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Selected Works of Tyler Johnson
Article
The marine sponge metabolite mycothiazole: a novel prototype mitochondrial complex I inhibitor.
Natural Sciences and Mathematics | Faculty Scholarship
  • 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 Cruz
  • Koneni V. Sashidhara, University of California, Santa Cruz
  • Phillip Crews, University of California Santa Cruz
  • Dale G. Nagle, University of Mississippi
  • Yu-Dong Zhou, University of Mississippi
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Department
Natural Sciences and Mathematics
Document Type
Article
Source
Bioorganic & Medicinal Chemistry
Publication Date
8-15-2010
Disciplines
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
Creative Commons License
Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International
Citation Information
J Brian Morgan, Fakhri Mahdi, Yang Liu, Veena Coothankandaswamy, et al.. "The marine sponge metabolite mycothiazole: a novel prototype mitochondrial complex I inhibitor." Vol. 18 Iss. 16 (2010) p. 5988 - 5994 ISSN: 1464-3391
Available at: http://works.bepress.com/tyler-a-johnson/12/