Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. Natural Product Reports www.rsc.org/npr Current developments in natural products chemistry Volume 29 | Number 6 | June 2012 | Pages 609–712 ISSN 0265-0568 COVER ARTICLE Du-Qiang Luo et al. The taxonomy, biology and chemistry of the fungal Pestalotiopsis genus 0265-0568(2012)29:6;1-# C Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. NPR Dynamic Article Links < Cite this: Nat. Prod. Rep., 2012, 29, 622 REVIEW www.rsc.org/npr The taxonomy, biology and chemistry of the fungal Pestalotiopsis genus Xiao-Long Yang,ab Jing-Ze Zhangc and Du-Qiang Luo*a Received 26th September 2011 DOI: 10.1039/c2np00073c Covering: 1991 to November 2011 A growing body of evidence indicates that the Pestalotiopsis genus represents a huge and largely untapped resource of natural products with chemical structures that have been optimized by evolution for biological and ecological relevance. So far, 196 secondary metabolites have been encountered in this genus. This review systematically surveys the taxonomy, biology and chemistry of the Pestalotiopsis genus. It also summarises the biosynthetic relationships and chemical synthesis of metabolites from this genus. There are 184 references. 1 2 3 3.1 3.2 3.3 3.4 3.5 4 4.1 4.1.1 4.1.2 4.1.3 4.2 4.2.1 4.2.2 4.3 4.4 4.5 4.6 4.7 4.8 5 6 7 Introduction Taxonomy of the Pestalotiopsis genus Biology of the Pestalotiopsis genus Distribution and biodiversity Host range Sexual and asexual forms Molecular biology Physiological and ecological roles Secondary metabolites of the Pestalotiopsis genus Terpenoids Sesquiterpenes Diterpenes Triterpenes Nitrogen-containing compounds Amines and amides Indole derivatives Quinone and semiquinone derivatives Coumarins Lactones Chromone derivatives Phenolic compounds Miscellaneous metabolites Concluding remarks Acknowledgements References a Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education and College of Life Science, Hebei University, Baoding, 071002, China. E-mail: duqiangluo@163.com. b College of Pharmaceutical Science, Hebei University, Baoding, 071002, China. E-mail: yxl19830915@163.com. c Institute of Biotechnology, Zhejiang University, Hangzhou, 310000, China 622 | Nat. Prod. Rep., 2012, 29, 622–641 1 Introduction Endophytes could be defined as microorganisms (fungi or bacteria) that can be detected at a given moment within the tissues of an apparently healthy host plant.1They live together with host plants for long periods of time, so most of them have the same or similar bioactive components as their hosts. These bioactive metabolites produced by endophytes may be involved in a host–endophyte relationship. As a direct result of the role that these metabolites may play in nature, they may ultimately be shown to have applicability in medicine. A worldwide scientific effort to isolate endophytes and study their natural products is now under way. The study of natural products from plants and their endophytes has shown that endophytes have been found to produce a significant number of interesting novel and bioactive metabolites. It has been shown that both novel structures produced by endophytes (51%) and their biologically active extracts (80%) occur in considerably higher numbers than those produced by soil microorganisms (38% of novel structures and 64% of bioactive extracts).2 Therefore, endophytes have been considered as an outstanding source of small molecules. One of the most commonly found endophytes is Pestalotiopsis spp.3 Generally representative of this fungal genus, it is among the most commonly isolated endophytic fungi of tropical plants, which are common in their distribution, and many are saprobes, while others are either pathogenic or endophytic to living plants.3–6 In a global perspective, given the wide distribution of this genus, it probably represents one of the largest biomasses of any plant-associated endophytic fungus in the world. Since discovery of the anticancer agent taxol from an endophytic fungal strain Pestalotiopsis microspora,3 interest in searching for bioactive compounds from this fungal genus has increased considerably. This journal is ª The Royal Society of Chemistry 2012 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. Professors Gusman and Vanhaelen described secondary metabolites of 38 endophytic fungi together with their biological activities 20 years ago.7 Since then, several other authors have reviewed the chemistry and bioactivity of endophyte metabolites, endophytic biodiversity and related ecological functions.8–19 Considering the recent flurry of reports in this area, herein we systematically review all the papers that have appeared in the literature from 1991 until November 2011, concerning the taxonomy, biology and chemistry of the genus Pestalotiopsis. It also summarises the biosynthesis relationships and chemical synthesis of metabolites from this genus. 2 Taxonomy of the Pestalotiopsis genus The genus Pestalotiopsis was established by Steyaert in 1949, following a taxonomic amendment to the genus Pestalotia.20–22 Steyaert restricted Pestalotia to a single species and reassigned Xiao-Long Yang was born in Ningxia province of China in 1983. He completed his Diploma in 2004 at Northwest A&F University and obtained a Ph.D. degree from Kunming Institute of Botany, Chinese Academy of Sciences, under the supervision of Professor Ji-Kai Liu, where he worked on the search for bioactive substances from medicinal plants and high fungi. Since 2009, he has worked as an Xiao-Long Yang associate Professor at Hebei University. His current research interests focus on the isolation, structure elucidation, bioactivities and chemical modification of natural products from medicinal plants and microorganisms. He has authored over twenty scientific publications in international journals. Jing-Ze Zhang was born in 1962. He completed his B. S. degree in 1988 and his M. S. degree in 1994 at Northwest A&F University. In 1994, he joined at Zhejiang University where he worked on plant protection. After receiving his Ph.D. degree from Zhejiang University in 2000, he initiated his research program on taxonomy of fungi genus Pestalotiopsis, plant pathogenic fungi Jing-Ze Zhang diseases and biological control. He became an associate Professor at Zhejiang University in 2001 and went to Australia, Belgium and the USA as a visiting scientist in 1998, 2004 and 2011. He has received several important awards, and has published over 60 papers. This journal is ª The Royal Society of Chemistry 2012 some species formerly placed in the Pestalotia to new anamorphic genera Pestalotiopsis and Truncatella Steyaert, but a majority of the species remained unstudied.20 In 1961, Guba reduced Pestalotiopsis and Truncatella to synonymy with Pestalotia and accepted 220 species in Pestalotia.23 Molecular studies have shown that Pestalotiopsis is a monophyletic genus, which is characterized by the relatively fusiform conidia formed within compact acervuli, and the conidia of Pestalotiopsis are usually fusiform, 5-celled, with three brown to fuliginous median cells and hyaline end cells, and with two or more apical appendages arising from the apical cell.24 Subsequently, a total of 137 out of 183 Pestalotia species placed in section quinqueloculatae by Guba (1961) were transferred into the Pestalotiopsis.25,26 At present, inter-specific delineation of this genus is based on morphology of the conidia,23 conidiogenesis27 and teleomorph association.28 Molecular studies indicated that Pestalotiopsis species isolated from same hosts are not necessarily related.29,30 It was proposed that when a new Pestalotiopsis species is described, morphological characters should be taken into account rather than host association, and molecular phylogenetic information is also necessary to prove that the taxon is unique from other known species. However, many Pestalotiopsis species have never been identified due to the complication and difficulty in using existing morphological characters.31–36 To date, 234 described species of Pestalotiopsis that are differentiated primarily on conidial characteristics, such as size, septation, pigmentation, and presence or absence of appendages, are listed in Index Fungorum (http://www.indexfungorum.org/ Names/Names.asp). 3 Biology of the Pestalotiopsis genus 3.1 Distribution and biodiversity Pestalotiopsis species are ubiquitous in distribution, occurring on a wide range of substrata. Endophytic Pestalotiopsis have often been reported and considered as a main part of the Pestalotiopsis Du-Qiang Luo was born in Shannxi province of China in 1968. He acquired his B. S. degree in 1991 and his Ph. D. degree in 2002 at Northwest A&F University. He then carried out postdoctoral research with Professor Ji-Kai Liu in Kunming Institute of Botany, Chinese Academy of Sciences. At present, he works as a Professor at Hebei University and serves as the vice Du-Qiang Luo director of Key Laboratory of Pharmaceutical Chemistry and Molecular Diagnosis of Ministry of Education. During his research career, he has published over 40 scientific papers and patents. His field of interest concerns bioactive natural compounds from fungi in special ecological environments. Nat. Prod. Rep., 2012, 29, 622–641 | 623 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. community in nature, which have been commonly isolated particularly in the subtropical and tropical regions.3 For example, more than 90 strains of Pestalotiopsis were isolated by Xu and his co-workers from different hosts of Podocarpaceae in China.34 Hyde and his co-workers also reported 132 strains of Pestalotiopsis from the bark and needles of Pinus armandii and leaves of Ribes species.33 The diversity of endophytic Pestalotiopsis species varied in the host plant’s tissues, sites and natural environmental conditions, and varied in different families of plants.29–34 In addition, it has been demonstrated that each plant hosted more than one endophytic Pestalotiopsis species and the species diversity varied among individual host species. For example, Liu and his coworkers reported 43 endophytic Pestalotiopsis species associated with 27 plant species belonging to four families, of which 23, 11, 9 and 8 species were obtained from families of Palmae, Rhizophoraceae, Podocarpaceae and Planchonellae, respectively. The species of Pestalotiopsis isolated from different hosts in the Palmae family varied from 1 to 7.37 A total of 302, 365 and 198 Pestalotiopsis isolates were also reported from plants of Podocarpaceae, Theaceae and Taxaceae, respectively, and 80 Pestalotiopsis species were isolated from Podocarpaceae, 16 from Theaceae and 4 from Taxaceae.38 3.2 Host range Generally the host range of Pestalotiopsis is broad. For example, Pestalotiopsis mangiferae has been reported to occur on multiple hosts, such as Elaeis guineensis, Hyphaene thebaica, Mangifera indica, Vitis vinifera and other unrelated hosts, and Pestalotiopsis photiniae was isolated from the plants belonging to three families: Camelliae japonica, Camelliae sasanqua, Podocarpus macrophyllus, Podocarpus nagi and Taxus chinensis.29,30 Furthermore, Pestalotiopsis microspora has been isolated as a saprophyte on bark and decaying plant material, and as an endophyte from the stems, leaves, flowers, and fruits of hundreds of tropical and subtropical rainforest plants.39 These reported results demonstrated that endophytic Pestalotiopsis species are not specific to their host plant. So far, Pestalotiopsis species were isolated from most host plants mainly belonging to the following twenty-five families: Musaceae, Goodeniaceae, Theaceae, Cephalotaxaceae, Euphorbiaceae, Ericaceae, Taxaceae, Rhizophoraceae, Pinaceae, Larix potaninii, Piperaceae, Crassulaceae, Asteraceae, Orchidaceae, Gentianaceae, Podocarpaceae, Dendrobium, Ebenaceae, Araceae, Sterculiaceae, Vacciniaceae, Lauraceae, Boraginaceae, Palmaceae and Chenopodiaceae.40 3.3 Sexual and asexual forms One fifth of all known anamorphic fungi lack known sexual states, and out of 2873 anamorphic genera names, 699 genera and 94 anamorph-like genera are linked to a sexual state.41 Pestalotiopsis is a species-rich anamorphic genus with species mostly lacking sexual morphogenesis, unlike the Coelomycetous genera Colletotrichum and Phyllosticta.42,43 The sexual states or teleomorphs of Pestalotiopsis species have been identified as Pestalosphaeria.44 The asexual Pestalotiopsis state and ascomycetous sexual state have rarely been recorded in the same host 624 | Nat. Prod. Rep., 2012, 29, 622–641 plant.45 However, it is not always clear that the two stages found are definitely the same biological species and therefore molecular evidence is needed to link them. 3.4 Molecular biology Of compelling interest is an explanation as to how the genes for taxol production may have been acquired by Pestalotiopsis microspora.3 Although the complete answer to this question is not at hand, some other relevant genetic studies have been done on this organism. Pestalotiopsis microspora Ne 32, is one of the most easily genetically transformable fungi that has been studied to date. In vivo addition of telomeric repeats to foreign DNA generates extrachromosomal DNAs in this fungus.46 Repeats of the telomeric sequence 50 -TTAGGG-30 were appended to nontelomeric transforming DNA termini. The new DNAs, carrying foreign genes and the telomeric repeats, replicated independently of the chromosome and expressed the information carried by the foreign genes. The addition of telomeric repeats to foreign DNA is unusual among fungi. This finding may have important implications in the biology of Pestalotiopsis microspora Ne 32, since it explains at least one mechanism through which new DNA can be captured by this organism and eventually expressed and replicated. Such a mechanism also points to an explanation of how the enormous biochemical variation may have arisen in this fungus. Also, this initial work represents a framework to aid in the understanding of the ways this fungus may adapt itself to the environment of its plant hosts, and suggests that the uptake of plant DNA into its own genome may occur. In addition, the telomeric repeats have the same sequence as human telomeres, and this points to the possibility that Pestalotiopsis microspora may serve as a means to make artificial human chromosomes, a totally unexpected result. As an alternate method, the gene encoding for this (taxol biosynthetic enzyme) has been used as a molecular marker for screening taxol-producing fungal endophytes.47 It also indicates that the formation of taxol by the fungus, Pestalotiopsis versicolor, was found to be the highest and suggests that the fungus can serve as a potential species for genetic engineering to enhance the production of taxol, which is currently underway. 3.5 Physiological and ecological roles The fungal Pestalotiopsis genus could be considered as the ‘‘Escherichia coli’’ of the rainforest because it is omnipresent.3 However, its role in the plant and in the ecosystem in general, is only beginning to be understood. One of the most commonly isolated endophytic species is Pestalotiopsis microspora.48 Organisms virtually identical to the taxonomic description of Pestalotiopsis microspora are numerous, and they have usually been isolated as leaf and stem pathogens of economically important tropical plants, such as the palms, pines, loquats, guavas, mangoes and a large number of ornamental plants.49 Generally, the commonly held view is that this fungus is a relatively weak plant pathogen, but at times acts in a more aggressive manner, resulting in major plant loss. It seems that this fungus and its close relatives are not as important as plant pathogens since they play some role as endophytic fungi living in symbiotic This journal is ª The Royal Society of Chemistry 2012 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. relationships to plants in each of the world’s temperate and tropical rainforests. intermediate, the direct precursor of the enolic form of the humulane 5. Alternatively, the whole process might work in the direction from humulane 5 through to 1. 4 Secondary metabolites of the Pestalotiopsis genus 4.1 Terpenoids 4.1.1 Sesquiterpenes. The genus Pestalotiopsis was proved to be a good source of sesquiterpenes. Detailed investigation on the first strain of endophytic fungus Pestalotiopsis sp. isolated from the bark and leaves of Taxus brevfolia, revealed three new caryophyllene-derived pestalotiopsins, (+)-pestalotiopsin A 1,50 ()-pestalotiopsin B 250 and (+)-pestalotiopsin C 3,51 coexisting with a drimane derivative 2a-hydroxydimeninol 451,52 and one humulene-type sesquiterpene 5 as the first humulane derivative reported from fungi.51,53 (+)-Pestalotiopsin A 1, the most polar among the pestalotiopsins, and (+)-pestalotiopsin C 3, the least polar among them, have an unprecedented oxatricyclic structure consisting of a geminally methylated cyclobutane ring fused with a high oxygenated (E)-cyclononene ring and a g-lactol, while bicyclic ()-pestalotiopsin B 2, the most abundant among them, appears to be a single entity on HPLC and HPTLC analysis, but exists as a mixture of two slowly equilibrating atropisomers (6 : 5 ratio of ba : bb) in chloroform solution at room temperature. Among them, pestalotiopsin A 1 showed cytotoxicity and immunosuppressive activity in the mixed lymphocyte reaction. Because of its novel molecular architecture and interesting biological activity, pestalotiopsin A 1 has been considered as an attractive synthetic target by many synthetic chemists.54–56 The absolute stereochemistry of 1 was determined by the total synthesis of its enantiomer ()-pestalotiopsin A by Tadano and his co-workers.55,56 Later, the synthesis of (+)-pestalotiopsin A 1 was also successfully total synthesized starting from two conveniently available materials, (1R)-camphorsultam and glyceraldehyde acetonide, by the same group.56 Caryophyllenes are thought to be biosynthesized from farnesyl pyrophosphate via a humulene cation,57 so a possible metabolic relationships between 1, 2 and 5 are proposed.51 First elimination of water from 1, and subsequent reduction of the aldehyde would yield 2, then deacetylation and oxidation leads to a hypothetical In 2003, three highly oxygenated caryophyllene sesquiterpene derivatives structurally related to the pestalotiopsins, named pestalotiopsolide A 6, taedolidol 7 and 6-epitaedolidol 8, were discovered in the liquid medium culture of a Pestalotiopis sp. obtained from the trunk bark of Pinus taeda. Although the pestalotiopsins were not identified in this fermentation experiments, they might be precursors of 6–8.58 The punctaporonins are a set of six caryophyllene sesquiterpenoids punctaporonins A–F that were originally isolated from the coprophilous fungus Poronia punctata, and the absolute configurations of punctaporonins A and D were determined by enantiospecific total synthesis.59–61 Chemical investigation of the culture of a fungicolous isolate of Pestalotiopis disseminata has afforded three new punctaporonins, including 6-hydroxypunctaporonin A 9, 6-hydroxypunctaporonin B 10 and 6-hydroxypunctaporonin E 11.62 Among them, compounds 10– 11 exhibited activity in standard agar disk diffusion assays at 100 mg/disk against Bacillus subtilis (ATCC 6051), each causing a 12 mm zone of inhibition, Staphylococcus aureus (ATCC 29213) were inhibited to a lesser extent by 10–11, the zone being 8 mm in both cases, while compound 9 showed no activity against Bacillus subtilis and Staphylococcus aureus at the same test condition. Pupukeananes are a group of sesquiterpenoids possessing the unique tricyclo-[4.3.1.03,7]-decane skeleton, and they were mainly isolated from marine sponges as isocyanates, thiocyanates, and isothiocyanates,63–69 which has made them attractive synthetic targets for the last three decades.70–72 Recently, eight chlorinated pupukeanane derivatives, chloropupukeananin 12,73 chloropestolide A 13,74 chloropupukeanolides A–E 14–18,75,76 and chloropupukeanone A 19,75 have been isolated from the This journal is ª The Royal Society of Chemistry 2012 Nat. Prod. Rep., 2012, 29, 622–641 | 625 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. Pestalotiopsis fici obtained from branches of an unidentified tree in the suburb of Hangzhou in different solid-substrate fermentation cultures. Chloropupukeananin 12, the first chlorinated pupukeanane derivative discovered from any sources and its tricyclo core skeleton was encountered for the first time for 626 | Nat. Prod. Rep., 2012, 29, 622–641 fungal metabolites, showed an inhibitory effect against HIV-1 replication in C8166 cells with an IC50 value of 14.6 mM. A concise synthesis of a highly functionalized chloropupukeananin 12 skeleton has been reported via a reverse electron-demand Diels–Alder reaction and intramolecular carbonyl–ene reaction sequence based on the proposed biosynthetic pathway.77 Compound 13, a highly functionalized spiroketal with an unprecedented skeleton derived from a chlorinated bicyclo[2.2.2]-oct-2-en-5-one ring and a 2,6-dihydroxy-4-methylbenzoic acid unit, showed significant inhibitory effects on growth of two human cancer cell lines, HeLa and HT29, with GI50 values of 0.7 and 4.2 mM, respectively, and which is about five to ten times the potency of the positive control 5-fuorouracil against the HeLa cells. Compounds 14–15 are chlorinated pupukeananes featuring an unprecedented spiroketal peroxide skeleton, and 14 showed an inhibitory effect on HIV-1 replication in C8166 cells, and cytotoxicity against the HeLa, MCF-7 and MDA-MB-231 human tumor cell lines. Metabolites 16–18, three highly functionalized secondary metabolites featuring a novel spiroketal skeleton derived from the chlorinated tricyclo-[4.3.1. 03,7]-decane and the 2,6-dihydroxy-4-methylbenzoic acid moieties, showed significant cytotoxicity against a small panel of human tumor cell lines and weak activities against the pathogens of tropical diseases. Compound 19 is a new analogue of 12. Two new sesquiterpenoid esters, pestalotiopin C 2078 and dihydroberkleasmin 2179 related to the eremophilane class, together with one known compound berkleasmin C 22,80 were isolated from the fermentation broth of Pestalotiopsis photiniae. Eremophilane-type sesquiterpenes widely exist as constituents of various plants, while there have been several reports as fungal secondary metabolites mostly from family Xylariaceae. This journal is ª The Royal Society of Chemistry 2012 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. Compounds 20–22 were reported for the first time from the genus Pestalotiopsis. 4.1.2 Diterpenes. Taxol 23, a highly functionalized diterpene and the world’s first billion dollar anticancer drug, was originally characterized from the inner bark of the Pacific Yew tree (Taxus brevifolia) in the early 1960s, and has been totally synthesized by Nicolau et al. in 1994.81,82 It has a unique mechanism of action, involving breakdown of microtubule during cell division.83,84 The major natural source of taxol is found in the bark of yew (Taxus), and which is found in extremely low concentrations of 0.01–0.05% in the needles, bark, and roots of Taxus spp. Additionally, the Taxus species are endangered and grow very slowly. The methods to obtain taxol from Taxus species are inefficient and environmentally costly. For example, 1 kg of taxol can treat only about five hundred patients, while the production of 1 kg of taxol requires 10 tons of bark or 300 trees. In order to satisfy the growing demand of the market and make it more widely available, alternative resources and a potential strategy should be developed. In the last 40 years, many efficient approaches, such as chemical synthesis, plant cell and tissue culture, microbial fermentation, have been developed for taxol production, and much progress has been achieved. In particular, microbial fermentation has demonstrated that the isolation and identification of taxol-producing endophytic fungi is a new and feasible approach to the production of taxol.85 Taxomyces andreanae, the first report endophytic fungus colonizing the inner bark of Pacific yew Taxus brevifolia, is capable of producing taxol and its analogue baccatin III when grown in semi-synthetic medium, which demonstrated that an organism other than Taxus spp. could produce taxol.86 However, the taxol accumulated in culture of Taxomyces andreanae at a low level of 24–25 ng L1. Subsequently, another isolate of an endophytic fungus, Pestalutiopsis microspora, obtained from the inner bark of Taxus wallacbiana, was reported to produce taxol in culture. Furthermore, the taxol isolated from this source is biologically active against certain cancer cell lines, and accumulates in cultures at the level of 60– 70 mg L1, which is approximately 1000 times higher than Taxomyces andreanae.3 These tremendous finding firstly indicated that the plant endophytic fungi also had the ability to produce taxol. Since then, most scientists have been increasing their interests in researching fungal endophytes as potential candidates for taxol production. For example, searching for taxol-producing endophytic fungi from Taxus species and other related plant species, microbial fermentation processes and genetic engineering for improving taxol production have been This journal is ª The Royal Society of Chemistry 2012 developed, and much progress has been achieved during the last two decades.87,88 Up to now, about 19 genera of endophytic fungi, including Alternaria, Aspergillus, Botryodiplodia, Botrytis, Cladosporium, Ectostroma, Fusarium, Metarhizium, Monochaetia, Mucor, Ozonium, Papulaspora, Periconia, Pestalotia, Pestalotiopsis, Phyllosticta, Pithomyces, Taxomyces, Tubercularia have been reported to have the ability to produce taxol and its analogues (i.e. baccatin III, 10-deacetylbaccatin III).87–92 Futhermore, most taxol-producing endophytes are species of Pestalotiopsis, such as Pestalotiopsis versicolor and Pestalotiopsis neglecta associated with Taxus cuspidata,93 Pestalotiopsis pauciseta VM1 isolated from Tabebuia pentaphylla,94 Pestalotiopsis pauciseta (strain CHP-11) isolated from the leaves of Cardiospermum helicacabum,95 Pestalotiopsis terminaliae isolated from Terminalia arjuna,96 Pestalotiopsis breviseta from coelomycetous fungi,97 Pestalotiopsis guepinii from Wollemi Pine and Wollemia nobilis,98 Pestalotiopsis sp W-x-3 and Pestalotiopsis sp W-1f-1 from Wollemia nobilis.98 Therefore, it is believed that taxol-producing fungus Pestalotiopsis species have a great potential to be applied in making the antitumor drug taxol in the future. From both an ecological and an economic point of view, the microbial source would supplant reliance on the yew. Through fungal fermentation, the taxol production will eliminate the shortfall of the raw material trees, and will virtually increase the supply of taxol in the market.87,88 4.1.3 Triterpenes. Triterpenoids as the major type of metabolites are widely distributed in plants and other bioresources, but there has been no reported from the genus Pestalotiopsis before the isolation of three new oleanane-type triterpenes 24–26, which have been identified from cultures of Pestalotiopsis clavispora isolated from the plant Bruguiera sexangula, Dongzhai, Hainan Province, China.99 Another four new ursane-type triterpenes 27–30 were characterized from an endophytic fungus Pestalotiopsis microspora isolated from medicinal plant Huperzia serrata when incubated with ursolic acid.100 Nat. Prod. Rep., 2012, 29, 622–641 | 627 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. confirmed by X-ray crystal structure analysis. The structure of 33 differs significantly from those known alkaloids105–109 by having a relatively rare 2,4-dichloro-5-methoxy-3-methylphenol moiety connected to the isoindolin-1-one core structure, and it displayed potent antifungal activity against Fusarium culmorum with an IC50 value of 0.89 mM. Surprisingly, compound 33 can be easily converted under almost neutral conditions from the marine antibiotic pestalone,110 a chlorinated and highly functionalized benzophenone produced by a marine fungus of the genus Pestalotia, and the total synthesis of pestalone has been achieved in only 10 steps with an overall yield of 16% starting from commercially available orcinol.111 This conversion of pestalone into 33 might explain the formation of the racemic natural product rac-33 in nature. 4.2 Nitrogen-containing compounds 4.2.1 Amines and amides. Cyclopeptolide antibiotic pestahivin 31 and an anti-HIV agent demethoxypestahivin 32 were characterized from an unidentified fungus Pestalotiopsis sp.101 Pestahivin 31, as a naturally-occurring inhibitor of inducible cell adhesion molecule expression and the prototypical lead of a new class of potential therapeutics for the treatment of chronic inflammatory disorders or autoimmune diseases, can potently suppress the cytokine-induced expression of VCAM-1 on human endothelial cells.102,103 Three new amides, pestalamides A–C 34–36,112 along with the known compounds aspernigrin A 37,113 and carbonarone A 38114, have been isolated from the solid-substrate fermentation culture of the plant pathogenic fungus Pestalotiopsis theae obtained from branches of Camellia sinensis at Hangzhou Botanical Garden, Hangzhou, Zhejiang Province, China. Compound 34 displayed inhibitory effects on HIV-1 replication in C8166 cells with an EC50 value of 64.2 mM and potent antifungal activity against Aspergillus fumigatus with IC50/MIC values of 1.50/57.8 mM. Another new amide, pestalotiopsoid A 39, was obtained from Pestalotiopsis sp. isolated from the Chinese mangrove plant Rhizophora mucronata.115 Due to the low amounts of compound 39 isolated, it was not possible to assign the stereochemistry of the chiral derivatives. A new chlorinated benzophenone alkaloid, pestalachloride A 33, was obtained from the solid-substrate fermentation culture of the plant endophytic fungus Pestalotiopsis adusta isolated from the stem of an unidentified tree in Xinglong, Hainan Province, China.104 It appeared in the NMR spectrum as a mixture of two inseparable atropisomers due to the hindered internal rotation, which indicated a non-enzymatic biosynthesis or a particularly facile mode of racemization and was 628 | Nat. Prod. Rep., 2012, 29, 622–641 This journal is ª The Royal Society of Chemistry 2012 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. Pestalactams A–C (40–42), three novel caprolactams and the first C-7 alkylated caprolactam natural products to be reported, were produced by an unidentified endophytic fungus Pestalotiopsis sp from the stems of Melaleuca quinquenervia (family Myrtaceae) in Australia.116 Among those metabolites, pestalactam A 40 and pestalactam C 42 are the first examples of natural products that contain a halogenated caprolactam ring, and compounds 40–41 displayed similar antimalarial activity with 16–41% parasite growth inhibition achieved at 25 mM and were modestly selective for malaria parasites versus the mammalian cell lines, with both giving 12–64% inhibition at 100 mM. The biogenesis of 40–42 was proposed, and the pestalactam carbon skeleton is presumably derived from leucine and two malonyl-CoA derived acetates and assembled by a hybrid NRPS–PKS. Oxidation and hydroxylation of the cyclised NRPS–PKS product by cytochrome P450s gives rise to the putative trione intermediate which, on tautomerisation, provides the enol dione 41. The chlorination of 41 to yield the major product 40 is most likely catalyzed by a heme-dependent chloroperoxidase. Subsequent dehydration of the leucine-derived side chain ultimately yields 42.117–119 4.2.2 Indole derivatives. Two new heterodimeric diketopiperazine alkaloids, (+)-pestalazines A–B 50–51112 that contain two tryptophan units, along with the known compound asperazine 52,123 have been isolated from the solid-substrate fermentation culture of Pestalotiopsis theae. The absolute configurations of 50 and 51 were determined using Marfey’s method on their acid hydrolysates and by comparison of their A detailed chemical investigation of the minor metabolites produced by the endophytic fungus Pestalotiopsis sp. isolated from the Chinese mangrove Rhizophora mucronata afforded five new amides of polyketide origin, pestalotiopamides A–E 43– 47.120,121 Compounds 43–47 have been proved to be devoid of significant activities against several pathogenic bacteria and four fungal strains in the bioassays used. A new eremophilane-type sesquiterpene named pestalotiopin B 48, which has an interesting lactam structure instead of a typical lactone, was isolated from the fermentation broth of Pestalotiopsis photiniae.78 Another lactam compound 49 with significant antifungal activities was also obtained from the liquid culture of Pestalotiopsis photiniae isolated from the Chinese Podocarpaceae plant Podocarpus macrophyllus.122 This journal is ª The Royal Society of Chemistry 2012 Nat. Prod. Rep., 2012, 29, 622–641 | 629 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. CD spectra with that of a model compound. Compounds 50 and 52 displayed inhibitory effects on HIV-1 replication in C8166 cells with EC50 values of 47.6 and 98.9 mM, respectively. Due to the striking architecture of (+)-pestalazine B 51, it has been considered as an attractive synthetic target by many synthetic chemists.124–132 The convergent synthesis of the proposed structure of (+)-pestalazine B 51 has been achieved in 4 steps using the N-alkylation of an unprotected tryptophan diketopiperazine with a 3a-bromopyrrolidinoindoline as the key step. Although the synthetic compound was confirmed by X-ray analysis, the spectroscopic data did not match those of the natural product, which suggested the need to reinvestigate the structure of natural (+)-pestalazine B 51. The same group finally revised (+)-pestalazine B 51 to (+)-pestalazine B 53 by the total synthesis.132 4.3 Quinone and semiquinone derivatives Two new phytotoxins, (+)-epiepoxydon 54 and PT-toxin 55, were isolated from the culture liquid of tea gray blight fungi, Pestalotiopsis longiseta and Pestalotiopsis thea, respectively.133 The threshold concentration of induced leaf necrosis by 54 and 55 were found to be about 60 mg mL1 and 4 mg mL1, which indicated that compound 54 greatly enhanced the phytotoxicity through substitution at position 2 or isomerization. A biosynthetic relationship between 54 and 55 has been proposed via gentisaldehyde, phyllostine, a 7-membered lactone, an acyclic intermediate and rearranged bicyclic compounds.134 (+)-Torreyanic acid 56, a selectively cytotoxic quinone epoxide dimer, was characterized from the endophytic fungus Pestalotiopsis microspora, originally obtained as an endophyte associated with the endangered tree Torreya taxifolia.135 This compound was found to be 5–10 times more potent in cell lines that are sensitive to protein kinase C (PKC) agonists, 12-o-tetradecanoyl phorbol-13-acetate (TPA) and showed G1 arrest of G0 synchronized cells (1–5 mg mL1). While the overall structure of 56 could be generated by a Diels–Alder dimerization of two identical monomers, the opposite relative configurations for C-9 and C-90 require two diastereomeric monomers. Several pathways can be envisioned to produce 56, one plausible pathway would involve the electrocyclic-possibly acid-catalyzed-closure, the enzymatic oxidation and the [4 + 2] addition reactions to give 56, and the stereochemistry of the final Diels–Alder reaction might be a consequence of keeping the two pentyl side chains opposite one another. The first total synthesis and absolute stereochemical assignment of the quinone epoxide dimer (+)-torreyanic acid 56 has been achieved by the proposed biomimetic route employing a [4 + 2] dimerization of diastereomeric 2H-pyran monomers via a key chiral quinone monoepoxide intermediate, which further confirmed its postulated Diels–Alder biogenesis.136,137 630 | Nat. Prod. Rep., 2012, 29, 622–641 (+)-Ambuic acid 57, a highly functionalized cyclohexenone epoxide structurally related to dimeric natural product torreyanic acid 56, was characterized from Pestalotiopsis spp. living in several of the major representative rainforests of the world.138 Its structure was deduced on the basis of incisive 2D-NMR analysis and further confirmed from more recent solid state NMR studies139 and total synthesis,137,140 which also secured the absolute configuration of the natural product. (+)-Ambuic acid 57 was found to be active against several plant pathogenic fungi and it has been speculated that such activity symbiotically protects the host plant. The complex structural attributes of 57 makes it an attractive synthetic target, and the first total synthesis of (+)-ambuic acid 57 has been reported by Porco and his co-workers through reduction of the quinone, an advanced intermediate in their total synthesis of the related dimeric natural product (+)-torreyanic acid 56, then ester deprotection led to (+)-ambuic acid 57.137 The total synthesis of ()-ambuic acid has also been completed by Mehta and his co-workers from the readily available Diels–Alder adduct of 2-allyl-p-benzoquinone and cyclopentadiene through a simple sequence with sound stereocontrol.140 The structurally related monomeric epoxyquinols ()-jesterone 58 and hydroxy-jesterone 59, two novel highly functionalized cyclohexenone epoxides, were characterized from a newly described endophytic fungus species Pestalotiopsis jesteri isolated from the inner bark of small limbs of Fragraea bodenii.141 Besides its highly functionalized architecture and mixed polyketide-isoprenoid biogenesis, compound 58 has attracted much attention on account of its selective biological activity (minimum inhibitory concentration values 6–25 mg mL1). More recently, jesterone 58 was found to exhibit activity against human breast and human leukemia cell lines.142 The absolute stereochemistry of 58 was determined by the total synthesis of ()-jesterone 58 and ()-jesterone accomplished by the groups of Porco and Mehta.142–144 Furthermore, six new ambuic acid derivatives 60–65 and a new torreyanic acid analogue 66, along with the This journal is ª The Royal Society of Chemistry 2012 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. known dimeric quinone (+)-torreyanic acid 56 and (+)-ambuic acid 57, have been isolated from the crude extract of endophytic fungus Pestalotiopsis sp. inhabiting the lichen Clavaroids sp.145 Among these metabolites, compound 60 displayed antimicrobial This journal is ª The Royal Society of Chemistry 2012 activity against Staphylococcus aureus with IC50 value of 27.8 mM, whereas other compounds did not show noticeable in vitro antibacterial or antifungal activities against the tested organisms (IC50 > 50mM). The isolation of (+)-ambuic acid 57 and its heterodimer (+)-torreyanic acid 56 further supports the proposed biosynthesis of (+)-torreyanic acid 56 via the oxidation, cyclization, and Diels–Alder dimerization of 57.137 Compounds 58–65 are analogues of (+)-ambuic acid 57, but differ from 57 by the presence of different aliphatic side chains at C-9 and substitution pattern. Twelve new cyclohexanone derivatives, pestalofones A–H 67– 74 and pestalodiols A–D 75–78, have been isolated from cultures of Pestalotiopsis fici.146,147 The biosynthesis of these compounds could be derived from two units of prenoids and a polyketide. Interestingly, compounds 68 and 69 possess a previously undescribed, unique highly functionalized skeleton with the presence of two polyoxygenated cyclohexanes, one is spirally joined to the cyclohexene moiety, and the other is linked by an exocyclic double bond. Additionally, compounds 73 and 74 were obtained as an inseparable mixture of two isomers in a 6 : 5 ratio, which was determined by the integration of some well-resolved 1HNMR resonances for each compound. The biological activities study indicated that pestalofones A 67, B 68 and E 71 displayed inhibitory effects on HIV-1 replication in C8166 cells, whereas pestalofones C 69 and E 71 showed significant antifungal activity against Aspergillus fumigatus, and pestalofones F–H 72–74 and pestalodiol C 77 showed cytotoxicity against HeLa and MCF-7 cells. The known compound iso-A82775C 79 was the deacetylation product of pestalodiol C 77,148 which was first isolated from an unidentified fungus, was also obtained from the same fungi.73 Biogenetically, compound 79 might be the putative Diels–Alder precursors for the biosynthesis of compounds 12–19 via putative intermediates.76 Nat. Prod. Rep., 2012, 29, 622–641 | 631 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. isoprenylated epoxyquinol derivatives featuring a previously undescribed nonacyclic skeleton that could be derived from Diels–Alder dimerization of diastereomeric 2H-pyran monomers, which were presumably derived from the co-isolated precursor 83 via oxidation, electrocyclization, and Diels–Alder reaction cascade.135 Pestafolide A 80, a new reduced spiroazaphilone derivative, has been isolated from solid cultures of an isolate of Pestalotiopsis foedan.149 The absolute configuration was determined by application of the CD excitation chirality and modified Mosher method. It displayed antifungal activity against Aspergillusfu migatus (ATCC10894), affording a zone of inhibition of 10 mm at 100 mg/disk. Chloroisosulochrin 84 and chloroisosulochrin dehydrate 85, two new plant growth regulators belonging to the anthraquinine derivatives, along with the structurally related known compounds isosulochrin 86 and isosulochrindehydrate 87, have been isolated from the Raulin-Thom medium cultured filtrate of Pestalotiopsis theae.152 In addition, another new anthraquinone derivative, guepinone 88, along with the known related compounds chloroisosulochrin 84 and isosulochrin 86, were isolated from a rice culture of Pestalotiopsis guepinii, an endophytic fungus of the medicinal palnt Virola michelii.153 Compounds 86 and 88 were completely inactive against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans, while compound 84 was toxic only to Staphylococcus aureus (13 mm inhibition zone). An efficient synthesis of 84 and 86 have been accomplished by Snider and his Two new isoprenylated epoxyquinol derivatives, pestaloquinols A–B 81–82,150 along with their putative biosynthetic precursor, cytosporin D 83,151 were obtained from the solidsubstrate fermentation culture of plant endophytic fungus Pestalotiopsis sp. isolated from the branches of Podocarpus macrophyllus. Compounds 81–82, exhibited cytotoxicity against HeLa cells, both showing an IC50 value of 8.8 mM, are unique 632 | Nat. Prod. Rep., 2012, 29, 622–641 This journal is ª The Royal Society of Chemistry 2012 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. co-workers using a novel ortho-selective chlorination of a phenol with sulfuryl chloride and 2,2,6,6-tetramethylpiperidine as the key step.154 Pestalachloride B 89, a new chlorinated benzophenone derivative structurally related to anthraquinine, has been isolated from cultures of an isolate of Pestalotiopsis adusta.104 It is the new member of the relatively rare chlorinated benzophenone type of metabolites. Compound 89 was evaluated for antifungal activities against a small panel of plant pathogenic fungi, and the results showed that it showed remarkable activity against Gibberella zeae, with an IC50 value of 1.1l mM. 4.5 Lactones Most of the oxysporone derivatives that have been reported from the fungus genus Pestalotiopsis, such as a minor new toxin, pestalopyrone 96,155 together with five known compounds oxysporone 97,156 nectriapyrone 98,157,158 fusalanipyrone 99,159 pestalotin 100160,161 and hydroxypestalotin 101,162 were isolated from a pathogen of evening primrose Pestalotiopsis oenotherae. Among them, compounds 96 and 97 are of comparable toxicity towards evening primrose, Sida spinosa, Sorghum halepense, Ipomoea sp., Chenopodium album and Agrostis abla, while compounds 100 and 101 are much less toxic to these weeds. An effective synthesis route towards 100 using asymmetric dihydroxylation was achieved in four steps.163 Hydroxypestalopyrone 102 as the phytotoxin was produced by a filamentous fungus, Pestalotiopsis microspora associated with the North American endangered tree Torreya taxifolia.164 The two novel phytotoxic g-lactonic dimers related to oxysporone, pestalotines A–B 103– 104,165 which exhibited significant potent phytotoxity against the radical growth of Echinochloa crusgalli with IC50 values of 1.85  104 M and 2.50  104 M, respectively, coexisting with one known compound 6-hydroxyramulosin 105,166 were isolated from Pestalotiopsis sp. HC02, a fungus residing in Chondracris rosee. Investigation of the fungi Pestalotiopsis spp. PSU-MA92 and PSU-MA119 isolated from the twigs of two mangrove plants, Rhizophora apiculata and Rhizophora mucronata, led to the isolation of three new a-pyrones, pestalotiopyrones A–C 4.4 Coumarins Five new coumarins, pestalasins A–E 90–94, along with the known compound 95, were characterized from an undescribed fungal strain of Pestalotiopsis sp.115 None of them showed any significant activity against several cancer cell lines when tested at an initial concentration of 10 mg mL1. This journal is ª The Royal Society of Chemistry 2012 Nat. Prod. Rep., 2012, 29, 622–641 | 633 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. 106–108.167 Chemical investigation of the endophytic fungus Pestalotiopsis sp. isolated from the leaves of the Chinese mangrove Rhizophora mucronata, led to the isolation of three new cytosporons J–L (109–111) along with one known related compound cytosporon C 112.115,168 the same specie.122 Virgatolides A–C 127–129, a new members of the rare benzannulated 6,6-spiroketal class of natural products with the characteristic 30 ,40 ,50 ,60 -tetrahydrospiro [chroman-2,20 -pyran] core, were isolated from the plant endophytic fungus Pestalotiopsis virgatula, and which showed modest cytotoxicity against HeLa cells, with IC50 values of 19.0, 22.5 and 20.6 mM, respectively.172 From a biosynthetic aspect, compounds 127–129 could be generated from a putative triacetic lactone, 3,6-dimethyl-4-hydroxy-2-pyrone and pestaphthalides A–B 114–115 of intermediates via different reaction cascades. Isobenzufuranones, such as isopestacin 113,169 have been frequently isolated from microbial sources. This novel dihydroisobenzofuranone was obtained from Pestalotiopsis microspora isolated from a combretaceaous plant Terminalia morobensis growing in the Sepik river drainage of Papua New Guinea. It is the first member of the isobenzofuranone family of natural products that contains a substituted benzene ring at C-3 of the benzofuranone ring. Strikingly, the resorcinol moiety is attached to the isobenzofuranone skeleton through its C-2 position. Though the structure of 113 contains a chiral center, the natural product isolated was composed of a racemic mixture. It possesses antifungal activity, and acts as an antioxidant toward superoxide radicals and hydroxy free radicals, the activity being comparable to vitamin C. The first total synthesis of 113 has been completed in a regiospecific manner starting from 2,5-dimethylanisole.170 Another two new isobenzofuranone derivatives, pestaphthalides A–B 114–115, were isolated from Pestalotiopsis foedan.149 The absolute configurations of 114–115 were determined by application of the CD excitation chirality and modified Mosher method. Pestaphthalide A 114 showed activity against Candida albicans, causing a zone of inhibition of 13 mm, and pestaphthalide B 115 showed activity against Geotrichum candidum with a 11 mm zone of inhibition when tested at the same level. Photinides A– F 116–121, six new unique benzofuranone-derived g-lactones, have been isolated from the crude extract of plant endophytic fungus Pestalotiopsis photiniae.171 Their absolute configurations were assigned by application of the CD excitation chirality method. Compounds 116–121 displayed modest cytotoxic effects against the human tumor cell line MDA-MB-231. Another five isobenzufuranone derivatives 122–126, exhibited significant antifungal activities, were also characterized from 634 | Nat. Prod. Rep., 2012, 29, 622–641 This journal is ª The Royal Society of Chemistry 2012 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. A novel metabolite 130 containing the benzo[c]oxepin skeleton was characterized from the fermentation broth of cultured Pestalotiopsis virgatula isolate TC-320 from Terminalia chebula through HPLC-SPE-NMR analysis and a detailed purification procedure.173 The biosynthesis of 130 presumably involves aromatization of a polyketide and hydroxylation of the terminal methyl group. Recently, two new 14-membered lactones pestalotioprolides A–B 143–144, along with three structurally related compounds 145–147, were reported from the mangrove-derived fungi Pestalotiopsis spp. PSU-MA92 and PSU-MA119.167 A detailed chemical investigation of the minor metabolites produced by Pestalotiopsis sp. led to the isolation of eleven new polyketide derivatives, including pestalotiopyrones A–H 131– 138, pestalotiopisorin A 140 and pestalotiollides A–B 141–142 along with one known compound nigrosporapyrone D 139.120 All compounds were proved to be devoid of significant activity against several pathogenic bacteria in the bioassay used. 4.6 Chromone derivatives Twelve new isoprenylated chromone derivatives, pestaloficiols A–L 148–159, have been isolated from a scale-up fermentation extract of the plant endophytic fungus Pestalotiopsis fici.174,175 The absolute configurations of 148, 153 and 156 were assigned using the modified Mosher method. Pestalociols A–E 148–152 are new members of the chromenone type of metabolites with a cyclopropane moiety joined spirally at C-8 to a cyclohexene unit, and pestalociols B–E 149–152 are the ring-opening products of pestalociols A 148. Among these compounds, pestalociols A 148, B 149 and D 151 showed inhibitory effects on HIV-1 replication in C8166 cells, with EC50 values of 26.0, 98.1 and 64.1 mM, respectively, while pestalociols C 150 and E 152 were not tested in this paper due to sample limitations. Biogenetically, 148–152 might be derived from two units of prenoids and one polyketide. Pestaloficiols F–L 153–159 are new isoprenylated chromone derivatives, and 156–158 could be derived from 153–155 via reactions including oxidation, reduction, and cyclization. Compounds 153–155 and 158 displayed inhibitory effects on HIV-1 replication in C8166 cells, whereas 156–159 showed cytotoxic activity against HeLa and MCF-7 cell lines. This journal is ª The Royal Society of Chemistry 2012 Nat. Prod. Rep., 2012, 29, 622–641 | 635 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. Mosher method. Biogenetically, compounds 160–162 could be derived from two units of isoprenoids and a polyketide. Pestalotiopsones A–F 163–168, a rare subtype of new chromones found in nature, along with the known derivative 169, were characterized from the mycelia and culture filtrate of the mangrove endophytic fungus Pestalotiopsis sp. isolated from leaves of the Chinese Mangrove plant Rhizophora mucronata.177 These metabolites are new chromones featuring both an alkyl side chain substituted at C-2 and a free or esterified carboxyl group at C-5. Compound 168 exhibited moderate cytotoxicity with an EC50 value of 8.93 mg mL1, whereas compounds 163– 167 and 169 had no cytotoxic activity. 4.7 Phenolic compounds Pestalotheols A 160, B 161 and D 162 as new members of the chromenone type of metabolites were reported from the solidsubstrate fermentation culture of Pestalotiopsis theae obtained from branches of an unidentified tree on Jianfeng Mountain, Hainan Province, China.176 The absolute configuration of pestalotheols A 160 was assigned by application of the modified 636 | Nat. Prod. Rep., 2012, 29, 622–641 Compound 170, a novel and non-peptide endothelin antagonist, was obtained from the culture broth of a fungus, Pestalotiopsis sp.178 It selectively inhibited the ET-1 binding to endothelin type A receptor (ETA receptor) with an IC50 value of 1.5 mM and the increase in intracellular Ca2+ concentration elicited by 1 nM in A10 cells. Its structure is very similar to that of asterric acid,179 the known metabolite first isolated from the culture broth of Aspergillus terreus, which can also inhibit binding of ET-1 to the ETA receptor. The structure of 170 is different from that of asterric acid in the positions of hydroxyl group and methoxy This journal is ª The Royal Society of Chemistry 2012 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. group. Interestingly, it inhibited the ET-1 binding to ETA receptor as potently as asterric acid, which suggests that the hydroxyl group and the methoxy group are essential for inhibitory binding activities, but the positions of both groups are not so important. A phytotoxin, pestaloside 171 with significant antifungal activities, was produced by the fungus Pestalotiopsis microspora obtained from Torreya taxifolia.164 A ubiquitous metabolite, p-hydroxybenzaldehyde 172, was characterized from the endophytic fungus Pestalotiopsis sp. isolated from the Chinese mangrove Rhizophora mucronata.108 A novel phenol, pestacin 173 possessing a dihydroisobenzofuran moiety, was isolated as a racemic mixture from Pestalotiopsis microspora.180 It exhibited a moderate antifungal activity against Pythium ultimum and significant antioxidant activity. The antioxidant activity of 173 is proposed to arise primarily via cleavage of an unusually reactive C–H bond and to a lesser extent, through O–H abstraction. Its racemization mechanism was proposed through a cationic intermediate. Seven unusual metabolites 180–186 were characterized from the fermentation medium extract of the endophytic fungus Pestalotiopsis virgatula derived from the plant Terminalia chebula using an HPLC-PDA-MS-SPE-NMR hyphenated system.183 Their structures and stereochemistry were determined by combination of HPLC-SPE-NMR with electronic circular dichroism (ECD) spectroscopy supported by time-dependent Compound 174, as the putative Diels–Alder precursors for the biosynthesis of compounds 12–19 via putative intermediates, was isolated from Pestalotiopsis fici.76,181 Pestalachloride C 175, a new chlorinated benzophenone derivative was characterized from Pestalotiopsis adusta, which was found to be a naturally occurring racemic mixture, as demonstrated by the X-ray data.104 Two new cytosporons M–N 176–177,115 along with one known compound dothiorelone B 178,182 have been isolated from Pestalotiopsis sp. Another phenolic compound 179 was isolated from Pestalotiopsis photiniae.122 This journal is ª The Royal Society of Chemistry 2012 Nat. Prod. Rep., 2012, 29, 622–641 | 637 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. density-functional theory calculations (TDDFT) of chiral electronic transitions. Interestingly, compounds 185–186 have a novel 1,9,11,18-tetraoxadispiro [6.2.6.2] octadecane skeleton. Most of the metabolites are structurally related and are derivatives of benzo[c]oxepin. These interesting metabolites are representatives of a small but growing group of natural benzo[c] oxepin derivatives of fungal origin. A new biphenyl derivative 196 was obtained from the fermentation broth of the plant endophytic fungus Pestalotiopsis zonata isolated from Cyrtotachys lakka in Hainan, China.184 It showed moderate activities against the bacteria Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, methicillin resistant Staphylococcus aureus, Acinetobacter baumannii and vancomycin-resistant Enterococcus with IC50 values of 0.75, 0.75, 0.82, 0.81, 0.84, 0.90 and 0.87 mM mL1, respectively. 4.8 Miscellaneous metabolites Three new C-methylated acetogenins, pestalotiopsols A–B 187– 188 and the related aldehyde 189, were reported from an unidentified endophytic fungus Pestalotiopsis spp.51 Compound 190 was obtained from Pestalotiopsis sp. HC02, a fungus residing in Chondracris rosee.165 Metabolites 191–192 were characterized from the endophytic fungus Pestalotiopsis sp.108 5 Pestalotheol C 193 as the biosynthetic precursor of compounds 160–162, was produced by Pestalotiopsis theae.176 Its absolute configuration was determined by application of the modified Mosher method. Compound 193 showed an inhibitory effect on HIV-1 replication in C8166 cells with an EC50 value of 16.1 mM. Two phthalic acid derivatives 194–195 were isolated from Pestalotiopsis photiniae, and both compounds displayed significant antifungal activities.122 Concluding remarks In the past two decades, the Pestalotiopsis genus has received considerable attention because of its biological and structural diversity. Pestalotiopsis species as an important group of endophytic fungi are a major source of biologically active natural substances. They have been demonstrated to produce an enormous number of bioactive secondary metabolites with broad biological activities, which may have medicinal, agricultural and industrial applications. There are potentially more bioactive compounds still to be discovered in Pestalotiopsis species, since up to now only a relatively small number of Pestalotiopsis species have been chemically investigated, and many of the remaining species are involved in interesting biological phenomena. These as yet unstudied species hold the promise of providing new natural substances. The large biodiversity of Pestalotiopsis species provides a huge resource for extending the chemodiversity of natural substances and for finding new lead structures for medicinal chemistry. Taxonomy of this genus has been previously based on morphology, with conidial characters being considered as important in distinguishing species and closely related genera. Molecular data have still not been successfully applied for species-level differentiation and names applied to data in GenBank are doubtful, as they are not linked to any type materials. Up to the present date, 196 metabolites have been characterized from this genus. Several compounds have novel carbon skeletons, such as chloropupukeananin 12, chloropestolide A 13, chloropupukeanolides A–E 14–18, chloropupukeanone A 19 and (+)-torreyanic acid 56. Some metabolites are demonstrated to have significant bioactivities, such as chloropupukeanone A 19 exhibited significant inhibitory effects on growth of HeLa and HT29 cell lines with GI50 values of 0.7 and 4.2 mM, respectively, pestalachloride A 33 with potent antifungal activity against Fusarium culmorum with an IC50 value of 0.89 mM and pestacin 173 with moderate antifungal properties and high antioxidant activity. These findings will most likely trigger studies on their total synthesis, biosynthesis and biological aspects. 6 Acknowledgements This work was supported by the programs for New Century Excellent Talents in University (NCET-09-0112), the Key Project 638 | Nat. Prod. Rep., 2012, 29, 622–641 This journal is ª The Royal Society of Chemistry 2012 Published on 17 January 2012. Downloaded by Universidad Nacional Agraria La Molina on 10/06/2016 16:38:11. of Chinese Ministry of Education (209010), the Key Applied Basic Research Programs of Hebei Province (0996030917D), Hebei Province Science Fund for Distinguished Young Scholars (C2011201113) and National Natural Science Foundation of China (31071701 and 30671385). 7 References 1 B. Schulz and C. Boyle, Mycol. Res., 2005, 109, 661–686. 2 B. Schulz, C. Boyle, S. Draeger, A. R€ ommert and K. Krohn, Mycol. Res., 2002, 106, 996–1004. 3 G. Strobel, X. Yang, J. Sears, R. Kramer, R. S. Sidhu and W. M. Hess, Microbiology, 1996, 142, 435–440. 4 R. 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