Cytotoxic Secondary Metabolites from the Endolichenic Fungus Hypoxylon fuscum

Abstract

As part of our search for new cytotoxic and antimicrobial natural products from endolichenic fungi, 19 compounds including 1 new 10-member lactone (2), 1 new polyacetylene glycoside (3), 1 new brasilane-type sesquiterpenoid glycoside (4), and 2 isobenzofuran-1(3H)-one derivatives (5 and 6) were isolated from the solid culture of the endolichenic fungus Hypoxylon fuscum. Their structures were unambiguously elucidated by NMR spectroscopic data, MS, ECD (electronic circular dichroism) calculation, and chemical methods. The cytotoxic effects on K562, SW480, and HEPG2 cell lines and the antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Candida albicans were assessed. Compounds 1, 2, and 5 exhibited moderate cytotoxicity against K562, SW480, and HEPG2 cell lines while compounds 1, 9, and 11 displayed weak antibacterial activity against S. aureus.

Key words

Hypoxylon fuscum - Hypoxylaceae - endolichenic fungi - polyacetylene - sesquiterpene - cytotoxicity - antimicrobial activity

• References

• 1 Honegger R. The lichen symbiosis-what is so spectacular about it?. Lichenologist 1998; 30: 193-212
• 2 Kellogg JJ, Raja HA. Endolichenic fungi: a new source of rich bioactive secondary metabolites on the horizon. Phytochem Rev 2017; 16: 271-293
• 3 Suryanarayanan TS, Thirunavukkarasu N. Endolichenic fungi: the lesser known fungal associates of lichens. Mycology 2017; 8: 189-196
• 4 Basnet BB, Liu L, Chen B, Suleimen YM, Yu H, Guo S, Li B, Liu H. Four new cytotoxic arborinane-type triterpenes from the endolichenic fungus Myrothecium inundatum . Planta Med 2019;
• 5 Bodo B, Tih RG, Davoust D, Jacquemin H. Hypoxylone, a naphthyl-naphthoquinone pigment from the fungus Hypoxylon sclerophaeum . Phytochemistry 1983; 22: 2579-2581
• 6 Fournier J, Köpcke B, Stadler M. New species of Hypoxylon from Western Europe and Ethiopia. Mycotaxon 2010; 113: 209-235
• 7 Mühlbauer A, Triebel D, Persoh D, Wollweber H, Seip S, Stadler M. Macrocarpones, novel metabolites from stromata of Hypoxylon macrocarpum, and new evidence on the chemotaxonomy of Hypoxylon species. Mycol Prog 2002; 1: 235-248
• 8 Quang DN, Hashimoto T, Tanaka M, Stadler M, Asakawa Y. Cyclic azaphilones daldinins E and F from the ascomycete fungus Hypoxylon fuscum (Xylariaceae). Phytochemistry 2004; 65: 469-473
• 9 Intaraudom C, Bunbamrung N, Dramae A, Boonyuen N, Kongsaeree P, Srichomthong K, Supothina S, Pittayakhajonwut P. Terphenyl derivatives and drimane – Phathalide/isoindolinones from Hypoxylon fendleri BCC32408. Phytochemistry 2017; 139: 8-17
• 10 Kuhnert E, Heitkämper S, Fournier J, Surup F, Stadler M. Hypoxyvermelhotins A–C, new pigments from Hypoxylon lechatii sp. nov. Fungal Biol 2014; 118: 242-252
• 11 Gu W, Ge HM, Song YC, Ding H, Zhu HL, Zhao XA, Tan RX. Cytotoxic benzo[j]fluoranthene metabolites from Hypoxylon truncatum IFB-18, an endophyte of Artemisia annua . J Nat Prod 2007; 70: 114-117
• 12 Quang DN, Hashimoto T, Stadler M, Radulović N, Asakawa Y. Antimicrobial azaphilones from the fungus Hypoxylon multiforme . Planta Med 2005; 71: 1058-1062
• 13 Quang DN, Stadler M, Fournier J, Asakawa Y. Carneic Acids A and B, chemotaxonomically significant antimicrobial agents from the Xylariaceous ascomycete Hypoxylon carneum . J Nat Prod 2006; 69: 1198-1202
• 14 Chinworrungsee M, Kittakoop P, Isaka M, Rungrod A, Tanticharoen M, Thebtaranonth Y. Antimalarial halorosellinic acid from the marine fungus Halorosellinia oceanica . Bioorg Med Chem Lett 2001; 11: 1965-1969
• 15 Sabitha G, Yadagiri K, Swapna R, Yadav JS. The first total synthesis of putaminoxin and determination of its absolute configuration. Tetrahedron Lett 2009; 50: 5417-5419
• 16 Shiono Y, Motoki S, Koseki T, Murayama T, Tojima M, Kimura K. Isopimarane diterpene glycosides, apoptosis inducers, obtained from fruiting bodies of the ascomycete Xylaria polymorpha . Phytochemistry 2009; 70: 935-939
• 17 Cameron DW, Craik JCA. Colouring matters of the aphididae. Part XXXVI. The configuration of the glucoside linkage in protoaphins. J Chem Soc C Org 1968; 0: 3068-3072
• 18 Kashiwada Y, Nonaka G, Nishioka I. Studies on rhubarb (rhei rhizoma). V. Isolation and characterization of chromone and chromanone derivatives. Chem Pharm Bull (Tokyo) 1984; 32: 3493-3500
• 19 Sumarah MW, Puniani E, Blackwell BA, Miller JD. Characterization of polyketide metabolites from foliar endophytes of Picea glauca . J Nat Prod 2008; 71: 1393-1398
• 20 Kokubun T, Shiu W, Gibbons S. Inhibitory activities of lichen-derived compounds against methicillin- and multidrug-resistant Staphylococcus aureus . Planta Med 2007; 73: 176-179
• 21 El Amrani M, Debbab A, Aly AH, Wray V, Dobretsov S, Müller WEG, Lin W, Lai D, Proksch P. Farinomalein derivatives from an unidentified endophytic fungus isolated from the mangrove plant Avicennia marina . Tetrahedron Lett 2012; 53: 6721-6724
• 22 Edwards RL, Maitland DJ, Pittayakhajonwut P, Whalley AJS. Metabolites of the higher fungi. Part 33. Grammicin, a novel bicyclic C₇H₆O₄ furanopyranol from the fungus Xylaria grammica (Mont.) Fr. J Chem Soc Perkin 1 2001; 11: 1296-1299
• 23 Weber D, Sterner O, Anke T, Gorzalczancy S, Martino V, Acevedo C. Phomol, a new anti-inflammatory metabolite from an endophyte of the medicinal plant Erythrina crista-galli. J Antibiot (Tokyo) 2004; 57: 559-563
• 24 Evidente A, Capasso R, Abouzeid MA, Lanzetta R, Vurro M, Bottalico A. Three new toxic pinolidoxins from Ascochyta pinodes . J Nat Prod 1993; 56: 1937-1943
• 25 Machado VR, Biavatti MW, Danheiser RL. A short and efficient synthesis of the polyacetylene natural product deca-4,6,8-triyn-1-ol. Tetrahedron Lett 2018; 59: 3405-3408
• 26 Lee MH, Son YK, Han YN. Tissue factor inhibitory sesquiterpene glycoside from Eriobotrya japonica . Arch Pharm Res 2004; 27: 619
• 27 Kasai R, Okihara M, Asakawa J, Mizutani K, Tanaka O. ¹³C NMR study of α- and β-anomeric pairs of d-mannopyranosides and l-rhamnopyranosides. Tetrahedron 1979; 35: 1427-1432
• 28 Hu ZY, Li YY, Huang YJ, Su WJ, Shen YM. Three new sesquiterpenoids from Xylaria sp. NCY2. Helv Chim Acta 2008; 91: 46-52
• 29 Roslund MU, Tähtinen P, Niemitz M, Sjöholm R. Complete assignments of the ¹H and ¹³C chemical shifts and J_H,H coupling constants in NMR spectra of D-glucopyranose and all D-glucopyranosyl-D-glucopyranosides. Carbohydr Res 2008; 343: 101-112
• 30 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery jr. JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ. Gaussian 09, Revision C.01. Gaussian Inc.: Wallingford; 2010
• 31 Xue GM, Zhu DR, Han C, Wang XB, Luo JG, Kong LY. Artemisianins A–D, new stereoisomers of seco-guaianolide involved heterodimeric [4 + 2] adducts from Artemisia argyi induce apoptosis via enhancement of endoplasmic reticulum stress. Bioorg Chem 2019; 84: 295-301
• 32 Tanaka T, Nakashima T, Ueda T, Tomii K, Kouno I. Facile discrimination of aldose enantiomers by reversed-phase HPLC. Chem Pharm Bull (Tokyo) 2007; 55: 899-901
• 33 Liu L, Wang L, Bao L, Ren J, Bahadur Basnet B, Liu R, He L, Han J, Yin WB, Liu H. Versicoamides F–H, prenylated indole alkaloids from Aspergillus tennesseensis . Org Lett 2017; 19: 942-945
• 34 Jiang X, Kopp-Schneider A. Statistical strategies for averaging EC50 from multiple dose-response experiments. Arch Toxicol 2015; 89: 2119-2127
• 35 Jiang X. Dose-Response Analysis of Multiple Experiments. Available at: http://biostatistics.dkfz.de/mdra_v1.3/ Accessed May 16, 2019
• 36 Eloff J. A sensitive and quick microplate method to determine the minimal inhibitory concentration of plant extracts for bacteria. Planta Med 1998; 64: 711-713
• 37 Nzogong R, Nganou B, Tedonkeu A, Awouafack M, Tene M, Ito T, Tan P, Morita H. Three new abietane-type diterpenoids from Plectranthus africanus and their antibacterial activities. Planta Med 2018; 84: 59-64