Cytotoxicity and Phytotoxicity of Trichothecene Macrolides from Myrothecium gramminum

Abstract

¹H-NMR guided fractionation of the EtOAc extract from the culture of Myrothecium gramminum (strain no. 3.1968) led to the isolation of eight cytotoxic trichothecene macrolides (1 – 8), all being substantially inhibitory against HepG2 (human hepatocellular carcinoma) and KB (human nasopharynyeal epidermoid tumor) cell lines with IC₅₀ values ranging from 2.2 to 12.2 μg/mL. Their inactivity to or weaker action on Vero cells (IC₅₀ values > 20 μg/mL, originated from the African green monkey kidney) highlighted preliminarily the nature of the selective cytotoxicity of the fungal metabolites against the test cancer cell lines. In addition, verrucarin A (1) and roridin A (5) were found to be potent inhibitors of the radial growth of Echinochloa crusgalli with corresponding IC₅₀ values of (7.96 ± 0.31) × 10^– 6 and (9.18 ± 0.44) × 10^– 6 M, respectively, which were more potent than that of the positive control (2,4-dichlorophenoxyacetic acid) [(9.40 ± 0.04) × 10^– 5 M].

Myrothecium gramminum - Tuberculariaceae - trichothecene macrolides - cytotoxicity - phytotoxicity

References

• 1 Sugawara T, Tanaka A, Nagai K, Suzuki K, Okada G. New members of the trichothecene family.  J Antibiot. 1997;  50 778-80
• 2 Shen L, Jiao R H, Ye Y H, Wang X T, Xu C, Song Y C. Absolute configuration of new cytotoxic and other bioactive trichothecene macrolides.  Chem Eur J. 2006;  12 5596-602
• 3 Pestka J J, Zhou H R, Moon Y, Chung Y J. Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox.  Toxicol Lett. 2004;  153 61-73
• 4 Isaka M, Punya J, Lertwerawat Y, Tanticharoen M, Thebtaranonth Y. Antimalarial activity of macrocyclic trichothecenes isolated from the fungus Myrothecium verrucaria. .  J Nat Prod. 1999;  62 329-31
• 5 Andolfi A, Boari A, Evidente A, Vurro M. Metabolites inhibiting germination of Orobanche ramosa seeds produced by Myrothecium verrucaria and Fusarium compactum. .  J Agric Food Chem. 2005;  53 1598-603
• 6 Steinmetz W E, Robustelli P, Edens E, Heineman D. Structure and conformational dynamics of trichothecene mycotoxins.  J Nat Prod. 2008;  71 589-94
• 7 Ge H M, Shen Y, Zhu C H, Tan S H, Ding H, Song Y C. Penicidones A – C, three cytotoxic alkaloidal metabolites of an endophytic Penicillium sp.  Phytochemistry. 2008;  69 571-6
• 8 Jiao R H, Xu S, Liu J Y, Ge H M, Ding H, Xu C. Chaetominine, a cytotoxic alkaloid produced by endophytic Chaetomium sp. IFB-E015.  Org Lett. 2006;  8 5709-12
• 9 Zhang Y L, Ge H M, Zhao W, Dong H, Xu Q, Li S H. Unprecedented immunosuppressive polyketides from Daldinia eschscholzii, a mantis-associated fungus.  Angew Chem Int Ed. 2008;  47 5823-6
• 10 Liu J Y, Huang L L, Ye Y H, Zou W X, Guo Z J, Tan R X. Antifungal and new metabolites of Myrothecium sp. Z16, a fungus associated with white croaker Argyrosomus argentatus. .  J Appl Microbiol. 2006;  100 195-202
• 11 Cole R J, Cox R H. Handbook of toxic fungal metabolites.  New York: Academic. Press;  1981 152-263
• 12 Murakamo Y, Okuda T, Shindo K. Roridin L, M and verrucarin M, new macrocyclic trichothecene group antitumor antibiotics, from Myrothecium verrucaria. .  J Antibiot. 2001;  54 980-3
• 13 Breitenstein W, Tamm C. ¹³C-NMR-spectroscopy of the trichothecene derivatives verrucarol, verrucarins A and B and roridins A, D and H.  Helv Chim Acta. 1975;  58 1172-80
• 14 Traxler P, Zurcher W, Tamm C h. Die Struktur des Antibiotikums Roridin E.  Helv Chim Acta. 1970;  53 2071-85
• 15 Matsumoto M, Minato H, Tori K, Ueyama M. Structures of isororidin E, epoxyisororidin E, and epoxy- and diepoxyroridin H, new metabolites isolated from cylindrocarpon species determined by carbon-13 and hydrogen-1 NMR spectroscopy. Revision of C-2′ : C-3′ double bond configuration of the roridin group.  Tetrahedron Lett. 1977;  18 4093-6
• 16 Abbas H K, Johnson B B, Shier W T, Tak H, Jarvis B B, Boyette C D. Phytotoxicity and mammalian cytotoxicity of macrocyclic trichothecene mycotoxins from Myrothecium verrucaria.  Phytochemistry. 2002;  59 309-13
• 17 Culter H G, Jarvis B B. Preliminary observations on the effects of macrocyclic trichothecenes on plant growth.  Environ Exp Bot. 1985;  25 115-28
• 18 Ge H M, Xu C, Wang X T, Huang B, Tan R X. Hopeanol: a potent cytotoxin with a novel skeleton from Hopea exalata. .  Eur J Org Chem. 2006;  24 5551-4
• 19 Pérez-Vásquez A, Reyes A, Linares E, Bye R, Mata R. Phytotoxins from Hofmeisteria schaffneri: isolation and synthesis of 2′-(2′′-hydroxy-4′′-methylphenyl)-2′-oxoethyl acetate.  J Nat Prod. 2005;  68 959-62