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.