Gr. Pettit et Jw. Lippert, Antineoplastic agents 429. Syntheses of the combretastatin A-1 and combretastatin B-1 prodrugs, ANTI-CAN DR, 15(3), 2000, pp. 203-216
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.