| Literature DB >> 20637638 |
J Brian Morgan1, Fakhri Mahdi, Yang Liu, Veena Coothankandaswamy, Mika B Jekabsons, Tyler A Johnson, Koneni V Sashidhara, Phillip Crews, Dale G Nagle, Yu-Dong Zhou.
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. Copyright 2010 Elsevier Ltd. All rights reserved.Entities:
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Year: 2010 PMID： 20637638 PMCID： PMC2918693 DOI： 10.1016/j.bmc.2010.06.072
Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641