CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 673 REVIEW Secondary Metabolites from the Genus Xylaria and Their Bioactivities by Fei Song, Shao-Hua Wu*, Ying-Zhe Zhai, Qi-Cun Xuan, and Tang Wang Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan Institute of Microbiology, Yunnan University, Kunming 650091, P. R. China (phone: þ86-871-65032423; e-mail: [email protected]) Contents 1. Introduction 2. Secondary Metabolites 2.1. Sesquiterpenoids 2.1.1. Eremophilanes 2.1.2. Eudesmanolides 2.1.3. Presilphiperfolanes 2.1.4. Guaianes 2.1.5. Brasilanes 2.1.6. Thujopsanes 2.1.7. Bisabolanes 2.1.8. Other Sesquiterpenes 2.2. Diterpenoids and Diterpene Glycosides 2.3. Triterpene Glycosides 2.4. Steroids 2.5. N-Containing Compounds 2.5.1. Cytochalasins 2.5.2. Cyclopeptides 2.5.3. Miscellaneous Compounds 2.6. Aromatic Compounds 2.6.1. Xanthones 2.6.2. Benzofuran Derivatives 2.6.3. Benzoquinones 2.6.4. Coumarins and Isocoumarins 2.6.5. Chroman Derivatives 2.6.6. Naphthalene Derivatives 2.6.7. Anthracenone Derivatives 2.6.8. Miscellaneous Phenolic Derivatives 2.7. Pyranone Derivatives 2.8. Polyketides 3. Biological Activities 3.1. Antimicrobial Activity 3.2. Antimalarial Activity 2014 Verlag Helvetica Chimica Acta AG, Zrich 674 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 3.3. Cytotoxic Activity 3.4. Other Activities 4. Conclusions 1. Introduction. – Xylaria Hill ex Schrank is the largest genus of the family Xylariaceae Tul.&C.Tul. (Xylariales, Sordariomycetes) and presently includes ca. 300 accepted species of stromatic pyrenomycetes [1]. Xylaria species are widespread from the temperate to the tropical zones of the earth [2]. The traditional view of Xylaria sp. as saprotrophic wood-destroyers had to be emended, since it was found that members of this genus occur ubiquitously as endophytes of vascular plant [3]. Not only Xylaria, but also the entire Xylariaceae appear to play an important ecological role, which has probably come about during their long co-evolution with seed plants [4]. Fungi of the genus Xylaria have been shown to be potential sources of novel secondary metabolites, and many of them possess biological activities relevant for drug discovery [5], including cytotoxic, antimalarial, and antimicrobial activities. In this review, we compile the most important secondary metabolites isolated from the genus Xylaria over the past few decades. The biological activities of the compounds isolated in recent years are also included. 2. Secondary Metabolites. – The secondary metabolites from Xylaria sp. include sesquiterpenoids, diterpenoids, diterpene glycosides, triterpene glycosides, steroids, N- containing compounds, aromatic compounds, pyrone derivatives, and polyketides. Their structures, 1–188 are shown below, and their names and the corresponding fungal sources are compiled in the Table (see below). 2.1. Sesquiterpenoids. A total of 46 sesquiterpenoids, 1–46, have been reported from Xylaria species. They possess various C-skeletons, such as eremophilanes, eudesma- nolides, presilphiperfolanes, guaianes, brasilanes, thujopsanes, and bisabolanes. 2.1.1. Eremophilanes. Compounds 1–8 are eremophilane-type sesquiterpenes, isolated from the endophytic Xylaria sp. BCC21097 [6]. Xylarenones A and B (9 and 10, resp.) were isolated from Xylaria sp. NCY2 [7]. An eremophilane sesquiterpenoid, xylarenic acid (11), was isolated from the AcOEt extract of Xylaria sp. 101, obtained from the fruiting body collected in Gaoligong Mountain [8]. Two eremophilane sesquiterpenes, phaseolinone (12) and phomenone (13), were isolated from Xylaria sp. PA-01, obtained from the leaves of Piper aduncum [9]. Compounds 14 and 15 were isolated from the wood-decay fungus Xylaria sp. BCC5484 [10]. Singh et al. [11] isolated integric acid (16) from Xylaria sp. MF6254. Xylarenals A and B (17 and 18, resp.) were found in Xylaria persicaria, associated with the fallen fruits of Liquidambar styracifua, in eastern North America [12]. Four eremophilane sesquiterpenoids, 19–22, were isolated from the mangrove endophytic fungus Xylaria sp. BL321 [13]. 2.1.2. Eudesmanolides. Four 12,8-eudesmanolide sesquiterpenoid lactones, 23–26, were isolated from the fungus Xylaria ianthinovelutina [14]. Two 12,8-eudesmanolides, 27 and 28, were isolated from the fermentation broth of the wood-decay fungus Xylaria sp. BCC5484 [10]. 2.1.3. Presilphiperfolanes. Two presilphiperfolane sesquiterpenes, 9,15-dihydroxy- presilphiperfolan-4-oic acid (29) and 15-acetoxy-9-hydroxypresilphiperfolan-4-oic acid (30), were isolated from Xylaria sp. PA-01 [9]. CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 675 676 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 2.1.4. Guaianes. Two guaiane sesquiterpenoids, xylaranols A and B (31 and 32, resp.) were isolated from Xylaria sp. 101, obtained from the fruiting body collected in Gaoligong Mountain [8]. 2.1.5. Brasilanes. Xylarenic acid (33) was isolated from Xylaria sp. NCY2 [7]. 2.1.6. Thujopsanes. Three sesquiterpenes, xylcarpins A–C (34–36, resp.), were obtained from Xylaria carpophila [15]. 2.1.7. Bisabolanes. Two sesquiterpenes, xylcarpins D and E (37 and 38, resp.) were obtained from Xylaria carpophila [15]. 2.1.8. Other Sesquiterpenes. Xylaric acids A –D (39–42, resp.), hydroheptelidic acid (43), gliocladic acid (44), chlorine heptelidic acid (45), and trichoderonic acid A (46) were isolated from the fungus Xylaria sp. associated with termite nests [16]. 2.2. Diterpenoids and Diterpene Glycosides. Four pimarane-type diterpenoids, 47– 50, and four pimarane diterpene glycosides, 51–54, have been reported from Xylaria species. Xylarenolide (47) was isolated from Xylaria sp. 101 [8]. Compounds 48 and 49 were isolated from the fungus Xylaria sp. BCC 5484, obtained from an unidentified dead wood in Hala Wildlife Sanctuary, Narathiwat Province, Thailand [10]. Sphaer- opsidin C (50) and xylopimarane (51) were isolated from the fungus Xylaria sp. BCC 4297 [17]. 16-(a-d-Mannopyranosyloxy)isopimar-7-en-19-oic acid (52), 15-hydroxy- 16-(a-d-mannopyranosyloxy)isopimar-7-en-19-oic-acid (53), and 16-(a-d-glucopyra- nosyloxy)isopimar-7-en-19-oic acid (54) were isolated from Xylaria polymorpha [16][18]. Sordaricin (55) was isolated from the endophytic Xylaria sp. PSU-D14 [19]. A sordaricin derivative, containing a tricyclic uronic acid moiety, 56, was isolated from the culture fluids of a wood-inhabiting Xylaria sp. [20]. CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 677 2.3. Triterpene Glycosides. Four triterpene glycosides, kolokosides A –D (57–60, resp.), have been reported from the Hawaiian wood-decay fungus Xylaria sp. NRRL 4019 [21]. 2.4. Steroids. Cerevisterol (61) was isolated from the wood-decay fungus Xylaria sp. BCC 9653 [22]. Ergosta-4,6,8(14),22-tetraen-3-one (63) was found in Xylaria sp. collected in Vietnam [23]. Blazein (62), ergosterin (64), and 5,8-epidioxyergosta-6,22- dien-3-ol (65) were isolated from an endolichenic Xylaria sp. [24]. 2.5. N-Containing Compounds. To date, 32 N-containing compounds have been isolated from species of Xylaria. More than half of these compounds are cytochalasins, which were mainly obtained from Xylaria hypoxylon and X. obovata. 678 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 2.5.1. Cytochalasins. A total of 18 cytochalasins, 66–83, have been reported from several Xylaria species. They are the most important bioactive components in the genus Xylaria. Among them, two new closely related cytotoxic cytochalasin compounds, 19,20-epoxycytochalasin Q (66) and deacetyl 19,20-epoxycytochalasin Q (67) were isolated from Xylaria obovata ADA-288, Xylaria sp. SCSIO156, and Xylaria hypoxylon [25–27]. 18-Deoxy-19,20-epoxycytochalasin Q (68), deacetyl 19,20-epoxycytochalasin C(69), and 19,20-epoxycytochalasin C (70), were isolated from the fungi Xylaria obovata and Xylaria hypoxylon [2][27]. 19,20-Epoxycytochalasin R (71), 18-deoxy- 19,20-epoxycytochalasin R (72), cytochalasin R (73), and 19,20-epoxycytochalasins D and E (74 and 75, resp.) were isolated from Xylaria hypoxylon, associated with a soil sample containing decayed wood chips collected at Tikal, Guatemala [27]. 18- Deoxycytochalasin Q (76), 21-O-deacetylcytochalasin Q (77), and cytochalasins Q and D(78 and 79, resp.) were isolated from the marine sediment-derived fungus Xylaria sp. SCSIO156, Xylaria obovata ADA-288, Xylaria sp. BCC9653, and Xylaria hypoxylon [2][22][26][27]. Deacetylcytochalasin D (80) and cytochalasin O (81) were isolated from the wood-decay fungus Xylaria sp. BCC9653 [22]. Cytochalasin B (82)was isolated from the endophytic Xylaria sp. [28]. A new cytochalasin derivative, xylarisin (83), was found in the marine-derived fungus Xylaria sp. PSU-F100 [29]. 2.5.2. Cyclopeptides. Five cyclopeptides have been reported from Xylaria sp. Cyclo(l-Pro-l-Tyr) (84) was isolated from the wood-decay fungus Xylaria sp. BCC 9653 [22]. Neoechinulin A (85) was isolated from the fruiting bodies of Xylaria euglossa [30]. A cyclic peptide containing an allenic ether of a N-(p-hydroxycinna- moyl) amide, xyloallenolide A (86), was isolated from Xylaria sp. No. 2508 [31]. Two cyclic pentapeptides, 87 and 88, were isolated from the crude extract of an endolichenic fungus Xylaria sp. [24]. 2.5.3. Miscellaneous Compounds. Uracil (89) was isolated from Xylaria sp. BCC 9653 [22]. A methyl p-aminobenzoate derivative, 90, quinoline-4-carbonitrile (91), and CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 679 quinoline-4-carboxaldehyde oxime (92) were isolated from the wood-decay fungus Xylaria sp. BCC 9653 [22]. Xylaramide (93) was isolated from the wood-inhabiting fungus Xylaria longipes [32].