Thwarting Resistance: Annonaceous Acetogenins as New Pesticidal and Antitumor Agents
ABSTRACT The Annonaceous acetogenins are C-32 or C-34 long-chain fatty acids that have been combined with a 2-propanol unit at C-2 to form a terminal D,E-unsaturated J-lactone. They often cyclize to form one, two, or three tetrahydrofuran (THF) or tetrahydropyran (THP) rings near the middle of the aliphatic chain. To date, nearly 400 of these compounds have been isolated from several genera of the plant family, Annonaceae. Biologically, they are among the most potent of the known inhibitors of complex I (NADH:ubiquinone oxidoreductase) in mitochondrial electron transport systems and of the plasma membrane NADH:oxidase that is characteristic of cancerous cells. These actions induce apoptosis (programmed cell death), perhaps as a consequence of ATP deprivation. Applications as pesticides and antitumor agents hold excellent potential, especially in the thwarting of resistance mechanisms which require ATP-dependent efflux.