The epipolythiodioxopiperazine (ETP) class of fungal toxins: distribution, mode of action, functions and biosynthesis

Gardiner, Donald M.; Waring, Paul; Howlett, Barbara J.

doi:10.1099/mic.0.27847-0

Cited by 406 publications

(401 citation statements)

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“…Epicoccin E (1) was assigned the molecular formula C 18 Absence of coupling between H-8 and H-9 implied that they were nearly perpendicular to each other. Thus, the relative configuration for the left portion of 1 was assigned to be the same as that of 9.…”

Section: Resultsmentioning

confidence: 99%

“…Epicoccins E (1) and F (2) are new DKPs possessing the characteristic internal sulfur bridge(s). Although another class of DKPs, the epipolythiodioxopiperazines (ETPs), possess an internal disulfide bridge on the DKP ring, 18 1 and 4 incorporated the rare cross-ring sulfur bridges significantly different from those of the common ETPs, with epicoccins A-D as the only examples. 11 However, 1 differs from its most closely related known precedent 9 by virtue of the presence of a sulfur bridge linking C-2′ and C-6′ instead of C-2′ and C-7′ in 9, whereas 2 differs from 7 by having a C-5′-OH instead of the C-5′ ketone functionality.…”

Section: Resultsmentioning

confidence: 99%

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Diketopiperazines from the Cordyceps-Colonizing Fungus Epicoccum nigrum

et al. 2009

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New diketopiperazines, epicoccins E-H (1-4) and diphenylalazines A (5) and B (6), have been isolated from the solid-substrate fermentation culture of the Cordyceps-colonizing fungus Epicoccum nigrum. The structures of 1-6 were determined primarily by NMR experiments, and the structure of 1 was confirmed by X-ray crystallography. The absolute configurations of 3 and 5 were assigned using the modified Mosher (3) and Marfey's (5) methods, respectively. Compounds 3-5 showed inhibitory effects on HIV-1 replication in C8166 cells. Diketopiperazines (DKPs) are an important class of compounds displaying a variety of biological effects, such as antimicorbial, herbicidal, antiviral, immunosuppressive, and antitumor activities. 1-3 Naturally occurring DKPs have frequently been isolated from fungal sources. Examples include golmaenone, a radical scavenger from a marine-derived Aspergillus sp., 4 the rostratins, cytotoxic DKP disulfides from a marine-derived Exserohilum rostratum, 5 the epicorazines, antibacterial metabolites from a basidiomycete Stereum hirsutum, 6 and the verticillins, dimeric DKPs from a marine-derived Penicillium sp. 7 Cordyceps sinensis (Berk.) Sacc. (Anamorph: Hirsutella sinensis; Clavicipataceae), 8 known as Chinese caterpillar fungus or "Dong Chong Xia Cao" (caterpillar-in-winter, herb-in-summer), is the combination of the fungus and the dead caterpillar larva of the moth Hepilus spp. It has been known and used for centuries in traditional Chinese medicine (TCM). 9 In nature, it is found only at high altitudes on the Himalayan Plateau and is therefore difficult to harvest. Chemical investigations of the fungal species that colonize the fruiting body of C. sinensis (Cordyceps-colonizing fungi) in our laboratory have led to the isolation of structurally diverse and biologically active metabolites. [10][11][12] In a search for anti-HIV-1 agents from this unique fungal source, the fungus Epicoccum nigrum (XZC04-CS-302) isolated from a sample of C. sinensis collected in Linzhi, Tibet, People's Republic of China, was grown in a solidsubstrate fermentation culture. Its organic solvent extract showed inhibitory effects on HIV-1 replication in C8166 cells. Fractionation of the extract afforded six new DKPs, named epicoccins E-H (1-4) and diphenylalazines A (5) and B (6), together with the known epicoccins A (7), B (8), and D (9), which were previously isolated by us from a different strain of Cordyceps-colonizing E. nigrum. 11 Details of the isolation, structure elucidation, and anti-HIV-1 activity of these metabolites are reported herein. Results and DiscussionEpicoccin E (1) was assigned the molecular formula C 18 H 18 N 2 O 7 S 2 (11 degrees of unsaturation) on the basis of its HRESIMS (m/z 461.0448 [M + Na] + ; ∆ +0.5 mmu). The 1 H and 13 C NMR data of 1 (Table 1) suggested the presence of three exchangeable protons (δ 5.56, 5.74, and 6.24, respectively), three methylenes, nine methines (five bonded to oxygen or nitrogen), two heteroatom-bonded sp 3 quaternary carbons, and four carbonyl carbons including ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Diketopiperazines from the Cordyceps-Colonizing Fungus Epicoccum nigrum

et al. 2009

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“…This cytotoxic activity is a well known property of the epipolythiodioxopiperazine (ETP) class of fungal toxins, in which the presence of a sulfur bridge as a structural feature allows the conjugation to proteins and/or the generation of reactive oxygen species via redox cycling. 17 Compound 2 is obviously derived from an ETP compound, such as chaetomin or the verticillins, and compounds 1 and 3 are probably metabolites produced from 2. The biosynthesis of ETPs has not been well studied and their primary physiological role is not yet known, although for several fungi, the ability to produce ETPs is associated with their causing animal and plant diseases.…”

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“…The biosynthesis of ETPs has not been well studied and their primary physiological role is not yet known, although for several fungi, the ability to produce ETPs is associated with their causing animal and plant diseases. 17 Production of ETPs by fungal species is not a universal phenomenon, although some generalizations may be made. For example, verticillins are produced by Sordariomycetes and Eurotiomycetes, and the closely related molecule chaetomin is produced by Sordariomycetes and Dothideomycetes.…”

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“…For example, verticillins are produced by Sordariomycetes and Eurotiomycetes, and the closely related molecule chaetomin is produced by Sordariomycetes and Dothideomycetes. 17 G. catenulatum is an anamorph of Hypocrea Fr., classified within the Sordariomycetes group, so that chaetomin or the verticillins may be the biogenetic precursors of 3,3¢-biindol. Verticillin D has previously been isolated from a G. catenulatum strain.…”

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