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Gamma-lactone-Functionalized antitumoral acetogenins are the most potent inhibitors of mitochondrial complex I
J R Tormo1, E Estornell, T Gallardo
1Departamento de Farmacología, Farmacognosia y Farmacodinamia, Universidad de Valencia, Spain.
Abstract:
To study the relevance of the terminal alpha,beta-unsaturated gamma-methyl-gamma-lactone moiety of the antitumoral acetogenins of Annonaceae for potent mitochondrial complex I inhibition, we have prepared a series of semisynthetic acetogenins with modifications only in this part of the molecule, from the natural rolliniastatin-1 (1) and cherimolin-1 (2). Some of the hydroxylated derivatives (1b, 1d and 1e) in addition to two infrequent natural beta-hydroxy gamma-methyl gamma-lactone acetogenins, laherradurin (3) and itrabin (4), are more potent complex I inhibitors than any other known compounds.
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