A common pharmacophore for Taxol and the epothilones based on the biological activity of a taxane molecule lacking a C-13 side chain
A common pharmacophore for Taxol and the epothilones based on the biological activity of a taxane molecule lacking a C-13 side chain
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DOI：
10.1021/bi992518p
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发表时间：
2000-04-11
期刊：
影响因子：
2.9
通讯作者：
Horwitz, SB
中科院分区：
文献类型：
--
作者：
He, LF;Jagtap, PGF;Horwitz, SB
用紫杉醇进行的广泛的结构-活性研究已经确定C-13的侧链是生物活性的要求之一。Baccatin III是紫杉醇的类似物，缺少C-13侧链，没有紫杉醇的任何生物学特性。由于2-间叠氮紫杉醇是一种在C-2苯甲酰环上带有间叠氮取代基的紫杉醇衍生物，其活性高于紫杉醇，因此我们怀疑2-间叠氮巴卡菌素III是否具有活性。2-m-叠氮巴卡菌素III在纳摩尔浓度下抑制人癌细胞的增殖，阻止细胞有丝分裂，并将间期微管重组为不同的微管，这是紫杉醇诱导的典型形态变化。与2-m-叠氮巴卡菌素III相比，2-对叠氮巴卡菌素III与巴卡菌素III相似，没有紫杉醇样活性，进一步表明了2-间位取代基的特异性和重要性。用紫杉醇的C-2苯甲酰环进行的分子模拟研究表明，它适合His227和Asp224在β-微管蛋白上形成的口袋，并且与2-对叠氮基相比，2-m-叠氮基能够增强苯甲酰基与Asp224侧链之间的相互作用。观察到C-13侧链不是紫杉烷分子生物活性的绝对要求，这使得紫杉醇和依西酮类药物之间的新的共同药效团模型的发展成为可能。
Extensive structure-activity studies done with Taxol have identified the side chain at C-13 as one of the requirements for biological activity. Baccatin III, an analogue of Taxol lacking the C-13 side chain, has none of the biological characteristics of Taxol. Since 2-m-azido Taxol, a Taxol derivative with a m-azido substituent in the C-2 benzoyl ring, has greater activity than Taxol, we questioned whether 2-m-azido baccatin III might be active. 2-m-Azido baccatin III inhibited the proliferation of human cancer cells at nanomolar concentrations, blocked cells at mitosis, and reorganized the interphase microtubules into distinct bundles, a typical morphological change induced by Taxol. In contrast to 2-m-azido baccatin III, 2-p-azido baccatin III was similar to baccatin III, having no Taxol-like activity, further indicating the specificity and significance of the 2-meta position substituent. Molecular modeling studies done with the C-2 benzoyl ring of Taxol indicated that it fits into a pocket formed by His227 and Asp224 on beta-tubulin and that the 2-m-azido, in contrast to the 2-p-azido substituent, is capable of enhancing the interaction between the benzoyl group and the side chain of Asp224. The observation that the C-13 side chain is not an absolute requirement for biological activity in a taxane molecule has enabled the development of a new common pharmacophore model between Taxol and the epothilones.