Pettit G R, Toki B, Herald D L, Verdier-Pinard P, Boyd M R, Hamel E, Pettit R K
Cancer Research Institute and Department of Chemistry, Arizona State University, Tempe, Arizona 85287-1604, USA.
J Med Chem. 1998 May 7;41(10):1688-95. doi: 10.1021/jm970644q.
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 Neisseriagonorrhoeae 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.
针对南非柳树（Combretum caffrum）的抗肿瘤成分康普他汀A - 4（1b）进行的结构 - 活性关系（SAR）研究，旨在维持烯烃二苯基取代基的（Z）- 二苯乙烯关系，从而合成了一种强效癌细胞生长抑制剂，命名为苯他汀（3b）。最初，通过雅各布森氧化康普他汀A - 4硅醚（1c→3a）意外得到了苯他汀硅醚（3a），随后大量合成了母体苯他汀（3b）（6a→3a→3b）。通过亚磷酸二苄酯磷酸化和随后的氢解序列（3b→3c→3d），将苯他汀转化为磷酸钠前药（3d）。苯他汀（3b）抑制了病原菌淋病奈瑟菌的生长，并且是微管蛋白聚合以及秋水仙碱与微管蛋白结合的强效抑制剂，与康普他汀A - 4（1b）相当。有趣的是，发现前药在这些生化测定中活性降低。虽然康普他汀A - 4的磷酸化衍生物（1d）未观察到明显的微管蛋白活性，但磷酸盐3d在两种测定中均保留了可检测的抑制作用。
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