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

Authors

J Brian Morgan, University of Mississippi, Mississippi, USA
Fakhri Mahdi, University of Mississippi, Mississippi, USA
Yang Liu, University of Mississippi, Mississippi, USA
Veena Coothankandaswamy, University of Mississippi, Mississippi, USA
Mika B. Jekabsons, University of Mississippi, Mississippi, USA
Tyler A. Johnson, University of California, Santa CruzFollow
Koneni V. Sashidhara, University of California, Santa CruzFollow
Phillip Crews, University of California Santa CruzFollow
Dale G. Nagle, University of Mississippi
Yu-Dong Zhou, University of Mississippi

Department

Natural Sciences and Mathematics

Document Type

Article

Source

Bioorganic & Medicinal Chemistry

Publication Date

8-15-2010

ISSN

1464-3391

Volume

18

Issue

16

First Page

5988

Last Page

5994

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.

PubMed ID

20637638

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