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Bioorg Med Chem. 2010 Aug 15;18(16):5988-94. doi: 10.1016/j.bmc.2010.06.072. Epub 2010 Jun 25.

The marine sponge metabolite mycothiazole: a novel prototype mitochondrial complex I inhibitor.

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1
Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, MS 38677, USA.

Abstract

A natural product chemistry-based approach was applied to discover small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1). A Petrosaspongia mycofijiensis marine sponge extract yielded mycothiazole (1), a solid tumor selective compound with no known mechanism for its cell line-dependent cytotoxic activity. Compound 1 inhibited hypoxic HIF-1 signaling in tumor cells (IC(50) 1nM) that correlated with the suppression of hypoxia-stimulated tumor angiogenesis in vitro. However, 1 exhibited pronounced neurotoxicity in vitro. Mechanistic studies revealed that 1 selectively suppresses mitochondrial respiration at complex I (NADH-ubiquinone oxidoreductase). Unlike rotenone, MPP(+), annonaceous acetogenins, piericidin A, and other complex I inhibitors, mycothiazole is a mixed polyketide/peptide-derived compound with a central thiazole moiety. The exquisite potency and structural novelty of 1 suggest that it may serve as a valuable molecular probe for mitochondrial biology and HIF-mediated hypoxic signaling.

PMID:
20637638
PMCID:
PMC2918693
DOI:
10.1016/j.bmc.2010.06.072
[Indexed for MEDLINE]
Free PMC Article
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