The marine sponge metabolite mycothiazole: A novel prototype mitochondrial complex I inhibitor
| Autor: | Veena Coothankandaswamy, Fakhri Mahdi, Koneni V. Sashidhara, Yu-Dong Zhou, Dale G. Nagle, Phillip Crews, J. Brian Morgan, Mika B. Jekabsons, Tyler A. Johnson, Yang Liu |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Cell Survival
Metabolite Clinical Biochemistry Pharmaceutical Science Biochemistry Article Cell Line chemistry.chemical_compound Oxidoreductase Cell Line Tumor Drug Discovery medicine Animals Humans Piericidin A Enzyme Inhibitors Molecular Biology Cells Cultured Neurons chemistry.chemical_classification Electron Transport Complex I Natural product Neovascularization Pathologic Organic Chemistry Biological activity Hypoxia-Inducible Factor 1 alpha Subunit In vitro Porifera Rats Thiazoles Gene Expression Regulation chemistry Mechanism of action Molecular Medicine Female Hypoxia-Inducible Factor 1 medicine.symptom |
| Zdroj: | Bioorganic & Medicinal Chemistry. 18:5988-5994 |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect