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 e fficient scale-up procedure for obtaining this antineoplastic stilbene, Sub sequent conversion to a useful prodrug was accomplished by diphosphorylatio n (to 10), with in situ formation of dibenzylchlorophosphite, followed by c leavage 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 hydrogena tion of phosphate 10 and treatment of the product with sodium methoxide led to combretastatin B-1 prodrug (5). The phosphoric acid precursor of prodru g 4 was employed in a parallel series of reactions to produce a selection o f metal and ammonium cation prodrug candidates. Each of the phosphate salts was evaluated from the perspective of relative solubility behavior and can cer cell growth inhibition. The sodium phosphate prodrug of combretastatin A-1 (4) was selected for detailed antineoplastic studies.