γ-Lactone-functionalized antitumoral acetogenins are the most potent inhibitors of Mitochondrial Complex I

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. Graphic