Synthesis of B-ring homologated estradiol analogues that modulate tubulin polymerization and microtubule stability.
Synthesis of B-ring homologated estradiol analogues that modulate tubulin polymerization and microtubule stability.
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DOI：
10.1021/jm0001119
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发表时间：
2000-05
影响因子：
7.3
通讯作者：
Zhiqiang Wang;Donglai Yang;A. Mohanakrishnan;P. Fanwick;P. Nampoothiri;Ernest Hamel;M. Cushman
中科院分区：
文献类型：
--
作者：
Zhiqiang Wang;Donglai Yang;A. Mohanakrishnan;P. Fanwick;P. Nampoothiri;Ernest Hamel;M. Cushman
2-甲氧基雌二醇是雌二醇的一种细胞毒性人体代谢物，能够结合微管蛋白的秋水仙碱位点并抑制其聚合，其2-乙氧基类似物甚至更有效。根据秋水仙碱与2-甲氧基炔雌醇结构间的假设关系，合成了一种B环扩环的2-乙氧基炔雌醇类似物，其中甾体的B环被秋水仙碱的B环取代。合成依赖于可用的6-酮雌二醇衍生物的B-环扩张，而不是同源类固醇框架的全合成。最终产物的两种差向异构体中的乙酰氨基取代基的相对构型通过NOESY NMR确定并通过X射线晶体学证实。具有6 α-乙酰氨基取代基的差向异构体作为微管蛋白聚合的抑制剂更有活性，并且它也比6 β-差向异构体更具细胞毒性。这些结果与提出的2-甲氧基紫杉醇和秋水仙碱的结构相似性一致。几个合成中间体被证明是有效的抑制剂微管蛋白聚合。另一方面，在C-6处具有酮的2-乙氧基紫杉醇的3，17 β-二乙酰化的B环扩展的类似物在其增强微管蛋白聚合和稳定微管的能力方面类似于紫杉醇（Taxol）。合成了相应的3-乙酸酯和17 β-乙酸酯，并且确定17 β-乙酸酯而不是3-乙酸酯赋予类固醇衍生物其紫杉醇样活性。
2-Methoxyestradiol is a cytotoxic human metabolite of estradiol with the ability to bind to the colchicine site of tubulin and inhibit its polymerization, and its 2-ethoxy analogue is even more potent. On the basis of a hypothetical relationship between the structures of colchicine and 2-methoxyestradiol, a B-ring-expanded 2-ethoxyestradiol analogue was synthesized in which the B-ring of the steroid is replaced by the B-ring of colchicine. The synthesis relied on the B-ring expansion of available 6-keto estradiol derivatives as opposed to a total synthesis of the homologated steroid framework. The relative configurations of the acetamido substituents in both epimers of the final product were determined by NOESY NMR and confirmed by X-ray crystallography. The epimer having the 6alpha-acetamido substituent was more active as an inhibitor of tubulin polymerization, and it was also more cytotoxic than the 6beta-epimer. These results are consistent with the proposed structural resemblance of 2-methoxyestradiol and colchicine. Several of the synthetic intermediates proved to be potent inhibitors of tubulin polymerization. On the other hand, a 3,17beta-diacetylated, B-ring-expanded analogue of 2-ethoxyestradiol having a ketone at C-6 resembled paclitaxel (Taxol) in its ability to enhance tubulin polymerization and stabilize microtubules. The corresponding 3-acetate and the 17beta-acetate were both synthesized, and it was determined that the 17beta-acetate, but not the 3-acetate, conferred on the steroid derivative its paclitaxel-like activity.