Microtubule interactions with chemically diverse stabilizing agents:: Thermodynamics of binding to the paclitaxel site predicts cytotoxicity
Microtubule interactions with chemically diverse stabilizing agents:: Thermodynamics of binding to the paclitaxel site predicts cytotoxicity
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DOI：
10.1016/j.chembiol.2005.09.010
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发表时间：
2005-12-01
影响因子：
--
通讯作者：
Díaz, JF
中科院分区：
文献类型：
--
作者：
Buey, RM;Barasoain, I;Díaz, JF
研究了微管与大多数被描述为稳定剂的化合物之间的相互作用。其中几种化合物(异氰菊酯、双库马罗尔、叶黄素和麻风烷聚酯)对微管没有任何稳定作用。塔卡洛内酯A和E在细胞内表现出紫杉醇样作用，但它们不能调节体外微管组装或结合微管，这表明其他因素参与了它们的细胞效应。测定了Epothilone、Eutherobin、Discodermolide、Sarcodictyins、3，17 beta-diacetoxy-2-ethoxy-6-oxo-B-homo-estra-1，3，5(10)triene，和dictyostatin与紫杉醇结合的结合常数、配体诱导组装的临界浓度以及它们对癌细胞的细胞毒性，并确定了这些参数之间的相关性。紫杉醇对细胞增殖的抑制作用与结合热变的相关性比与结合常数的相关性更好，这表明在设计细胞毒性较高的紫杉醇部位药物时，需要较大的、有利的结合热效应。
The interactions of microtubules with most compounds described as stabilizing agents have been studied. Several of them (lonafarnib, dicumarol, lutein, and jatrophane polyesters) did not show any stabilizing effect on microtubules. Taccalonolides A and E show paclitaxel-like effects in cells, but they were not able to modulate in vitro tubulin assembly or to bind microtubules, which suggests that other factors are involved in their cellular effects. The binding constants of epothilones, eleutherobin, discodermolide, sarcodictyins, 3,17 beta-diacetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)triene, and dictyostatin to the paclitaxel site; the critical concentrations of ligand-Induced assembly; and their cytotoxicity in carcinoma cells have been measured, and correlations between these parameters have been determined. The inhibition of cell proliferation correlates better with the binding enthalpy change than with the binding constants, suggesting that large, favorable enthalpic contribution to the binding is desired to design paclitaxel site drugs with higher cytotoxicity.