Novel inhibitors of mitochondrial respiratory chain: endoperoxides from the marine tunicate Stolonica socialis.
The Mediterranean tunicate Stolonica socialis contains a new class of powerful cytotoxic acetogenins, generically named stolonoxides. In this paper, which also details the isolation and chemical characterization of a minor component (3a) of the tunicate extract, we report the potent inhibitory activity (IC(50) < 1 microM) of stolonoxides (1a and 3a) on mitochondrial electron transfer. The compounds affect specifically the functionality of complex II (succinate:ubiquinone oxidoreductase) and complex III (ubiquinol:cytochrome C oxidoreductase) in mammalian cells, thereby causing a rapid collapse of the whole energetic metabolism. This result, which differs from the properties of similar known products (e.g., 6), reflects the molecular features of stolonoxides.
Fontana
A
A
Istituto per la Chimica di Molecole di Interesse Biologico (ICMIB) del CNR, Via Toiano 6, 80072, Arco Felice (Na), Italy. afontana@icmib.na.cnr.it
Cimino
G
G
Gavagnin
M
M
González
M C
MC
Estornell
E
E
D000818:Animals; D002417:Cattle; D004148:Dioxolanes / Q000737:chemistry* / Q000494:pharmacology; D004579:Electron Transport; D042967:Electron Transport Complex I; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008522:Mediterranean Sea; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009206:Myocardium / Q000648:ultrastructure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010545:Peroxides / Q000737:chemistry* / Q000494:pharmacology; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors; D014561:Urochordata / Q000737:chemistry*
D004148:Dioxolanes; D004791:Enzyme Inhibitors; D005663:Furans; D009097:Multienzyme Complexes; D010545:Peroxides; C430902:stolonoxide C methyl ester; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III