Novel inhibitors of mitochondrial respiratory chain: endoperoxides from the 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 (IC50<1 mM) 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, that differs from the properties of similar known products (e.g. 6), reflects the molecular features of stolonoxides.