γ-Lactone-functionalized antitumoral acetogenins are the most potent inhibitors of mitochondrial complex I

Abstract To study the relevance of the terminal α,β-unsaturated γ-methyl-γ-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 β-hydroxy γ-methyl γ-lactone acetogenins, laherradurin ( 3 ) and itrabin ( 4 ), are more potent complex I inhibitors than any other known compounds.