Chemistry for Sustainable Development  "!`& 13 Natural Chlorine-Containing Xanthones VALERY M. DEMBITSKY1 a nd GENRICH A. TOLSTIKOV2 1 Department of Pharmaceutical Chemistry and Natural Products, School of Pharmacy, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120 (Israel) E-mail: dvalery@cc.huji.ac.il 2 Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Pr. Akademika Lavrentyeva 9, Novosibirsk 630090 (Russia) E-mail: gtolstik@nioch.nsc.ru (Received October 10, 2002) Abstract Chlorine-containing xanthones were found in fungi, higher plants, and lichens. The structures of more than 70 compounds are considered, and data about their biological activity are given. Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xanthones with an unchanged skeleton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other compounds with a xanthone fragment in the molecule . . . . . . . . . . . . . . . . . . . . . . . INTRODUCTION Xanthones are secondary metabolites found in the families of higher plants such as Asteraceae, Betulaceae, Caryophyllaceae, Clusiaceae, Gentian aceae, Gesneriaceae, Guttiferae, Iridaceae, Loganiaceae, Lytraceae, Moraceae, Podostemaceae, Polygalaceae, Polygalaceae [1, 2], in some species of fungi: Aspergillus versicolor, Bi polaris sorokinian, Helminthosporium ravenelii, H. turcicum, Penicillium patulum [2–4], and in lichens [1, 2, 5, 6]. While xanthones have a symmetric structure, the carbon atoms vary depending on the nature of biosynthesis. Thus carbon atoms 1–4 (ring A) are associated with biosynthesis from the acetate, and carbon atoms 5–8 (ring B) result from biosynthesis according to the known route followed by shikimic acid [7]. The num- 13 14 17 bering of the carbon atoms in xanthones is based on the structural skeleton of xanthen-9-one (1) [8]. If ring B is oxidized, the numbering of oxidized xanthones is preserved for ring A [7]. All of the currently known n atural xanthones form five major groups: 1) simple oxidized xanthones, 2) xanthone glycosides, 3) prenyl(isopentyl)-containing and related xanthones, 4) xanthonolignoids, and 5) mixed xanthones [9]. Each of these major groups may be further subdivided into minor xanthone groups [1, 2, 5–9]. Xanthones are specific organic substances occasionally used in plant chemotaxonomy [1, 2]. 14 VALERY M. DEMBITSKY a nd GENRICH A. TOLSTIKOV TABLE 1 Monochloroxanthones Xanthone R1 R2 R3 R4 R5 R6 R7 R8 2 OH Cl OH H H OH H Me 3 OH Cl OH H H OMe H Me 4 OH Cl OMe H H OMe H Me No. 5 OH H OH Cl H OH H Me 6 OH H OH Cl H OMe H Me 7 OH H OH H Cl OH H Me 8 OH H OH H Cl OMe H Me 9 OH H OMe H Cl OH H Me 10 OH H OMe H Cl OMe H Me 11 OH H OH H H OH Cl Me 12 OH H OH H H OMe Cl Me 49 OH H Me OMe H H Cl OH 50 OMe H Me OMe H H Cl OH 51 OMe H Me OMe Cl H H OH 52 OH H Me OMe Cl H H OH Of greatest interest, however, are the pharmacological properties of xanthones [10]. A number of publications have reported that they exhibit antibacterial, antifungal, and anticancer activities [1, 2]. They also inhibit the development of the human immunodeficiency virus [11, 12]. Of almost 800 xanthones found in nature, only 68 are chlorine-containing ones. These are primarily synthesized by lichens [1, 2, 5, 6, 13, 14] and are found in several species of fungi and plants [13, 14]. XANTHONES WITH AN UNCHANGED SKELETON The first chlorine-containing xanthone, 2-chloronorlichexanthone (2), was found in 1966 in the lichen Lecanora rupicola [15]. Later it was isolated from the lichens Lecanora sp.: L. populicola, L. salina è Lecidella vorax [16]. 6-O-Methyl-2-chloronorlichexanthone (3) is present in extracts from the lichens Lecanora salin a, Pertusaria cicatricosa [16] and P. sulphurata [17]. 2-Chlorolichexanthone (4) was found in Lecanora sp., Pertusaria cicatricosa [16] and P. sulphurata [17]. The lichen Lecanora straminea contains 4-chloronorlichexanthone (5), 6-O-methyl-5-chloronorlichexanthone (7) [18–21], and 2,4-dichloronorlichexanthone (13) [16, 21]. 6-O-Methyl-4-chloronorlichexanthone (6) is present in the lichen Pertusaria sulphurata [16]. The lichen Lecanora contractula contains 5-chloro-6-O-methylnorlichexanthone (8) and 5-chlorolichexanthone (10) [16]. Other compounds isolated from the lichens of the same genus include vinetorin (9) (L. vinetorum) [16, 22], 7-chloronorlichexanthone (11) (L. populicola) [16], and 7-chloro-6-O-methylnorlichexanthone (12) (L. populicola and L. salin a) [16]. 2,4-Dichloronorlichexanthone (13) [21] was isolated from the lichen Lecidella vorax. Thiophaninic acid (14) is synthesized by several species of lichen: Dimelaenà sp. [23], D. cf. australiensis [16], Pertusaria sp. [24], P. flavicans [25], P. flavicunda [26] and P. sulphurata [17]. 2,4-Dichlorolichexanthone (15) was found in extracts from the lichens Dimelaenà cf. australiensis [16], Pertusaria sp. [27] and P. cicatricosa [16]. 2,5-Dichloronorlichexanthone (16) was found in the lichens Buellia sp. [28], Lecanora 15 NATURAL CHLORINE-CONTAINING XANTHONES TABLE 2 Dichloroxanthones Xanthone R1 R2 R3 R4 R5 R6 R7 R8 13 OH Cl OH Cl H OH H Me 14 OH Cl OH Cl H OMe H Me 15 OH Cl OMe Cl H OMe H Me 16 OH Cl OH H Cl OH H Me 17 OH Cl OH H Cl OMe H Me 18 OH Cl OMe H Cl OH H Me No. 19 OH Cl OMe H Cl OMe H Me 20 OH Cl OH H H OH Cl Me 21 OH Cl OH H H OMe Cl Me 22 OH Cl OMe H H OH Cl Me 23 OH Cl OMe H H OMe Cl Me 24 OH H OH Cl Cl OH H Me 25 OH H OH Cl Cl OMe H Me 26 OH H OMe Cl Cl OMe H Me 27 OH H OH Cl H OH Cl Me 28 OH H OH H Cl OH Cl Me Me 29 OH H OMe H Cl OH Cl 46 OH H Me OMe Cl H Cl OH 47 OMe H Me OMe Cl H Cl OH 48 OH H Me OH Cl H Cl OH 53 Me OH Me H Cl H Cl OH 54 Me OMe Me H Cl H Cl OH broccha, Lecidella meiococca and L. vorax [16]. 2,5-Dichloro-6-O-methylnorlichexanthone (17) was isolated from Dimelaenà sp. [23], D. cf. australiensis, Pertusaria cicatricose and Lecanora contracta [16]. The rarely occurring 3-O-methyl2,5-dichloronorlichexanthone (18) was also found in Dimelaenà cf. australiensis [16], Lecanora sp. [29]. 2,5-Dichlorolichexanthone (19) was isolated from the lichens Pertusaria sp., Pertusaria aleianàta and Pertusaria cicatricose [16, 27]. 2,7-Dichloronorlichexanthone (20) was extracted from the lichens Buellia sp. [28], Lecanora sp., L. behringii [16], L. broccha [16, 28], L. populicola, L. salin a, and Lecidella meiococca [16]. 2,5-Dichloro-6-O-methylnorlichexanthone (21) was found in the lichens Lecanora sp., L. behringii, L. populicola, L. salin a [16]; 2,7-dichloro-3-O-methylnorlichexanthone (22), in the lichens Lecanora sp., L. behringii, L. salin a [16]. The species Buellia glaziouana [30], Lecanora sp., L. behringii, L. populicola, L. salin a [16], and Lopadium sp., Pertusaria sp. [31] contained 2,7-dichlorolichexanthone (23), while 4,5-dichloronorlichexanthone (24) was revealed in Lecanora flavo-pallescens [32], L. straminea [18–20, 33], Lecidella asema [28], L. vorax [16], Micarea austrotern aria [32], and M. isabellina, Pertusaria pycnothelia [16]. 4,5-Dichloro-6-O-methylnorlichexanthone (25) was found in only two Australian lichens: Dimelaen a sp. [23] and D. cf. australiensis [16]. 4,5-Dichlorolichexanthone (26) was isolated from four species: Buellia glaziouan a [18–20, 33], Dimelaen a cf. australiensis [16], Lecanora straminea [18–20, 33], and Pertusaria cicatricosa [16]. 4,7-Dichloronorlichexanthone (27) was found in only two species belonging to the genus Lecidella: Låñ. asema [28] and Låñ. meiococca [16]. The 16 VALERY M. DEMBITSKY a nd GENRICH A. TOLSTIKOV TABLE 3 Tri- and Tetrachloroxanthones Xanthone R1 R2 R3 R4 R5 R6 R7 R8 No. 30 OH Cl OH Cl Cl OH H Me 31 OH Cl OH Cl Cl OMe H Me 32 OH Cl OMe Cl Cl OH H Me 33 OH Cl OMe Cl Cl OMe H Me 34 OMe Cl OMe Cl Cl OMe H Me 35 OH Cl OAc Cl Cl OAc H Me 36 OH Cl OH Cl H OH Cl Me 37 OH Cl OH H Cl OH Cl Me 38 OH Cl OMe H Cl OH Cl Me 39 OH Cl OMe H Cl OMe Cl Me 40 OH H OH Cl Cl OH Cl Me 41 OH H OH Cl Cl OMe Cl Me 42 OH H OMe Cl Cl OH Cl Me 43 OH Cl OH Cl Cl OH Cl Me 44 OH Cl OH Cl Cl OMe Cl Me 45 OH Cl OMe Cl Cl OH Cl Me lichens Buellia sp. [28], Lecanora broccha [16, 28], Lecidella asema, Låñ. subalpicida [28] and Låñ. vorax [16] contain 5,7-dichloronorlichexanthone (28); the lichens Lecànora broccha, Låñ. vinetorum, [16, 28], Lecidella meiococca and Låñ. vorax [16] produce 5,7-dichloro-3-O-methylnorlichexanthone (29). A new xanthone, arthothelin (30), was first isolated from the lichen Arthothelium pacificum [26]. Later it was found in 16 other species: Buellia sp. [28, 34], Dimelaenà cf. australiensis [16], Lecànora broccha [34], L. flavo-pallescens [32], L. pinguis [26], L. reuteri [35], Lecanora straminea [36], L. sulphurata [16, 32], Lecidella meiococca [16] è Lec. vorax [24], Micarea austroternaria [32], M. isabellinà [16], Pertusaria cicatricosa [16] and Tapellaria epi phylla [31]. 6-O-Methylfluorothelin (31) and thuringione (32) were isolated from the lichens Dimelaen a sp. [23, 37], D. cf. australiensis, Micarea isabellin a, Pertusaria pycnothelia [16], and Lecidea pinguis [24], L. carpathica [37], respectively. 2,4,6-Trichlorolichexanthone (33) and 1,3,6tri-O-methylarthothelin (34) were extracted from two species of lichen: Dimelaenà sp. and D. cf. australiensis [23, 38]. Compound (33) was also found in two species of Australian lichen: Pertusaria sp. [27] and P. cicatricosa [16]. Erythrommone (35) was isolated from only one species: Haematomma erythromma [27, 39], while 2,4,7-trichloro-norlichexanthone (36) was found in two species of the genus Lecanora: L. flavo-pallescens [30, 32] and L. sulphurata [16, 30, 32]. Isoarthothelin (37) was isolated from Buellia sp. [28, 34], Lecanora broccha [16, 28, 34], L. sulphurata [16, 32], Lecidella meiococca [16], L. subalpicida [28] and L. vorax [16]. 3-O-Methyl-2,5,7-trichloronorlichexanthone (38) was found in Lecanora brîccha [16, 28], L. capistrata [30], Lecidella meiococca [16], L. subalpicida [28] and Lecidella vorax [16]. 2,5,7-trichloronorlichexanthone (39) was found in two species: Dimelaenà cf. australiensis and Lecanora brîccha [16]. 6-O-Methylasemone (41) was isolated from one species: Pertusaria pycnothelia [16]. Asemone (40) and 3-Omethylasemone (42) were extracted from NATURAL CHLORINE-CONTAINING XANTHONES 17 thylthiophanic ether (45) was contained in Lecidella meiococca [16]. Thiophanic acid (43), isolated from the lichen Lecanora rupicola [15], is the first member of the large group of xanthones (2)–(45). This acid (40) and other xanthones from this series were synthesized independently by different research groups [16, 18–20, 27]. These are related compounds, which are formed in n ature from polyketides via the polyhydroxybenzophenone intermediate [5, 6]. A comparatively small group of biogenically related xanthones know as ravenelines was discovered in the Australian lichen Rinodin a thiomela and R. lepida. These are thiomelin (46) and its an alogs (47)–(54) [41, 42]. Lecanora broccha [16]; (40) was addition ally found in Lecidella asema [28], Micarea isabellin a [16, 32], Pertusaria pycnothelia [16], while (42) was also identified in Lecidella meiococca [16]. Thiophanic acid (43) was extracted from 12 species of lichen: Buellia sp. [28], Lecanora flavo-pallescens [32], L. rupicola [15], L. straminea [36], L. sulphurata [16,32], Lecidella asema [28], L. meiococca [16], L. quernea [24], L. vorax [16], Micarea austrotern aria [32], M. isabellin a, Pertusaria pycnothelia [16]. 6-O-Methylthiophanic ether (44) was found in only one species: Micarea isabellin a [16], while 3-O-me- OTHER COMPOUNDS WITH A XANTHONE FRAGMENT IN THE MOLECULE About a dozen chlorine-containing compounds with a classical or modified xanthone fragment in a molecule have been isolated and identified. For example, the parasitic fungus Monilinia fructicola, affecting the cherry-tree, produces not only 4-chloropinselin (5), but also the product of its oxidative transformation – chloromonilicin (56) [43–46]. Another parasitic fungus, Aspergillus ustus, whose home is South Africa, synthesizes two new metabolites: austocystin A (57) and austocystin C (58) [47, 48]. 18 VALERY M. DEMBITSKY a nd GENRICH A. TOLSTIKOV The African plant Psorospermum febrifugum (family Guttiferae) contains two highly toxic xanthones: psorospermin chlorohydrin (59) and its an alog (60) [49, 50]. The latter shows high activity against the 9PS cancer cells (ED50 < 0.01 ng/ml) [50]. Lysoli pin I (61), produced by the microorganism Streptomyces violaceoniger, is a derivative of an unstable antibiotic lysoli pin X (62) [51, 52]. Biosynthesis of these interesting antibiotics was reported in [53]. The parasitic beetroot fungus Cercospora beticola, occurring worldwide, produces a series of interesting complex metabolites: beticolin-1 (63), 2 (64), 3 (65), 4 (66), 6 (67), and beticolin-8 (68) [54–59]. Beticolin-2 (64) was also isolated by another research group and was n amed “cebetin A” [58]. REFERENCES 1 V. Peres, T. J. Nagem and F. F. de Oliveira, Phytochemistry, 55 (2000) 683. 2 V. Peres and T. J. Nagem, Ibid., 44 (1997) 191. 3 W. B. Turner and D. C. Aldridge, Fungal Metabolites, 2nd Ed., Acad. 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