Inhibition of farnesyl-protein transferase by gliotoxin and acetylgliotoxin.

Pyl, Didier Van Der; Inokoshi, Junji; Shiomi, Kazuro; Yang, Hong; Tanaka, Hideo; Ōmura, Satoshi

doi:10.7164/antibiotics.45.1802

Cited by 81 publications

(3 citation statements)

References 9 publications

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“…The NMR spectra data of compound 8 closely resembled those of 7 , except for one additional 1 H resonance signal of the acetyl group. Its structure was identified as acetylgliotoxin, which was isolated from fungus strain FO2047 previously, and showed broad activities, including inhibition of fungi, bacteria and viruses [26] (Table 3 and Supplementary Figures S49 and S50). Compound 9 , having NMR data similar to those of 7 , was identified as reduced gliotoxin, which was the reduced dithiol form of 7 (Table 3 and Supplementary Figures S51 and S52).…”

Section: Resultsmentioning

confidence: 99%

Exploring the Chemodiversity and Biological Activities of the Secondary Metabolites from the Marine Fungus Neosartorya pseudofischeri

Liang

et al. 2014

Marine Drugs

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The production of fungal metabolites can be remarkably influenced by various cultivation parameters. To explore the biosynthetic potentials of the marine fungus, Neosartorya pseudofischeri, which was isolated from the inner tissue of starfish Acanthaster planci, glycerol-peptone-yeast extract (GlyPY) and glucose-peptone-yeast extract (GluPY) media were used to culture this fungus. When cultured in GlyPY medium, this fungus produced two novel diketopiperazines, neosartins A and B (1 and 2), together with six biogenetically-related known diketopiperazines,1,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxopyrazino[1,2-a]indole (3), 1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole (4), 1,2,3,4-tetrahydro-2-methyl-1,3,4-trioxopyrazino[1,2-a] indole (5), 6-acetylbis(methylthio)gliotoxin (10), bisdethiobis(methylthio)gliotoxin (11), didehydrobisdethiobis(methylthio)gliotoxin (12) and N-methyl-1H-indole-2-carboxamide (6). However, a novel tetracyclic-fused alkaloid, neosartin C (14), a meroterpenoid, pyripyropene A (15), gliotoxin (7) and five known gliotoxin analogues, acetylgliotoxin (8), reduced gliotoxin (9), 6-acetylbis(methylthio)gliotoxin (10), bisdethiobis(methylthio) gliotoxin (11) and bis-N-norgliovictin (13), were obtained when grown in glucose-containing medium (GluPY medium). This is the first report of compounds 3, 4, 6, 9, 10 and 12 as naturally occurring. Their structures were determined mainly by MS, 1D and 2D NMR data. The possible biosynthetic pathways of gliotoxin-related analogues and neosartin C were proposed. The antibacterial activity of compounds 2–14 and the cytotoxic activity of compounds 4, 5 and 7–13 were evaluated. Their structure-activity relationships are also preliminarily discussed.

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Section: Resultsmentioning

confidence: 99%

Exploring the Chemodiversity and Biological Activities of the Secondary Metabolites from the Marine Fungus Neosartorya pseudofischeri

Liang

et al. 2014

Marine Drugs

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“…Traditionally, the usefulness of gliotoxin and related fungal metabolites has been limited by their toxicity. However, studies highlighting the potential of gliotoxin as an anticancer agent [69,70] may provide important research into the development and evaluation of less toxic analogues of gliotoxin.…”

Section: Discussionmentioning

confidence: 99%

Antiviral activity of gliotoxin, gentian violet and brilliant green against Nipah and Hendra virus in vitro

Aljofan

Sganga

et al. 2009

Virol J

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BackgroundUsing a recently described monolayer assay amenable to high throughput screening format for the identification of potential Nipah virus and Hendra virus antivirals, we have partially screened a low molecular weight compound library (>8,000 compounds) directly against live virus infection and identified twenty eight promising lead molecules. Initial single blind screens were conducted with 10 μM compound in triplicate with a minimum efficacy of 90% required for lead selection. Lead compounds were then further characterised to determine the median efficacy (IC50), cytotoxicity (CC50) and the in vitro therapeutic index in live virus and pseudotype assay formats.ResultsWhile a number of leads were identified, the current work describes three commercially available compounds: brilliant green, gentian violet and gliotoxin, identified as having potent antiviral activity against Nipah and Hendra virus. Similar efficacy was observed against pseudotyped Nipah and Hendra virus, vesicular stomatitis virus and human parainfluenza virus type 3 while only gliotoxin inhibited an influenza A virus suggesting a non-specific, broad spectrum activity for this compound.ConclusionAll three of these compounds have been used previously for various aspects of anti-bacterial and anti-fungal therapy and the current results suggest that while unsuitable for internal administration, they may be amenable to topical antiviral applications, or as disinfectants and provide excellent positive controls for future studies.

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“…Gliotoxin and the related fungal metabolites gliovirin and sporedesmin are low molecular weight non-polar compounds characterised by an intramolecular disulfide bridge that is the active moiety [29,30,31]. It has been observed that gliotoxin inhibits farnesyltransferase (FTase) at low micromolar concentrations [32,33,34], and has antiproliferative activity in lymphosarcoma cells. Ellipticine ( 29 , Figure 7) is an antineoplastic agent, the mode of action of which was considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II [35,36].…”

Section: Indole: Chemical and Biological Importancementioning

confidence: 99%