Antineoplastic Agents. 379. Synthesis of Phenstatin Phosphate1a,
- 21 April 1998
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 41 (10) , 1688-1695
- https://doi.org/10.1021/jm970644q
Abstract
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 Neisseria 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 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.Keywords
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