Asimin, asiminacin, and asiminecin: novel highly cytotoxic asimicin isomers from Asimina triloba

Activity-directed fractionation of the stem bark extracts of the North American paw paw tree, Asimina triloba (Annonaceae), has yielded three further acetogenins: asimin (2), asiminacin (3), and asiminecin (4). 2-4 are structural isomers of asimicin (1), which is a potent inhibitor of mitochondrial NADH:ubiquinone oxidoreductase, and thus exhibits potent antitumor and pesticidal effects. 2-4 have the same carbon skeleton and configurations as those of 1, but they have the third hydroxyl group located at C-10, C-28, and C-29, respectively, rather than at C-4. The determinations of the hydroxyl group locations were largely based on mass spectral analyses of TMSi and TMSi-d9 derivatives. 2-4 all showed highly potent cytotoxicities (ED50 values as low as < 10(-12) micrograms/mL) with notable selectivities for the HT-29 human colon Cancer cell line. The presence of a third hydroxyl at C-4, C-10, C-28, or C-29, as in 1-4, greatly enhances the bioactivity of 4-deoxyasimicin (5).