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).
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
G X
GX
Zhao
L R
LR
Miesbauer
D L
DL
Smith
J L
JL
McLaughlin
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D007783:Lactones; C061022:bullatacin; C088264:asimin; C088265:asiminacin; C088266:asiminecin