytoprotective heme oxygenase-1 expression through activation of the nuclear factor E2-related factor 2 in HepG2 cells. Eur. J. Pharmacol. 565, 37–44. Jeong, S.J., Onoda, K., Miyamoto, T., Higuchi, R., Ono, M., Kuwano, M., Kim, Y.C., 2001. Research for novel angiogenesis inhibitors from natural products. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 43, 109–114. Jeong, S.J., Itokawa, T., Shibuya, M., Kuwano, M., Ono, M., Higuchi, R., Miyamoto, T., 2002. Costunolide, a sesquiterpene lactone from Saussurea lappa, inhibits the VEGFR KDR/Flk-1 signaling pathway. Cancer Lett. 187, 129–133. Jiang, X., Han, B., Li, X., Wang, Y., Luo, H., 1996. Study on centaurepensin by nuclear magnetic resonance. Zhongguo Yaowu Huaxue Zazhi 6, 276–282. Jin, M., Lee, H.J., Ryu, J.H., Chung, K.S., 2000. Inhibition of LPS-induced NO production and NF-jB activation by a sesquiterpene from Saussurea lappa. Arch. Pharm. Res. 23, 54–58. Jolad, S.D., Wiedhopf, R.M., Cole, J.R., 1974. Tumor-inhibitory agent from Zaluzania robinsonii (Compositae). J. Pharm. Sci. 63, 1321–1322. Jung, J.H., Ha, J.Y., Min, K.R., Shibata, F., Nakagawa, H., Kang, S.S., Chang, I.M., Kim, Y., 1998. Reynosin from Sassurea lappa as inhibitor on CINC-1 induction in LPSstimulated NRK-52E cells. Planta Med. 64, 454–455. Kakuda, H., Helal, A.M., Nakamura, N., Hattori, M., 1998. 8a-Hydroxy-11a,13dihydrozaluzanin C. Acta Crystallogr. C Cryst. Struct. Commun. C54, 113–114. Kaminskii, I.P., Saprykina, E.V., Krasnov, E.A., Kadyrova, T.V., Anosova, E.A., 2010a. The investigation of Centaurea scabiosa antiopisthorchiasis activity. Vopr. Biol. Med. Farm. Khim., 20–24. Kaminskii, I.P., Krasnov, E.A., Kadyrova, T.V., Sazonov, A.E., Rakhimova, B.B., Ivasenko, S.A., Adekenov, S.M., 2010b. Antiopisthorchiasis properties of extracts from Centaurea scabiosa. Rastit. Resur. 46, 106–111. Kaminskii, I.P., Kadyrova, T.V., Krasnov, E.A., 2010c. Accumulation dynamics of sesquiterpene lactones in above-ground parts of Centaurea scabiosa. Vopr. Biol. Med. Farm. Khim., 39–41. Kaminskii, I.P., Krasnov, E.A., Kadyrova, T.V., Ivasenko, S.A., Rakhimova, B.B., Adekenov, S.M., 2011. Quantitative HPLC determination of cynaropicrin in Centaurea scabiosa dry extract. Pharm. Chem. J. 45, 560–563. Kang, J.S., Yoon, Y.D., Lee, K.H., Park, S.K., Kim, M.H., 2004. Costunolide inhibits interleukin-1b expression by down-regulation of AP-1 and MAPK activity in LPS-stimulated RAW 264.7 cells. Biochem. Biophys. Res. Commun. 313, 171– 177. Kanno, S.I., Kitajima, Y., Kakuta, M., Osanai, Y., Kurauchi, K., Ujibe, M., Ishikawa, M., 2008. Costunolide-induced apoptosis is caused by receptor-mediated pathway and inhibition of telomerase activity in NALM-6 cells. Biol. Pharm. Bull. 31, 1024–1028. Karamenderes, C., Bedir, E., Pawae, R., Baykan, S., Khan, I.A., 2007a. Elemanolide sesquiterpenes and eudesmane sesquiterpene glycosides from Centaurea hierapolitana. Phytochemistry 68, 609–615. Karamenderes, C., Bedir, E., Abou-Gazar, H., Khan, I.A., 2007b. Chemical constituents of Centaurea cadmea. Chem. Nat. Comp. 43, 694–695. Karawya, M.S., Hilal, S.M., Sayed, H., Hifnawy, M.S., El-Hawary, S.S., 1975. Isolation and preliminary pharmacological and microbiological screening of cnicin from Centaurea calcitrapa L. growing in Egypt. Egypt J. Pharm. Sci. 16, 445–455. Karioti, A., Skaltsa, H., Lazari, D., Sokovic, M., Garcia, B., Harvala, C., 2002. Secondary metabolites from Centaurea deusta with antimicrobial activity. Z. Naturforsch. C 57c, 75–80, erratum 2004, 59c, 612. Kassuya, C.A.L., Cremoneze, A., Barros, L.F.L., Simas, A.S., da R. Lapa, F., Mello-Silva, R., Stefanello, M.E.A., Zampronio, A.R., 2009. Antipyretic and anti-inflammatory properties of the ethanolic extract, dichloromethane fraction and costunolide from Magnolia ovata (Magnoliaceae). J. Ethnopharmacol. 124, 369–376. Kataria, H., 1995. Phytochemical investigation of medicinal plants Cnicus wallichii and Cnicus benedictus. Asian J. Chem. 7, 227–228. Kelm, M.A., Nair, M.G., Schutzki, R.A., 1997. Mosquitocidal compounds from Magnolia salicifolia. Int. J. Pharmacogn. 35, 84–90. Kelsey, R.G., Locken, L.J., 1987. Phtytotoxic properties of cnicin, a sesquiterpene lactone from Centaurea maculosa. J. Chem. Ecol. 13, 19–34. Khan, S., Yasmeen, S., Afza, N., Malik, A., Iqbal, L., Lateef, M., 2008. Cotonoates A and B, new aromatic esters from Cotoneaster racemiflora. Z. Naturforsch. B 63b, 1219–1222. Khan, S.B., 2004. Phytochemical Investigation on the Constituents of Amberboa ramosa. Doct. Thesis University of Karachi, Pakistan. Khan, S.B., Riaz, N., Afza, N., Malik, A., Haq, A.U., Ahmed, Z., Lodhi, M.A., Choudhary, M.I., 2004a. Urease inhibiying guaianolides from Amberboa ramosa. Polish J. Chem. 78, 2075–2080. Khan, S.B., Afza, N., Malik, A., Haq, A.U., Ahmed, Z., 2004b. Structure determination of ramosine, a guaianolide, by NMR spectroscopy. Magn. Res. Chem. 42, 1063– 1065. Khan, S.B., Malik, A., Afza, N., Jahan, N., Haq, A.U., Ahmed, Z., Nawaz, S.A., Choudhary, M.I., 2004c. Enzyme inhibiying terpenoids from Amberboa ramosa. Z. Naturforsch. B 59b, 579–583. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Khan, S.B., Haq, A.U., Perveen, S., Afza, N., Malik, A., Nawaz, S.A., Shah, M.R., Choudhary, M.I., 2005a. Butyrylcholinesterase inhibitory guaianolides from Amberboa ramosa. Arch. Pharm. Res. 28, 172–176. Khan, S.B., Perveen, S., Afza, N., Malik, A., Haq, A.U., 2005b. Phytochemical studies on Amberboa ramosa. J. Chem. Soc. Pakistan 27, 437–439. Khan, S.B., Akhtar, K., Malik, A., Jang, E.S., Han, H., 2010. Pharmaceutical prospecting of natural products from the genus Amberboa. J. Med. Plant Res. 4, 1039–1052. Kim, D.H., Choi, J.H., Park, H.J., Park, J.H., Lee, K.T., 2010. Costunolide induces apoptosis via modulation of cyclin-dependent kinase in HL-60 human leukemia cells. Biomol. Ther. 18, 178–183. Kim, E.J., Lim, S.S., Park, S.Y., Shin, H.K., Kim, J.S., Park, J.H.Y., 2008. Apoptosis of DU145 human prostate cancer cells induced by dehydrocostus lactone isolated from the root of Saussurea lappa. Food Chem. Toxicol. 46, 3651–3658. Kim, J.I., Lee, S.H., Park, J.H., Park, H.J., Lee, K.T., 1999. Induction of differentiation on the human histocytic lymphoma cell line U-937 by costunolide. Saengyak Hakhoechi 30, 7–11. Kim, S.H., Kang, S.N., Kim, H.J., Kim, T.S., 2002. Potentiation of 1,25dihydroxyvitamin D3-induced differentiation of human promyelocytic leukemia cells into monocytes by costunolide, a germacranolide sesquiterpene lactone. Biochem. Pharmacol. 64, 1233–1242. Kokoska, L., Janovska, D., 2009. Chemistry and pharmacology of Rhaponticum carthamoides, a review. Phytochemistry 70, 842–855. Konishi, T., Shimada, Y., Nagao, T., Okabe, H., Konoshima, T., 2002. Antiproliferative sesquiterpene lactones from the roots of Inula helenium. Biol. Pharm. Bull. 25, 1370–1372. Konishi, T., Kondo, S., Uchiyama, N., 2008. Larvicidal activities of sesquiterpenes from Inula helenium (Compositae) against Aedes albopictus (Diptera, Culicidae) and Paratanytarsus grimmii (Diptera, Chironomidae). Appl. Entomol. Zool. 43, 77–81. Koo, T.H., Lee, J.H., Park, Y.J., Hong, Y.S., Kim, H.S., Kim, K.W., Lee, J.J., 2001. A sesquiterpene lactone, costunolide, from Magnolia grandiflora inhibits NF-j B by targeting Ij B phosphorylation. Planta Med. 67, 103–107. Korte, F., Beckmann, G., 1958. Chemical classification of plants XVII. The bitter principle of Cnicus benedictius. Naturwissenschaften 45, 390. Koukoulitsa, E., Skaltsa, H., Karioti, A., Demetzos, C., Dimas, K., 2002. Bioactive Sesquiterpene lactones from Centaurea species and their cytotoxic/cytostatic activity against human cell lines in vitro. Planta Med. 68, 649–652. Krasnov, E.A., Raldugin, V.A., Kadyrova, T.V., Kaminskii, I.P., 2006. Isolation of grosshemin from the Siberian population of Centaurea scabiosa. Chem. Nat. Comp. 42, 495–496. Krasnov, E.A., Kaminskii, I.P., Shul’ts, E.E., Kadyrova, T.V., 2011. Isolation of repin from the aerial part of Centaurea scabiosa. Chem. Nat. Comp. 47, 311–312. Krishna Kumari, G.N., Masilamani, S., Ganesh, M.R., Aravind, S., 2003. Microbiol transformation of zaluzanin-D. Phytochemistry 62, 1101–1104. Kuo, P.L., Ni, W.C., Tsai, E.M., Hsu, Y.L., 2009. Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells. Mol. Cancer Ther. 8, 1328–1339. Kunari, G.N.K., Masilamani, S., Ganesh, M.R., Aravind, S., Sridhar, S.R., 2003. 12Carboxyeudesma-3,11(13)-diene. Novel sesquiterpenic acid with a narrow antifungal spectrum. Fitoterapia 74, 479–482. Kurma, S.R., Mishra, S.H., 1997. Screening of anti-inflammatory and hepatoprotective activities of alantolactone, isolated from the roots of Inula racemosa. Indian Drugs 34, 571–575. Lakhal, H., Boudiar, T., Kabouche, A., Kabouche, Z., Touzani, R., Bruneau, C., 2010. New sesquiterpene lactone and other constituents from Centaurea sulphurea (Asteraceae). Nat. Prod. Commun. 5, 849–850. Landau, H., Müller-Schärer, H., Ward, P.I., 1994. Influence of cnicin, a sesquiterpene lactone from Centaurea maculosa, on specialist and generalist insect herbivores. J. Chem. Ecol. 20, 929–942. Lazari, D., Garcia, B., Skaltsa, H., Pedro, J.R., Harvala, C., 1998. Sesquiterpene lactones from Onopordum laconicum and O. sibthorpianum. Phytochemistry 47, 415–422. Lazari, D., Tsioumela, C., Pegklidou, K., Karioti, A., Demopoulos, V., Skaltsa, H., Arfan, M., 2008. Inhibitory activity of extracts and bioactive constituents of Centaurea phyllocephala Boiss. (Asteraceae) on aldose reductase in vitro. Planta Med. 74, 974–975. Lee, H.J., Kim, N.Y., Jang, M.K., Son, H.J., Kim, K.M., Sohn, D.H., Lee, S.H., Ryu, J.H., 1999. A sesquiterpene, dehydrocostus lactone, ininhibits the expression of inducibile. Nitric oxide synthhase and TNF in LPS-activated macrophages. Planta Med. 65, 104–108. Lee, J.S., Min, B.S., Lee, S., Na, M.K., Kwon, M.B., Lee, C.O., Kim, Y.H., Bae, K.H., 2002. Cytotoxic sesquiterpene lactones from Carpesium abrotanoides. Planta Med. 68, 745–747. Lee, K.D., Park, K.H., Kim, H., Kim, J., Rim, Y.S., Yang, M.S., 2003. Cytotoxic activity and structural analogues of guaianolide derivatives from the flowers of Chrysanthemum coronarium L.. Agric. Chem. Biotechnol. 46, 29–32. Lee, M.G., Lee, K.T., Chi, S.G., Park, J.H., 2001. Costunolide induces apoptosis by ROSmediated mitochondrial permeability transition and cytochrome C release. Biol. Pharm. Bull. 24, 303–306. Lee, Y.S., Choi, E.M., 2011. Costunolide stimulates the function of osteoblastic MC3T3-E1 cells. Int. Immunopharmacol. 11, 712–718. Li, X., Liu, J., Cai, J., Cai, P., 2008. Complete 1H and 13C data assignments of two new guaianolides isolated from Ainsliaea fragrans. Magn. Res. Chem. 46, 1070–1073. Li, Y., Jia, Z.J., 1989. Guaianolides from Saussurea involucrata. Phytochemistry 28, 3395–3397. 71 Li, Z., 2005. Application of santamarine as cytotoxic anticancer agent. Faming Zhuanli Shenqing Gongkai Shuomingshu. CN 1634034 A 20050706. Liu, C.Y., Chang, H.S., Chen, I.S., Chen, C.J., Hsu, M.L., Fu, S.L., Chen, Y.J., 2011. Costunolide causes mitotic arrest and enhances radiosensitivity in human hepatocellular carcinoma cells. Radiat. Oncology 6, 56. Locken, L.J., Kelsey, R.G., 1987. Cnicin concentration in Centaurea maculosa. Biochem. Syst. Ecol. 15, 313–320. Lonergan, G., Routsi, E., Georgiadis, T., Agelis, G., Hondrelis, J., Matsoukas, J., 1992. Isolation, NMR studies, and biological activities of onopordopicrin from Centaurea sonchifolia. J. Nat. Prod. 55, 225–228. Lopes-Rodriguez, M., Garcia, V.P., Zater, H., Benayache, S., Benayache, F., 2009. Cynaratriol, a sesquiterpene lactone from Centaurea musimomum. Acta Cryst. E65, o1867–o1868. Lotina-Hennsen, B., Bernal-Morales, E., Romo de Vivar, A., Perez-C, A.L., Castro-R, A., Aguilar-Martinez, M., 1992. Inhibition of oxygen evolution by zaluzanin C. J. Chem. Ecol. 18, 1891–1900. Luna-Herrera, J., Costa, M.C., Gonzalez, H.G., Rodrigues, A.I., Castilho, P.C., 2007. Synergistic antimycobacterial activities of sesquiterpene lactones from Laurus spp.. J. Antimicr. Chem. 59, 548–552. Lyss, G., Glasl, S., Jurenitsch, J., Pahl, H.L., Merfort, I.A., 2000. A sesquiterpene and sesquiterpene lactones from the Achillea millefolium group possess antiinflammatory properties but do not inhibit the transcription factor NF-kB. Pharm. Pharmacol. Lett. 10, 13–15. Ma, G., Chong, L., Li, Z., Cheung, A.H.T., Tattersall, M.H.N., 2009. Anticancer activities of sesquiterpene lactones from Cyathocline purpurea in vitro. Cancer Chemother. Pharm. 64, 143–152. Macias, F.A., Galindo, J.C.G., Castellano, D., Velasco, R.F., 1999a. Sesquiterpene lactones with potential use as natural herbicide models (I), trans,transgermacranolides. J. Agric. Food Chem. 47, 4407–4414. Macias, F.A., Galindo, J.C.G., Molinillo, J.M.G., Castellano, D., Velasco, R.F., Chinchilla, D., 1999b. Developing new herbicide model from allelochemicals. Pest. Sci. 55, 662–665. Macias, F.A., Galindo, J.C.G., Castellano, D., Velasco, R.F., 2010. Sesquiterpene lactones with potential use as natural herbicide models. 2. Guaianolides. J. Agric. Food Chem. 48, 5288–5296. Mahajan, R., Singh, P., Bajaj, K.L., Kalsi, P.S., 1986. Nematocidal activity of some sesquiterpenoids against root-knot nematode (Meloidogyne incognita). Nematologica 32, 119–123. Mahmoud, Z.F., Kasem, F.F., Abdel Salam, N.A., 1986. Sesquiterpene lactones and flavonoids of Centaurea ragusina ssp. ragusina growing in Egypt. Egypt J. Pharm. Sci. 27, 283–289. Malik, M.M., Naqvi, S.H.M., 1984. Isolation and identification of an insect repellent compound from Saussurea lappa C.B. Clarke. Pakistan J. Sci. Ind. Res. 27, 144– 145. Mallabaev, A., Saitbaeva, I.M., Sidyakin, G.P., 1982. Components of Acroptilon repens. Khim. Prir. Soedin., 123. Marco, J.A., Sanz, J.F., Yuste, A., Jakupovic, J., 1991. A novel germacranolideaminoacid adduct dimer from Centaurea aspera. Tetrahedron Lett. 32, 5193– 5194. Marco, J.A., Sanz, J.F., Sancenon, F., Susanna, A., Rustayan, A., Saber, M., 1992. Sesquiterpene lactones and lignans from Centaurea species. Phytochemistry 31, 3527–3530. Marco, J.A., Sanz, J.F., Albiach, R., Rustaiyan, A., Habibi, Z., 1993. Bisabolene derivatives and sesquiterpene lactones from Cousinia species. Phytochemistry 32, 395–400. Marco, J.A., Sanz-Cervera, J.F., Garcia-Lliso, V., Susanna, A., Garcia-Jacas, N., 1994. Sesquiterpene lactones, lignan and aromatic esters from Cheirolophus species. Phytochemistry 37, 1101–1107. Marco, J.A., Sanz-Cervera, F.J., Yuste, A., Sancenòn, F., Carda, M., 2005. Sesquiterpenes from Centaurea aspera. Phytochemistry 66, 1644–1650. Massanet, G.M., Collado, I.G., Macias, F.A., 1983. Structural determination of clementein, a new guaianolise isolated from Centaurea clementei. Tetrahedron Lett. 24, 1641–1642. Massiot, G., Morfaux, A.M., Le Men-Olivier, L., Bouquant, J., Madaci, A., Mahamoud, A., Chopova, M., Alcinou, P., 1986. Guaianolides from the leaves of Centaurea incana. Phytochemistry 25, 258–261. Mata, R., Rivero-Cruz, I., Rivero-Cruz, B., Bye, R., Timmermann, B.N., 2002. Sesquiterpene lactones and phenylpropanoids from Cosmos pringlei. J. Nat. Prod. 65, 1030–1032. Matsuda, H., Shimoda, H., Uemura, T., Yoshikawa, M., 1999. Preventive effect of sesquiterpenes from bay leaf on blood ethanol elevation in ethanol-loaded rat, structure requirement and suppression of gastric emptying. Bioorg. Med. Chem. Lett. 9, 2647–2652. Matsuda, H., Kagerura, T., Toguchida, I., Ueda, H., Morikawa, T., Yoshikawa, M., 2000a. Inhibitory effects of sesquiterpenes from bay leaf on nitric oxide production in lipopolysaccharide-activated macrophages, structure requirement and role of heat shock protein induction. Life Sci. 66, 2151–2157. Matsuda, H., Kageura, T., Inoue, Y., Morikawa, T., Yoshikawa, M., 2000b. Absolute stereostructures and synthesis of saussureamines A, B, C, D and E, amino-acid sesquiterpenes conjigates with gastroprotective effect, from roots of Saussurea lappa. Tetrahedron 56, 7763–7777. Matsuda, H., Shimoda, H., Ninomiya, K., Yoshikawa, M., 2002. Inhibitory mechanism of costunolide, a sesquiterpene lactone isolated from Laurus nobilis, on bloodethanol elevation in rats. Involvement of inhibition of gastric emptying and increase in gastric juice secretion. Alcohol Alcohol. (Oxford, UK) 37, 121–127. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 72 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Matsuda, H., Toguchida, I., Ninomiya, K., Kageura, T., Morikawa, T., Yoshikawa, M., 2003. Effect of sesquiterpene and amino acid-sesquiterpene conjugate from the roots of Sassurea lappa on inducible nitric oxide synthase and heat shock protein in lipopolysaccharide activated macrophages. Bioorg. Med. Chem. 11, 709–715. Mattern, G., Weckert, E., Youssef, D., Frahm, A.W., 1996. Absolute configuration of chlorojanerin, a chloro-containing guaianolide from Centaurea scoparia. Acta Crystallogr. C Cryst. Struct. Commun. C52, 1791–1793. Maymò, A.C., Cervera, A., Garcerà, M.D., Martinez, R., 1999. Sesquiterpene-related compounds as endocrine disrupters in Oncopeltus fasciatus and potential reduced glutathione synthesis modifiers. Sci. Total Environ. 233, 263–266. Medjroubi, K., Benayache, F., Benayache, S., Akkal, S., Khalfallah, N., Aclinou, P., 1997. Guaianolides of Centaurea musimomum. Phytochemistry 45, 1449–1451. Medjroubi, K., Benayache, F., Benayache, S., Akkal, S., Kaabeche, M., Tillequin, F., Seguin, E., 1998. Eudesmanolide from Centaurea granata. Phytochemistry 49, 2425–2427. Medjroubi, K., Bounderdara, N., Benayache, F., Akkal, S., Seguin, E., Tillequin, F., 2003a. Sesquiterpene lactones of Centaurea nicaensis. Chem. Nat. Comp. 39, 506–507. Medjroubi, K., Benayache, F., Leon, F., Bermejo, J., 2003b. Complete assignment of 13 C and 1H spectra of two known guaianolides isolated from Centaurea musimomun. Rev. Colomb. Quim. 32, 17–22. Medjroubi, K., Benayache, F., Bermejo, J., 2005. Sesquiterpene lactones from Centaurea musimomum. Antiplasmodial and cytotoxic activity. Fitoterapia 76, 744–746. Meepagala, K.M., Osbrink, W., Sturtz, G., Lax, A., 2006. Plant-derived natural products exhibiting activity against Formosan subterranean termites (Coptotermes formosanus). Pest Manag. Sci. 62, 565–570. Meragelman, K.M., Espinar, L.A., Sosa, V.E., 1998. New sesquiterpene lactones and other constituents from Helianthus petiolaris. J. Nat. Prod. 61, 105–107. Merrill, G.B., Stevens, K.L., 1985. Sesquiterpene lactones from Centaurea solstitialis. Phytochemistry 24, 2013–2018. Mezache, N., Bendjeddou, D., Satta, D., Mekkiou, R., Benayache, S., Benayache, E., 2010. Secondary metabolites from Centaurea lippii. Chem. Nat. Comp. 46, 801– 802. Milkova, T., Marekov, N., Welzel, P., Hobert, K., 1993. Constituens of Centaurea diffusa. Dokl. Bulg. Akad. Nauk. 46, 29–31. Mir-Babaev, N.F., Sereda, N.P., 1987. Antioxidant activity of alantolactone and isoalantolactone. Khim. Prir. Soedin., 752–753. Modonova, L.D., Semenov, A.A., Zhapova, T., Ivanova, N.D., Dzhaparova, A.K., Fedoseev, A.P., Kirdei, E.G., Malkova, T.I., 1986. Biological activity of extracts of Saussurea amara. Khim.-Farm. Zh. 20, 1472–1475. Monea, M., 1986. Phytochemical investigation of the Grossheimia macrocephala species. Farmacia (Romania) 34, 187–190. Mori, H., Kawamori, T., Tanaka, T., Ohnishi, M., Yamahara, J., 1994. Chemopreventive effect of costunolide, a constituent of oriental medicine, on azoxymethaneinduced intestinal carcinogenesis in rats. Cancer Lett. 83, 171–175. Muhammad, I., Takamatsu, S., Mossa, J.S., El-Feraly, F.S., Walker, L.A., Clark, A.M., 2003. Cytotoxic sesquiterpene lactones from Centaurthamnus maximus and Vicoa pentanema. Phytother. Res. 17, 168–173. Mukhametzhanov, N.M., Sheichenko, V.I., Ban’kovskii, A.I., Rybalko, K.S., Boryaev, K.I., 1969a. Stizolin, a new sesquiterpene lactone from Stizolophus balsamita. Khim. Prir. Soedin. 5, 56–57. Mukhametzhanov, M.N., Sheichenko, V.I., Rybalko, K.S., Pakaln, D.A., 1969b. A new sesquiterpene lactone from Stizolophus coronopifolia. Khim. Prir. Soedin. 5, 125. Mukhametzhanov, M.N., Shreter, A.I., Pakaln, D.A., 1969c. Stizolicin from Centaurea solstitialis. Khim. Prir. Soedin. 5, 590–591. Mukhametzhanov, M.N., Sheichenko, V.I., Rybalko, K.S., Boryaev, K.I., 1969d. Isolation of grosshemin from Chartolepis intermedia. Khim. Prir. Soedin. 5, 184–186. Mukhametzhanov, M.N., Sheichenko, V.I., Ban’kovskii, A.I., Rybalko, K.S., 1970. Structure of the sesquiterpene lactone stizolicin. Khim. Prir. Soedin. 7, 505–508. Mukhametzhanov, M.N., Sheichenko, V.I., Ban’kovskii, A.I., Rybalko, K.S., 1971. A sesquiterpene lactone from Stizolophus balsamita. Khim. Prir. Soedin. 6, 405– 412. Naidenova, E., Kolarova-Parlova, I., Popov, D.V., Dimitrova-Konaklieva, S., Dryanovska-Noniska, L., 1988. Isolation and obtaining of sesquiterpene lactones with antitumor properties – xanthinin, stizolicin and solstitialin. Dokl. Bulg. Akad. Nauk. 41, 105–106. Navarro, J.J., Caballero, M.C., Moran, J.R., Medarde, M., Grande, M., Anaya, J., 1990. Guaianolides and eudesmanolides from Centaurea ornata. J. Nat. Prod. 53, 573– 578. Ndom, J.C., Mbafor, J.T., Wansi, J.D., Kamdem, A.W., Meva’a, L.M., Vardamides, J.C., Toukam, D., Pegyemb, D., Ngando, T.M., Laatsch, H., Fomum, Z.T., 2006. Sesquiterpene lactone from Crepis cameroonica. Nat. Prod. Res. 20, 435–442. Negrete, R.E., Backhouse, N., Avendano, S., Martin, A.S., 1984. Dehydrocostus lactone et 8-a-hidroxydehydrocostus lactone de Centaurea chilensis. Plantes Med. Phytother. 18, 226–232. Negrete, R.E., Backhouse, N., San Martin, A., Casseis, B.K., Hartmann, R., Breitmaier, E., 1988a. Guaianolides from Centaurea chilensis and C. floccosa. Chem. Ztg. 112, 144–146. Negrete, R.E., Latorre, I., Backhouse, N., Peña, R., Delporte, C., 1988b. Etudes anatomiques et phytochimique, flavonoides et lactone de Centaurea chilensis. Plantes Med. Phytother. 22, 1–10. Negrete, R.E., Backhouse, N., Cajigal, I., Delporte, C., Cassels, B.K., Breitmaier, E., Eckhardt, G., 1993. Two new antiinflammatory elemanolides from Centaurea chilensis. J. Ethnopharmacol. 40, 149–153. Neves, M., Morais, R., Gafner, S., Stoeckli-Evans, H., Hostettmann, K., 1999. New sesquiterpene lactones from Portuguese livewort Tagionia lorbeeriana. Phytochemistry 50, 967–972. Nowak, G., Droźdź, B., Georgiadis, T., 1984. Sesquiterpene lactones. XXIX. Cnicin in species of the subgenus Acrolophus. Acta Soc. Bot. Pol. 53, 199–205. Nowak, G., Droźdź, B., Kroszczyňski, W., Holub, M., 1986a. Sesquiterpene lactones. XXX. Cynaropicrin in species of the subtribe Centaureinae. Acta Soc. Bot. Pol. 55, 17–22. Nowak, G., Droźdź, B., Holub, M., Lagodziňska, A., 1986b. Sesquiterpene lactones. XXXIII. Guaianolides in the subgenus Psephellus, genus Centaurea. Acta Soc. Bot. Pol. 55, 629–637. Nowak, G., Droźdź, B., Holub, M., 1986c. Sesquiterpene lactones. XXXii. Guaianolides in species from the genus Chartolepis Cass. Acta Soc. Bot. Pol. 55, 233–238. Nowak, G., Droźdź, B., Holub, M., Budesinsky, M., Šman, D., 1986d. New guaianolides in Centaurea bella and C. adjarica. Acta Soc. Bot. Pol. 55, 227–231. Nowak, G., Holub, H., Buděšinský, M., 1988. Sesquiterpene lactones. XXXIV. Guaianolides in the genus Leuzea. Acta Soc. Bot. Pol. 57, 157–163. Nowak, G., Holub, M., Buděšinský, M., 1989a. Sesquiterpene lactones. XXXVI. Sesquiterpene lactones in several subgenera of the genus Centaurea. Acta Soc. Bot. Pol. 58, 95–102. Nowak, G., Droźdź, B., Buděšinský, M., Holub, M., 1989b. Sesquiterpene lactones. Germacranolides in the genus Stizolophus. Acta Soc. Bot. Pol. 58, 247–251. Nowak, G., 1990. Thin-layer chromatography of guaianolides of the subtribe Centaureinae. J. Chromatogr. 505, 417–423. Nowak, G., 1992. A chemotaxonomic study of sesquiterpene lactones from subtribe Centaureinae of the Compositae. Phytochemistry 31, 2363–2368. Nowak, G., 1993a. Isolation and chromatography of 15-deoxyrepin and 25 other sesquiterpene lactones from Centaurea bella. Acta Soc. Bot. Pol. 62, 33–36. Nowak, G., 1993b. Chromatography of 26 sesquiterpene lactones from Centaurea bella. Chromatographia 35, 325–328. Nowak, G., Droźdź, B., Holub, M., 1996. Sesquiterpenes lactones of the Cardueae, sutribe Centaureinae. Proc. Int. Compositae Conf. Kew 1, 219–227. Oh, G.S., Pae, H.O., Chung, H.T., Kwon, J.W., Lee, J.H., Kwon, T.O., Kwon, S.Y., Chon, B.H., Yun, Y.G., 2004. Dehydrocostus lactone enhances tumor necrosis factor-ainduced apoptosis of human leukemia HL-60 cells. Immunopharm. Immunot. 26, 163–175. Ohno, N., Hirai, H., Yoshioka, Y., Dominguez, X.A., Mabry, T.J., 1973. Cynaropicrin, a sesquiterpene lactone from Centaurea americana. Phytochemistry 12, 221–222. Öksüz, S., Ulubelen, A., Aynechi, Y., Wagner, H., 1982. A guaianolide from Centaurea behen. Phytochemistry 21, 2747–2749. Öksüz, S., Putun, E., 1983. Guaianolide from Centaurea kotschyi. Phytochemistry 22, 2615–2616. Öksüz, S., Ayyildiz, H., 1986. Sesquiterpene lactones from Centaurea coronopifolia. Phytochemistry 25, 536–537. Öksüz, S., Clark, R.J., Herz, W., 1993. A guaianolide diol monoacetate from Centaurea behen and C. solstitialis subsp. schouwii. Phytochemistry 33, 1267–1268. Öksük, S., Topçu, G., 1994. Guaianolides of Centaurea glastifolia. Phytochemistry 37, 487–490. Öksük, S., Serin, S., Topçu, G., 1994. Sesquiterpene lactones of Centaurea hermanii. Phytochemistry 35, 435–438. Öksük, S., Serin, S., 1997. Triterpenes of Centaurea ptosimopappoides. Phytochemistry 46, 545–548. Okugawa, H., Ueda, R., Matsumoto, K., Kawanishi, K., Kato, A., 1996. Effect of dehydrocostus lactone and costunolide from Saussurea root on the central nervous system in mice. Phytomedicine 3, 147–153. Okukawa, H., Kawanishi, K., Kato, A., 2000. Effects of sesquiterpenoids from oriental incenses on sedative and analgesic action. Aroma Res. 1, 34–38. Omar, A., El-Ghazouly, M., Seif El-Din, A., Khafagy, S., 1983. Two guaianolide lactones from Amberboa tubulifera. Acta Pharm. Jugosl. 33, 233–235. Otoguro, K., Iwatsuki, M., Ishiyama, A., Namatame, M., Nishihara-Tukashima, A., Kiyohara, H., Hashimoto, T., Asakawa, Y., Omura, S., Yamada, H., 2011. In vitro antitrypanosomal activity of plant terpenes against Trypanosoma brucei. Phytochemistry 72, 2024–2030. Ozcelik, B., Gubruz, I., Karaoglu, T., Yesilada, E., 2009. Antiviral and antimicrobial activities of three sesquiterpene lactones from Centaurea solstitialis subsp. solstitialis. Microbiol. Res. 164, 545–552. Panagouleas, C., Skaltsa, H., Lazari, D., Skaltsounis, A.L., Sokovic, M., 2003. Antifungal activity of secondary metabolites of Centaurea raphanina ssp. mixta, growing wild in Greece. Pharm. Biol. 41, 266–270. Panero, J.L., Funk, V.A., 2002. Toward a phylogenetic subfamilial classification for the Compositae. Proc. Biol. Soc. Wash. 115, 909–922. Panero, J.L., Funk, V.A., 2008. The value of sampling anomalous taxa in phylogenetic studies, major clades of the Asteraceae revealed. Mol. Phylogenet. Evol. 47, 757– 782. Park, H.J., Kwon, S.H., Han, Y.N., Choi, J.W., Miyamoto, K.I., Lee, S.H., Lee, K.T., 2001. Apoptosis-inducing costunolide and a novel acyclic monoterpene from the stem bark of Magnolia sieboldii. Arch. Pharm. Res. 24, 342–348. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Park, H.W., Lee, J.H., Choi, S.U., Baek, N.I., Kim, S.H., Yang, J.H., Kim, D.K., 2010. Cytotoxic germacranolide sesquiterpenes from the bark of Magnolia kobus. Arch. Pharm. Res. 33, 71–74. Park, J.B., Lee, C.K., Park, H.J., 1997. Anti-Helicobacter pylori effect of costunolide isolated from the stem bark of Magnolia sieboldii. Arch. Pharm. Res. 20, 275–279. Park, S.H., Choi, S.U., Lee, C.O., Yoo, S.E., Yoon, S.K., Kim, Y.K., Ryu, S.Y., 2001. Costunolide, a sesquiterpene from the stem bark of Magnolia sieboldii, inhibits the RAS-farnesyl-proteintransferase. Planta Med. 67, 358–359. Piacentini, P., Benzi Cipelli, R., Zizzi, E., Gorini, G., Ciardelli, L., Castelli, F., 1986. Cytotoxic activity of some derivatives of Grosheimia macrocephala. Planta Med. 52, 548–549. Piacentini, P., Zizzi, E., Ciardelli, L., Benzi Cipelli, R., Gorini, G., Castelli, F., Barbetti, P., Chiappini, I., Fardella, G., 1987. Cytotoxic activity of some a,b-unsaturated clactones in vitro. Essenz. Deriv. Agrum. 57, 85–99. Picher, M.T., Seoane, E., Tartajada, A., 1984a. Flavones, sesquiterpene lactones and glycosides isolated from Centaurea aspera subsp. stenophylla. Phytochemistry 23, 1995–1998. Picher, M.T., Seoane, E., Tartajada, A., 1984b. A germacranolide isolated from Centaurea aspera subsp. stenophylla. Phytochemistry 23, 2956–2958. Picman, A.K., Elliott, R.H., Towers, G.H.N., 1978. Insect feeding deterrent property of alantolactone. Biochem. Syst. Ecol. 6, 333–335. Picman, A.K., 1983a. Antibacterial activity of sesquiterpene lactones. Biochem. Syst. Ecol. 11, 321–327. Picman, A.K., 1983b. Antifungal activity of helenin and isohelenin. Biochem. Syst. Ecol. 11, 183–186. Picman, A.K., 1984. Antifungal activity of sesquiterpene lactones. Biochem. Syst. Ecol. 12, 13–18. Picman, A.K., Schneider, E.F., 1993. Inhibition of fungal growth by selected sesquiterpene lactones. Biochem. Syst. Ecol. 21, 307–314. Popova, A.I., Rybalko, K.S., Evstratova, R.I., Prisyazhyuk, N.P., 1974. Sesquiterpene lactones from Artemisia lagocephala, A. schrenkiana and Grossheimia ossica. Khim. Prir. Soedin. 9, 528. Ragasa, C.Y., Nacpil, Z.D., Penalosa, B.A., Coll, J.C., Rideout, J.A., 1997. Antimutagen and antifungal compounds from Cosmos caudatus. Philippine J. Sci. 126, 199– 206. Rayan, N.A., Baby, N., Pitchai, D., Indraswari, F., Ling, E.A., Lu, J., Dheen, T., 2011. Costunolide inhibits proinflammatory cytokines and iNOS in activated murine BV2 microglia. Front. Biosci. Elite Ed. E3, 1079–1091. Ren, G., Yu, Z.M., Chen, Y.L., Wu, S.H., Fu, C.X., 2007. Sesquiterpene lactones from Saussurea alata. Nat. Prod. Res. 21, 221–226. Robles, M., Wang, N., Kim, R., Choi, B.H., 1997. Cytotoxic effects of repin, a principal sesquiterpene lactone of Russian knapweed. J. Neurosci. Res. 47, 90–97. Rojatkar, S.R., Pujar, P.P., Patewad, B.R., Nagasampagi, B.A., 1997. Guaianolide from Amberboa divericata. Indian J. Heterocycl. Chem. 7, 67–68. Rosinski, G., Bloszyk, E., Harmatha, J., Knapik, A., 1988. Changes produced by sesquiterpenes in some physiological processes in Tenebrio molitor larvas. Prace. Nauk. Inst. Chem. Org. Fiz. Politecn. Wrocl. 33, 91–94. Rosselli, S., Maggio, A., Raccuglia, R.A., Simmonds, M.S.J., Arnold, N.A., Bruno, M., 2006a. Guaianolides from the aerial parts of Centaurea hololeuca. Nat. Prod. Commun. 1, 281–285. Rosselli, S., Maggio, A., Bellone, G., Bruno, M., 2006b. The first example of natural cyclic carbonate in terpenoids. Tetrahedron Lett. 47, 7047–7050. Rosselli, S., Maggio, A.M., Raccuglia, R.A., Morris-Natscke, S.L., Bastow, K.F., Lee, K.H., Bruno, M., 2010. Acid Rearrangment from epoxy-germacranolides and absolute configuration of 1b,10a-epoxy-salonitenolide. Nat. Prod. Commun. 5, 675–680. Rubinchik, M.A., Rybalko, K.S., Evstratova, R.I., Konovalova, O.A., 1976. Sesquiterpene lactones of higher plants as a possible source of new antiprotozoal drugs. Rastit. Resur. 12, 170–181. Rustaiyan, A., Niknejad, A., Zdero, C., Bohlmann, F., 1981a. A guaianolide from Centaurea behen. Phytochemistry 20, 2427–2429. Rustaiyan, A., Nazarians, L., Bohlmann, F., 1981b. Guaianolide from Acroptilon repens. Phytochemistry 20, 1152–1153. Rustaiyan, A., Niknejad, A., Aynehchi, Y., 1982. Chemical constituents of Centaurea brugueriana. Planta Med. 44, 185–186. Rustaiyan, A., Ardebili, S., 1984. New guaianolides from Centaurea kandavanensis. Planta Med. 50, 363–364. Rustaiyan, A., Nazarians, L., 1984. New guaianolides Acroptilon repens. Iranian J. Chem. Chem. Eng. 4, 65–71. Rustaiyan, A., Sharif, Z., Tajarodi, A., Ziesche, J., Bohlmann, F., 1984. Neue guajanolide aus Centaurea imperialis. Planta Med. 50, 193–194. Rustaiyan, A., Feramarzi, S., 1988. Sesquiterpene lactones from Serratula latifolia. Phytochemistry 27, 479–481. Rybalko, K.S., Ban’kovskii, A.I., Kibal’chich, P.N., 1964. Grosshenemine, a new sesquiterpene lactone from Centaurea macrocephala. Zh. Obshch. Khim. 34, 1385–1389. Rybalko, K.S., Sheichenko, V.I., 1965. Structure of grosshemin, the sesquiterpene lactone from Grossheimia macrocephala. Zh. Obshch. Khim. 35, 580–584. Rybalko, K.S., Pakalne, D., Evstratova, R.I., Shreter, A.I., 1975. Prospects for research of plants containing sesquiterpene lactones. Plants from the subtribe Centaureinae, family Asteraceae. Rastit. Resur. 11, 131–144. Rybalko, K.S., Mukhametzhanov, M.N., Sheichenko, V.I., Konovalova, O.A., 1976. Sesquiterpene lactones of Stizolophus balsamita. Khim. Prir. Soedin., 467–472. 73 Rychlewska, U., Szczepańska, B., Daniewskii, W.M., Nowak, G., 1992. Crystal structure of salograviolide A, a guaiane-type sesquiterpene lactone. J. Cryst. Spectr. Res. 22, 659–663. Sakakibara, J., Shirai, N., Ishida, N., Yasue, M., 1977. Studies on the constituents of yellow star thistle (Centaurea solstitialis L.). Nagoya-shiritsu Daigaku Yakugakubu Kenkyu Nenpo 25, 29–33. Salan, Ü., Öksük, S., 1999. Chemical constituents of Centaurea cuneifolia. Turk. J. Chem. 23, 15–20. Salan, Ü., Öksük, S., 2003. Sesquiterpene lactones, a cyclohexenone and aromatic compounds from Centaurea salonitana. J. Pharm. Istanbul Univ., 77–82. Samek, M., Holub, M., Herout, V., Šorm, F., 1969. Revision of the structure of cnicin. Tetrahedron Lett., 2931–2934. Sanchez, L.A., Capitan, Z., Romero, L.I., Ortega-Barria, E., Gerwick, W.H., Cubilla-Rios, L., 2007. Bio-assay guided isolation of germacranes with anti-protozoan activity from Magnolia sororum. Nat. Prod. Commun. 2, 1065–1069. Sanchez Paradera, I., Sanchez Paradera, J., Viguera, J.M., 1968. Principios organicos en plantas del levante espanol. IV. Estenofilolido, nueva lactona sesquiterpenica. An. Quim. 64, 633–636. Santamaria, F., Zaera, E., Vazquez, D., Jimenez, A., 1984. The mode of action of Zaluzanin C, an inhibitor of translation in eukaryotes. Biochem. Biophys. Res. Commun. 123, 59–63. Santos, S.M.B.P., Brito Palma, F.M.S., Urones, J.G., Grande, M., 1988. Sesquiterpene lactones from Leuzea longifoila. Phytochemistry 27, 3672–3673. Santos, S.M.B.P., Brito Palma, F.M.S., Grande, M., 1995. Constituents of Centaurea rothmalerana. Fitoterapia 66, 285. Sarg, T.M., El-Domiaty, M., El-Dahmy, S., 1987. Further guaianolides from Centaurea aegyptiaca. Sci. Pharm. 55, 107–110. Sarg, T., El-Dahmy, S., El-Domiaty, M., Ateya, A., 1988. Guaianolides and other constituents from Centaurea sinaica. Acta Pharm. Hung. 58, 129–134. Sarg, T., El-Dahmy, S., El-Domiaty, M., El-Shazly, A., 1989. Germacranolides and elemanolides of Centaurea eryngioides. Sci. Pharm. 57, 63–67. Saroglou, V., Karioti, A., Demetzos, C., Dimas, K., Skaltsa, H., 2005. Sesquiterpene lactones from Centaurea spinosa and their antibacterial and cytotoxic activity. J. Nat. Prod. 68, 1404–1407. Sattar, E.A., Galal, A.M., Mossa, G.S., 1996. Antitumor germacranolides from Anvillea garcinii. J. Nat. Prod. 59, 403–405. Schinor, E.C., Salvador, M.J., Ito, I.Y., De Albuquerque, S., Dias, A.D., 2004. Trypanocidal and antimicrobial activities of Moquinia kingii. Phytomedicine 11, 224–229. Schmidt, T.J., Nour, A.M.M., Khalid, S.A., Kaiser, M., Brun, R., 2009. Quantitative structure–antiprotozoal activity relationships of sesquiterpene lactones. Molecules 14, 2062–2076. Schneider, G., Lachner, I., 1987. Analysis and pharmacological activity of cnicin. Planta Med. 53, 247–251. Seo, J.Y., Lim, S.S., Kim, J.R., Lim, J.S., Ha, Y.R., Lee, I.A., Kim, E.J., Park, J.H.Y., Kim, J.S., 2008. Nrf2-mediated induction of detoxifying enzymes by alantolactone present in Inula helenium. Phytother. Res. 22, 1500–1505. Serkerov, S.V., Aleskerova, A.N., 1982. Sesquiterpene lactone from Acroptilon repens. Khim. Prir. Soedim., 712–715. Sham’yanov, I.D., Akhmedov, U.A., Saidkhodzhaev, A.I., 1998. Sesquiterpene lactones and other components of Centaurea iberica. Khim. Prir. Soedin. 34, 339–340. Sheichenko, V.I., Rybalko, K.S., 1970. Structure of grosshemin. Khim. Prir. Soedin. 5, 687–691. Sheichenko, V.I., Rybalko, K.S., 1972. NMR spectra, structure and stereochemistry of grosshemin. Khim. Prir. Soedin. 7, 724–730. Shi, Y., Bao, Y.L., Wu, Y., Yu, C.L., Huang, Y.X., Sun, Y., Zheng, L.H., Li, Y.X., 2011. Alantolactone inhibits cell proliferation by interrupting the interaction between Cripto-1 activin receptor type II A in activin signaling pathway. J. Biomol. Screening 16, 525–535. Shimoda, H., Ninomiya, K., Nishida, N., Yoshino, T., Morikawa, T., Matsuda, H., Yoshikawa, M., 2003. Anti-Hyperlipidemic sesquiterpenes and new sesquiterpene glycosides from the leaves of artichoke (Cynara scolymus L.), structure requirement and mode of action. Bioorg. Med. Chem. Lett. 13, 223– 228. Shin, S.G., Kang, J.K., Lee, K.R., Lee, H.W., Han, J.W., Choi, W.S., 2005. Suppression of inducible nitric oxide synthase and cyclooxygenase-2 expression in raw 264.7 macrophages by sesquiterpene lactones. J. Toxicol. Environ. Health A 68, 2119– 2131. Shoeb, M., Çelik, S., Nahar, L., MacManus, S.M., Kong-Thu-lin, P., Jaspar, M., Sarker, S.D., 2007a. Two salonitenolide derivatives from the aerial parts of Centaurea gigantea inhibit the growth of colorectal cancer cells in vitro. Nat. Prod. Commun. 2, 121–125. Shoeb, M., MacManus, S.M., Kong-Thu-lin, P., Jaspar, M., Nahar, L., Sarker, S.D., 2007b. Bioactivity of the extract and isolation of lignans and a sesquiterpene from the aerial parts of Centaurea pamphylica (Asteraceae). Daru J. Fac. Pharm. 15, 118–122. Shoji, N., Umeyama, A., Saito, N., Takemoto, T., Kajiwara, A., Ohizumi, Y., 1984. Vasoactive substances from Saussurea lappa. J. Nat. Prod. 49, 1112–1113. Shtacher, G., Kashman, Y., 1970. 12-Carboxyeudesma-3,11(13)-diene. Novel sesquiterpenic acid with a narrow antifungal spectrum. J. Med. Chem. 13, 1221–1223. Siedle, B., Garcia-Pineres, A.J., Murillo, R., Schulte-Moenting, J., Castro, V., Ruengeler, P., Klaas, C.A., Da Costa, F.B., Kisiel, W., Merfort, I., 2004. Quantitative structure– Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 74 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx activity relationship of sesquiterpene lactones as inhibitors of the transcription factor NF-jB. J. Med. Chem. 47, 6042–6054. Singhal, A.K., Chowdhury, P.K., Sharma, R.P., 1982. Guaianolides from Tricholepsis glaberrima. Phytochemistry 21, 462–463. Skaltsa, H., Lazari, D., Georgiadou, E., Kakavas, S., Constantinidis, T., 1999. Sesquiterpene lactones from Centaurea species, C. thessala subsp. drakiensis and C. attica subsp. attica. Planta Med. 65, 393. Skaltsa, H., Lazari, D., Garcia, B., Pedro, J.R., Sokovic, M., Constantinidis, T., 2000a. Sesquiterpene lactones from Centaurea achaia, a Greek endemic species. Antifungal activity. Z. Naturforsch. C 55c, 534–539. Skaltsa, H., Lazari, D., Panagouleas, C., Georgiadou, E., Garcia, B., Sokovic, M., 2000b. Sesquiterpene lactones from Centaurea thessala and C. attica, antifungal activity. Phytochemistry 55, 903–908. Smissen, R.D., 2003. Asterales (Sunflower). In: Encyclopedia of Life Sciences. John Wiley & Sons Ltd., New York, pp. 1–3. Sorova, H., Optetal, L., Sajfrtova, M., Bartlova, M., 2008. Supercritical fluid extraction of cynaropicrin and 20-hydroxyecdysone from Leuzea carthamoides DC. J. Sep. Sci. 31, 1387–1392. Sosa, A., Fusco, M.R., Rossomando, P., Juarez, A., Robles, S., Petenatti, S., Pelzer, L., 2011. Anti-inflammatory properties from isolated compounds of Cyclolepis genistoides. Pharm. Biol. 49, 675–678. Sosa, V.E., Oberti, J.C., Gil, R.R., Ruveda, E.A., Goedken, V.L., Gutierrez, A.B., Herz, W., 1989. 10-Epideoxycumambrin B and other constituents of Stevia yaconensis var. subeglandulosa. Phytochemistry 28, 1925–1929. Starykh, V.V., Konovalov, D.A., 1997. Phytotoxic activity of some sesquiterpene lactones isolated form species of Asteraceae. Rastit. Resur. 33, 17–27. Steinbach, A., Scheidig, A.J., Klein, C.D., 2008. The unusual binding mode of cnicin to the antibacterial target enzyme MurA revealed by X-ray crystallography. J. Med. Chem. 51, 5143–5147. Stevens, K.L., 1982. Sesquiterpene lactones from Centaurea repens. Phytochemistry 21, 1093–1098. Stevens, K.L., Merrill, G.B., 1985. Sesquiterpene lactones and allelochemicals from Centaurea species. ACS Symposium Series 268 (Chem. Allelopathy), 83–98. Stevens, K.L., Wong, R.Y., 1986. Structure of chlororepdiolide, a new sesquiterpene lactone from Centaurea repens. J. Nat. Prod. 49, 833–837. Stevens, K.L., Riopelle, R.J., Wong, R.Y., 1990. Repin, a sesquiterpene lactone from Acroptilon repens possessing exceptional biological activity. J. Nat. Prod. 53, 218–221. Stevens, K.L., Witt, S.C., Kunt, S., Haddon, W.F., Benson, M., 1991. Picrolide A, an unusual sesquiterpene lactone from Acroptilon repens. J. Nat. Prod. 54, 276–280. Su, W.C., Fang, J.M., Cheng, Y.S., 1995. Sesquiterpenes from leaves of Cryptomeria japonica. Phytochemistry 39, 603–607. Suchy, M., Herout, V., Šorm, F., 1959a. Cnicin, a new guaianolide-type lactone. Chem. Ind. 45, 517–518. Suchy, M., Benešova, V., Herout, V., Šorm, F., 1959b. Structure of cnicin, the bitter principle of Cnicus benedictius. Tetrahedron Lett., 5–9. Suchy, M., Benešova, V., Herout, V., Šorm, F., 1960. The structure of cnicin, a sesquiterpene lactone from Cnicus benedictius. Chem. Ber. 93, 2449–2456. Suchy, M., Herout, V., 1962. On terpenes. CXXXVI. Identity of the bitter principle from Centaurea stoebe with cnicin. Coll. Czech. Chem. Coll. 27, 1510–1512. Suchy, M., Herout, V., Šorm, F., 1962a. On terpenes. CXXXIX. Isolation and structure of scabiolide, further sesquiterpenic lactone with a ten-membered ring in the molecule. Coll. Czech. Chem. Coll. 27, 1905–1913. Suchy, M., Herout, V., Šorm, F., 1962b. On terpenes. CXLI. Absolute configuration of cnicin and scabiolide. Coll. Czech. Chem. Coll. 27, 2398–2403. Suchy, M., Samek, M., Herout, V., Šorm, F., 1965a. Terpenes. CLXXV. Revision of structure of arctiopicrin, cnicin, and scabioside. Coll. Czech. Chem. Coll. 30, 3473–3478. Suchy, M., Herout, V., Šorm, F., 1965b. On terpenes. CLXXIV. The structure of salonitolide, a sesquiterpenic lactone of germacrane type from Centaurea salonitana. Coll. Czech. Chem. Coll. 30, 2863–2864. Suchy, M., Samek, M., Herout, V., Šorm, F., 1967. On terpenes. CLXXVI. The structure of salonitenolide, a sesquiterpenic lactone of germacrane type from Centaurea salonitana. Coll. Czech. Chem. Coll. 32, 2016–2020. Suchy, M., Samek, M., Herout, V., Šorm, F., 1968. The structure and absolute configuration of scabiolide. Coll. Czech. Chem. Coll. 33, 2238–2244. Suleimenov, E.M., Morozova, O.V., Raldugin, V.A., Gatilov, Yu.V., Rybalova, T.V., Shakirov, M.M., Seidakhmetova, R., Aksartov, R.M., Adekenov, S.M., 2005a. Sesquiterpene lactones from Stizolophus balsamita and their biological activity. Chem. Nat. Comp. 41, 556–560. Suleimenov, E.M., Raldugin, V.A., Gatilov, Yu.V., Bagrynkaya, I.Yu., Seidakhmetova, R., Aksartov, R.M., Adekenov, S.M., 2005b. Absolute configuration of stizolicin and synthesis and biological activity of its amino derivatives. Chem. Nat. Comp. 41, 561–564. Sun, C.M., Syu Jr., W., Don, M.J., Lu, J.J., Lee, G.H., 2003. Cytotoxic sesquiterpene lactones from the root of Sassurrea lappa. J. Nat. Prod. 66, 1175–1180. Susanna, A., Garcia-Jacas, N., 2007. The tribe Cardueae. In: Kadereit, J., Jeffrey, C., (Eds.), Flowering Plants. Eudicots. Asterales. Vol. VIII in K. Kubitzki, ed. The Families and Genera of Vascular Plants. Springer Verlag, Berlin, Heidelberg, pp. 123–146. Susanna, A., Galbany-Casals, M., Romaschenko, K., Barres, L., Martín, J., Garcia-Jacas, N., 2011. Lessons from Plectocephalus (Compositae, Cardueae-Centaureinae): ITS disorientation in annuals and Beringian dispersal as revealed by molecular analyses. Ann. Bot. 108, 263–277. Tang, Y.P., Hou, P.F., Duan, J.A., Liu, P., Su, S.L., 2010. Inhibitory effects of sesquiterpenes from Common Aucklandia root on proliferation of five kinds cultured cancer cells in vitro. Zhonghua Zhongyiyao Zazhi 25, 2180–2182. Taniguchi, M., Kataoka, T., Suzuki, H., Uramoto, M., Ando, M., Arao, K., Magae, J., Nishimura, T., Otake, N., Nagai, K., 1995. Costunolide and dehydrocostus lactone as inhibitors of killing function of cytotoxic T lymphocytes. Biosci. Biotech. Biochem. 59, 2064–2067. Tarasov, V.A., Kasymov, Sh.Z., Sidakyn, G.P., 1973. The isolation of cnicin from Centaurea squarrosa. Khim. Prir. Soedin. 8, 437. Tariku, Y., Hymete, A., Hailu, A., Rohloff, J., 2011. In vitro evaluation of antileishmanial activity and toxicity of essential oils of Artemisia absinthium and Echinops kebericho. Chem. Biodivers. 8, 614–623. Tešević, V., Vais, V., Janaćković, P., Todorović, N., Djoković, D., Marin, P., Milosavljević, S., 1998a. Sesquiterpene lactones from Centaurea species, C. derventana and C. kosaninii. Planta Med. 64, 488. Tešević, V., Vais, V., Todorović, N., Ðoković, D., Marin, P., Milosavljević, S., 1998b. Sesquiterpene lactones from plant species, Centaurea solstitialis. J. Serb. Chem. Soc. 63, 131–135. Tešević, V., Milosavljević, S., Vajs, V., Janaćkovic, P., Ðordevic, I., Jadranin, M., Vučkovic, I., 2007. Quantitative analysis of sesquiterpene lactone cnicin in seven Centaurea species wild-growing in Serbia and Montenegro using 1H NMR spectroscopy. J. Serb. Chem. Soc. 72, 1275–1280. Thiessen, W.E., Hope, H., Zarghami, N., Heinz, D.E., Deuel, P., Hahn, E.A., 1969. A new sesquiterpene lactone from Centaurea solstitialis L.. Chem. Ind., 460–461. Thiessen, W.E., Hope, H., 1970. The structure and absolute configuration of solstitialin. Acta Cryst. B26, 554–560. Topçu, G., Öksük, S., Shieh, H.L., Cordell, G.A., Pezzuto, M.J., Bozok-Johansson, C., 1993. Cytotoxic and antibacterial sesquiterpenes from Inula graveolens. Phytochemistry 33, 407–410. Tortajada, A., Picher, M.T., Reventos, M.M., Amigo, J.M., 1988. Structure and stereochemistry of melitensin, an elemanolide from Centaurea aspera subsp. stenophylla. Phytochemistry 27, 3549–3550. Trendafilova, A., Todorova, M., Bancheva, S., 2007. Secondary metabolites from Centaurea moesiaca. Biochem. Syst. Ecol. 35, 544–548. Tsankova, E., Ognyanov, I., 1985. New sesquiterpene lactones from Centaurea phrygia. Planta Med. 51, 465–466. Tsankova, E., Trendafilova, A., Gussev, Ch., 1994. Chemical constituens of Cnicus benedictus. Dokl. Bulg. Akad. Nauk. 47, 53–55. Tukov, F.C., Anand, S., Gadepalli, R.S.V.S., Gunatilaka, A.A.L., Matthews, J.C., Rimoldi, J.M., 2004. Inactivation of the cytotoxic activity of repin, a sesquiterpene lactone from Centaurea repens. Chem. Res. Toxicol. 17, 1170–1176. Turdybekov, K.M., Adekenov, S.M., Timofeeva, T.V., Lindeman, S.V., Struchkov, Yu.T., 1989. Molecular and crystal structure of the germacranolides salonitenolide and hanphyllin. Khim. Prir. Soedin., 781–785. Tyson, R.L., Chang, C.J., McLaughlin, J.L., Aynehchi, Y., Cassady, J.M., 1981. 9-aHydroxyparthenolide, a novel antitumor sesquiterpene lactone from Anvillea garcini (Burm.) DC. Experientia 37, 441–442. Uchiyama, N., Matsunaga, K., Kiuchi, F., Honda, G., Tsubouchi, A., NakajimaShimada, J., Aoki, T., 2002. Trypanocidal terpenoids from Laurus nobilis L.. Chem. Pharm. Bull. 50, 1514–1516. Vajs, V., Todorović, N., Risić, M., Tešević, V., Todorović, B., Janaćković, P., Marin, P., Milosavljević, S., 1999. Guaianolides from Centaurea nicolai, antifungal activity. Phytochemistry 52, 383–386. Vanhaelen, M., Vanhaelen-Fastre, R., 1975. Lactonic lignans from Cnicus benedictus. Phytochemistry 14, 2709. Vanhaelen-Fastre, R., 1968. Cnicus benedictus. Separation of antimicrobial constituents. Plantes Med. Phytother. 2, 294–299. Vanhaelen-Fastre, R., 1972. Antibiotic and cytotoxic activities of cnicin isolated from Cnicus benedictus. J. Pharm. Belg. 27, 683–688. Vanhaelen-Fastre, R., Vanhaelen, M., 1974. Presence of salonitenolide in Cnicus benedictus. Planta Med. 26, 375–379. Vanhaelen-Fastre, R., Vanhaelen, M., 1976. Activite antibiotique et cytotoxique de la cnicin et de ses produits d’hidrolyse. Planta Med. 29, 179–189. Wagenitz, G., Hellwig, F.H., 1996. Evolution of characters and phylogeny of the Centaureinae. In: Hind, D.J.N., Beentje, H.J. (Eds.), Compositae, Systematics. Proceedings of the International Compositae Conference, Kew, 1994. Vol 1. Compositae, Systematics. Royal Botanic Gardens, Kew, pp. 491–510 . Wahab, S., Tandon, R.N., Jacob, Z., Sagar, P., Srivastava, O.P., 1981. In vitro activity of a phytochemical, alantolactone from Inula racemosa Hook. f. against some pathogenic and opportunistic fungi. J. Indian Bot. Soc. 60, 278–281. Wang, B.G., Hong, X., Li, L., Zhou, J., Hao, X.J., 2000. Chemical constituents of two Chinese Magnoliaceae plants, Tsoongiodendron odorum and Manglietiastrum sinicum, and their inhibition of platelet aggregation. Planta Med. 66, 511–515. Wang, H., Wu, T., Yan, M., Liu, G., Li, P., Zhang, X.Q., Ye, W.C., Ye, L.Y., 2009. Sesquiterpenes from Ainsliaea fragrans and their inhibitory activities against cyclooxynases 1 and 2. Chem. Pharm. Bull. 57, 597–599. Wang, Y., Hamburger, M., Cheng, C.H.K., Costall, B., Naylor, R.J., Jenner, P., Hostettmann, K., 1991. Neurotoxic sesquiterpenoids from the yellow starthistle. Helv. Chim. Acta 74, 117–123. Wang, Y., Wang, Q., Mao, F., Zhang, Y., Huang, F., Dou, C., 2001. Pharmacological study on Radix Aucklandiae. Zhongguo Yaoke Daxue Xuebao 32, 146–148. Watanabe, Y., Mihara, R., Mitsunaga, T., Yoshimura, T., 2005. Termite repellent sesquiterpenoids from Callitris glaucophylla heartwood. J. Wood Sci. 51, 514– 519. Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002 M. Bruno et al. / Phytochemistry xxx (2013) xxx–xxx Wedge, D.E., Galindo, J.C.G., Macias, F.A., 2000. Fungicidal activity of natural and synthetic sesquiterpene lactones analogs. Phytochemistry 53, 747–757. Wei, H.X., Gao, W.Y., Tian, Y.J., Guan, Y.K., Huang, M.H., Cheng, D.L., 1997. New eudesmane sesquiterpene and thiophene derivatives from the roots of Rhaponticum uniflorum. Pharmazie 52, 245–247. Wu, Z.J., Xu, X.K., Zeng, H.W., Shen, Y.H., Tian, J.M., Su, J., Li, H.L., Shan, L., Liu, R.H., Zhang, W.D., 2011. New sesquiterpenoids from Ainsliaea macrocephala and their nitric oxide inhibitory activity. Planta Med. 77, 1545–1550. Yae, E., Yahara, S., El-Aasr, M., Ikeda, T., Yoshimitsu, H., Masuoka, C., Ono, M., Hida, I., Nakata, Y., Nohara, T., 2009. Studies on the constituents of whole plants of Youngia japonica. Chem. Pharm. Bull. 57, 719–723. Yang, H., Xie, J., Sun, H., 1997. Study on chemical constituents of Saussurea lappa. Acta Bot. Yunnanica 19, 85–91. Yayli, N., Baltaci, C., Gök, Y., Aydin, E., Üçüncü, O., 2006. Sesquiterpene lactones from Centaurea helenioides Boiss. Turk. J. Chem. 30, 229–233. Yesilada, E., Gürbüz, I., Bedir, E., Tatli, I., Khan, I.A., 2004. Isolation of antiulcerogenic sesquiterpene lactones from Centaurea solstitialis L. ssp. solstitialis through bioassay-guided fractionation procedures in rats. J. Ethnopharmacol. 95, 213–219. Yoshikawa, M., Shimoda, H., Uemura, T., Morikawa, T., Kawahara, Y., Matsuda, H., 2000. Alcohol absorption inhibitors from bay leaf (Laurus nobilis), structurerequirements of sesquiterpenes for the activity. Bioorg. Med. Chem. 8, 2071– 2077. Youssef, D., Frahm, A.W., 1994a. Constituents of the Egyptian Centaurea scoparia; chlorinated guaianolides of the aerial parts. Planta Med. 60, 267–271. Youssef, D., Frahm, A.W., 1994b. Constitents of the Egyptian Centaurea scoparia; II. Guaianolides of the aerial parts. Planta Med. 60, 572–575. Youssef, D., 1998. Sesquiterpene lactones of Centaurea scoparia. Phytochemistry 49, 1733–1737. Zarghami, N., Heinz, D.E., 1969. Solstitialin acetate, a sesquiterpene lactone from Centaurea solstitialis. Chem. Ind., 1556–1557. Zha, Zj., Hou, X.R., 2008. Sesquiterpenoid alkaloid from Acroptilon repens. Nat. Prod. Res. 22, 222–226. Zhang, Y., Yang, Y., Li, Z., Fang, T., Liu, Y., Chen, Q., 2007. Antitumor activity of santamarin and its effect on topoisomerase. Zhongguo Yaolixue Tongbao 23, 1370–1374. Zhang, X.P., Zhang, J., Dong, M., Zhang, M.L., Huo, C.H., Shi, Q.W., Gu, Y.C., 2010. Chemical constituents of plants from the genus Rhaponticum. Chem. Biodivers. 7, 594–609. Zhao, D., Zhang, W., Li, M., Liu, X., 2006. Studies on chemical constituents of Acroptilon repens. Zhongguo Zhongyao Zazhi 31, 1869–1872. Zhao, F., Xu, H., He, E.Q., Jiang, Y.T., Liu, K., 2008. Inhibitory effects of sesquiterpenes from Saussurea lappa on the overproduction of nitric oxide and TNF-a release in LPS-activated macrophages. J. Asian Nat. Prod. Res. 10, 1045–1053. Zhao, Y., 1997. Eudesmane sesquiterpenes from Laggera ptedoronta. Phytochemistry 44, 459–464. Zidorn, C., Ellmerer, E.P., Konwalinka, G., Schwaiger, N., Stuppner, H., 2004. 13Chloro-3-O-b-D-glucopyranosylsolstitialin from Leontodon palisae, the first genuine chlorinated sesquiterpene lactone glucoside. Tetrahedron Lett. 45, 3433–3436. Zong, M.R., Zhao, Y.H., Zhang, K., Yang, L.F., Zheng, Y.C., He, C.Y., 2011. Inhibitory effects of natural compound alantolactone on human non-small cell lung cancer A549 cells. Chem. Res. Chin. Univ. 27, 241–244. 75 President of the Italian Republic appointed him as ‘‘Commendatore dell’Ordine al Merito della Repubblica Italiana’’ for his contributions to the scientific research. At the present he is President of the Societá Chimica Italiana – Sez. Sicilia. Svetlana Temelkova Bancheva is associate professor of botany at the Institute of Biodiversity and Ecosystem Research, Bulgarian Academy of Sciences. She is currently Head of the Department of Plant and Fungal Diversity and Resources and Curator of the Herbarium (SOM) of the Institute of Biodiversity and Ecosystem Research at Bulgarian Academy of Sciences. Her interests are focused on the taxonomy and biosystematics of vascular plants, endemism, plant protection, protected sites and chemotaxonomy. She is author of more than 66 scientific publications and member of the Managing Committee of the Balkan alliance for Nature protection, member of the Commission for Floristic Researches of OPTIMA, member of the Bulgarian Society of Botany and member of the Society of the Bulgarian Scientists. Sergio Rosselli is assistant professor of organic chemistry at the University of Palermo. His scientific interests are mainly devoted to the chemistry of secondary metabolites from plants and their potential biological applications. His expertise ranges from isolation and purification to structural elucidation of natural products with regard to NMR techniques; he is also interested in the characterization of the essential oils, in chemical modification of natural products and structure–activity relationships. His scientific activity is demonstrated by about 110 scientific publications. Antonella Maggio is assistant professor of organic chemistry at the University of Palermo. The scientific activity of Dr. Maggio has always been focused on the chemistry of natural substances. In particular she is interested in the chemistry of the diterpenes and sesquiterpenes of plant origin, notably from the Mediterranean basin. The research work of Dr. Maggio has been and is orientated specifically towards the study of plants of the family Labiatae and Compositae for the isolation of new natural products-type diterpene and sesquiterpene. She is co-author of about 60 scientific publications. Maurizio Bruno is full professor of organic chemistry at the University of Palermo. He studied at the Florida State University with Prof. Werner Herz and at the Imperial College, London, with Prof. Steven Ley. He works in natural organic products chemistry on natural and semi-synthetic terpenoids with antifeedant activity. He is interested in sesquiterpenes from Compositae, in natural and semi-synthetic compounds with anti-HIV and cytotoxic activity and in the extraction and analysis of essential oils with antibacterial and antifungal properties. He is author of more than 240 papers on international journals. He was coordinator of joint programs CNR-CSIC (Spain) and CNR-BAS (Bulgaria). From 2002 he has been included in the ISI list as one of the most cited Italian researchers in the world. In 2005 the Please cite this article in press as: Bruno, M., et al. Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties. Phytochemistry (2013), http://dx.doi.org/10.1016/j.phytochem.2013.07.002

RELATED PAPERS

RELATED TOPICS

Log In

Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties

Sesquiterpenoids in subtribe Centaureinae (Cass.) Dumort (tribe Cardueae, Asteraceae): Distribution, 13C NMR spectral data and biological properties

Related Papers

RELATED PAPERS

RELATED TOPICS