Antineoplastic agents. 379. Synthesis of phenstatin phosphate
Antineoplastic agents. 379. Synthesis of phenstatin phosphate
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DOI：
10.1021/jm970644q
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发表时间：
1998-05-07
影响因子：
7.3
通讯作者：
Pettit, RK
中科院分区：
文献类型：
--
作者：
Pettit, GR;Toki, B;Pettit, RK
对南非杨柳树（Combretum caffrum）中的组分Combretastatin A-4（1b）进行了结构-活性关系（SAR）研究，旨在维持烯烃二苯基取代基的（Z）-芪关系，从而合成了一种有效的癌细胞生长抑制剂，命名为芬他汀（3b）。最初，通过考布他汀A-4甲硅烷基醚（1c -> 3a）的Jacobsen氧化意外地获得了芬他汀甲硅烷基醚（3a），随后大量合成了母体芬他汀（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），将酚他丁转化为磷酸钠前药（3d）。芬他汀（3b）可抑制病原性淋病奈瑟氏菌的生长，并且是微管蛋白聚合和秋水仙素与微管蛋白结合的有效抑制剂，与考布他汀A-4（1b）相当。有趣的是，发现前药在这些生物化学测定中具有降低的活性。虽然用考布他汀A-4的磷酸化衍生物（1d）未观察到显著的微管蛋白活性，但磷酸盐3d在两种测定中均保持可检测的抑制作用。
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.