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


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.

SUBMITTER: Morgan JB 

PROVIDER: S-EPMC2918693 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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

Morgan J Brian JB   Mahdi Fakhri F   Liu Yang Y   Coothankandaswamy Veena V   Jekabsons Mika B MB   Johnson Tyler A TA   Sashidhara Koneni V KV   Crews Phillip P   Nagle Dale G DG   Zhou Yu-Dong YD  

Bioorganic & medicinal chemistry 20100625 16


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 pr  ...[more]

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