期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 18, 期 16, 页码 5988-5994出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.06.072
关键词
Hypoxia-inducible factor-1 (HIF-1); Marine natural products; Mitochondrial complex I inhibitor; NADH-ubiquinone oxidoreductase
资金
- NIH [CA98787, P20RR021929, CA047135, C06 RR-14503-01]
- NOAA/NIUST [NA16 RU1496]
- Government of India
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 (IC50 1 nM) 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. (C) 2010 Elsevier Ltd. All rights reserved.
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