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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
16
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pubmed:dateCreated |
2010-8-9
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-10891253,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-15165135,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-15646992,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-16384701,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-16410795,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-16441088,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-17052163,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-17622130,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-18219320,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-18598079,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-19091749,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-19209899,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-19671047,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-19682988,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20637638-7539918
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1464-3391
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pubmed:author |
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pubmed:copyrightInfo |
Copyright 2010 Elsevier Ltd. All rights reserved.
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
18
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5988-94
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pubmed:dateRevised |
2011-8-16
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pubmed:meshHeading |
pubmed-meshheading:20637638-Animals,
pubmed-meshheading:20637638-Cell Line,
pubmed-meshheading:20637638-Cell Line, Tumor,
pubmed-meshheading:20637638-Cell Survival,
pubmed-meshheading:20637638-Cells, Cultured,
pubmed-meshheading:20637638-Electron Transport Complex I,
pubmed-meshheading:20637638-Enzyme Inhibitors,
pubmed-meshheading:20637638-Female,
pubmed-meshheading:20637638-Gene Expression Regulation,
pubmed-meshheading:20637638-Humans,
pubmed-meshheading:20637638-Hypoxia-Inducible Factor 1,
pubmed-meshheading:20637638-Hypoxia-Inducible Factor 1, alpha Subunit,
pubmed-meshheading:20637638-Neovascularization, Pathologic,
pubmed-meshheading:20637638-Neurons,
pubmed-meshheading:20637638-Porifera,
pubmed-meshheading:20637638-Rats,
pubmed-meshheading:20637638-Thiazoles
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pubmed:year |
2010
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pubmed:articleTitle |
The marine sponge metabolite mycothiazole: a novel prototype mitochondrial complex I inhibitor.
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pubmed:affiliation |
Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, N.I.H., Extramural
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