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.

• Authors: J Brian Morgan, Fakhri Mahdi, Yang Liu, Veena Coothankandaswamy, Mika B Jekabsons, Tyler A Johnson, Koneni V Sashidhara, Phillip Crews, Dale G Nagle, Yu-Dong Zhou
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 16 Pg. 5988-94 (Aug 15 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20637638 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Thiazoles
• mycothiazole
• Electron Transport Complex I

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cells, Cultured
• Electron Transport Complex I (antagonists & inhibitors, metabolism)
• Enzyme Inhibitors (isolation & purification, pharmacology)
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Hypoxia-Inducible Factor 1 (antagonists & inhibitors, genetics, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Neovascularization, Pathologic (drug therapy)
• Neurons (drug effects)
• Porifera (chemistry)
• Rats
• Thiazoles (isolation & purification, pharmacology)