The marine sponge metabolite mycothiazole: a novel prototype mitochondrial complex I inhibitor.
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.
Morgan
J Brian
JB
Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Mahdi
Fakhri
F
Liu
Yang
Y
Coothankandaswamy
Veena
V
Jekabsons
Mika B
MB
Johnson
Tyler A
TA
Sashidhara
Koneni V
KV
Crews
Phillip
P
Nagle
Dale G
DG
Zhou
Yu-Dong
YD
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects; D011161:Porifera / Q000737:chemistry*; D051381:Rats; D013844:Thiazoles / Q000302:isolation & purification / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013844:Thiazoles; C508681:mycothiazole; D042967:Electron Transport Complex I