Antineoplastic agents 429. Syntheses of the combretastatin A-1 and combretastatin B-1 prodrugs.
The original synthesis of combretastatin A-1 (1) was modified to allow an efficient scale-up procedure for obtaining this anti-neoplastic stilbene. Subsequent conversion to a useful prodrug was accomplished by diphosphorylation (to 10), with in situ formation of dibenzylchlorophosphite, followed by cleavage of the benzyl ester protecting groups with trimethyliodosilane. The phosphoric acid intermediate was treated with sodium methoxide to complete a practical route to the sodium phosphate prodrug (4). Selective hydrogenation of phosphate 10 and treatment of the product with sodium methoxide led to combretastatin B-1 prodrug (5). The phosphoric acid precursor of prodrug 4 was employed in a parallel series of reactions to produce a selection of metal and ammonium cation prodrug candidates. Each of the phosphate salts was evaluated from the perspective of relative solubility behavior and cancer cell growth inhibition. The sodium phosphate prodrug of combretastatin A-1 (4) was selected for detailed antineoplastic studies.
Pettit
G R
GR
Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287-2404, USA.
Lippert
J W
JW
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D010755:Organophosphates / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D012995:Solubility; D013267:Stilbenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D010755:Organophosphates; D011355:Prodrugs; D000644:Quaternary Ammonium Compounds; D013267:Stilbenes; C414983:combretastatin B-1; C063690:combretastatin A-1