Antineoplastic agents. 379. Synthesis of phenstatin phosphate.
A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (1b) directed at maintaining the (Z)-stilbene relationship of the olefin diphenyl substituents led to synthesis of a potent cancer cell growth inhibitor designated phenstatin (3b). Initially phenstatin silyl ether (3a) was unexpectedly obtained by Jacobsen oxidation of combretastatin A-4 silyl ether (1c --> 3a), and the parent phenstatin (3b) was later synthesized (6a --> 3a --> 3b) in quantity. Phenstatin was converted to the sodium phosphate prodrug (3d) by a dibenzyl phosphite phosphorylation and subsequent hydrogenolysis sequence (3b --> 3c --> 3d). Phenstatin (3b) inhibited growth of the pathogenic bacterium Neisseriagonorrhoeae and was a potent inhibitor of tubulin polymerization and the binding of colchicine to tubulin comparable to combretastatin A-4 (1b). Interestingly, the prodrugs were found to have reduced activity in these biochemical assays. While no significant tubulin activity was observed with the phosphorylated derivative of combretastatin A-4 (1d), phosphate 3d retained detectable inhibitory effects in both assays.
Pettit
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Cancer Research Institute and Department of Chemistry, Arizona State University, Tempe, Arizona 85287-1604, USA.
Toki
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Herald
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Verdier-Pinard
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Boyd
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Hamel
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Pettit
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D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D001577:Benzophenones / Q000138:chemical synthesis* / Q000494:pharmacology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007941:Leukemia P388 / Q000473:pathology; D046911:Macromolecular Substances; D015394:Molecular Structure; D009344:Neisseria gonorrhoeae / Q000187:drug effects; D010755:Organophosphates / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D001577:Benzophenones; D046911:Macromolecular Substances; D010755:Organophosphates; D011355:Prodrugs; D014404:Tubulin; C112107:phenstatin phosphate; D003078:Colchicine