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

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. (C) 2001 Elsevier Science Ltd. All rights reserved.