ANTINEOPLASTIC AGENTS - 379 - SYNTHESIS OF PHENSTATIN PHOSPHATE

A structure-activity relationship (SAR) study of the South African wil low 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 sil yl ether (3a) was unexpectedly obtained by Jacobsen oxidation of combr etastatin A-4 silyl ether (1c --> 3a), and the parent phenstatin (3b) was later synthesized (6a --> 3a --> 3b) in quantity. Phenstatin was c onverted 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 Neis seria gonorrhoeae 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 acti vity in these biochemical assays. While no significant tubulin activit y was observed with the phosphorylated derivative of combretastatin A- 4 (1d), phosphate 3d retained detectable inhibitory effects in both as says.