Endowing Indole-Based Tubulin Inhibitors with an Anchor for Derivatization: Highly Potent 3-Substituted Indolephenstatins and Indoleisocombretastatins
Endowing Indole-Based Tubulin Inhibitors with an Anchor for Derivatization: Highly Potent 3-Substituted Indolephenstatins and Indoleisocombretastatins
复制标题
DOI：
10.1021/jm3015603
复制
发表时间：
2013-04-11
影响因子：
7.3
通讯作者：
Pelaez, Rafael
中科院分区：
文献类型：
--
作者：
Alvarez, Raquel;Puebla, Pilar;Pelaez, Rafael
带有吲哚B环的秋水仙碱位点配体是有效的微管蛋白聚合抑制剂。基于1-甲基-5-吲哚基的异溴化酯（1,1-二乙烯基）和苯他汀类药物在吲哚3位上的结构修饰使它们具有进一步衍生化的锚点，从而产生了高效的化合物。通过细胞周期分析、共聚焦显微镜和微管蛋白聚合抑制活性研究表明，这些取代衍生物对几种人类癌细胞系显示出强大的细胞毒性，并通过caspase-3激活促进细胞杀伤。通过MTC位移的荧光测量证实了秋水仙碱位点的结合。分子模拟表明，微管蛋白的秋水仙碱位点的对流层酮结合区可以适应携带小的极性取代基。异苯他汀类药物比苯他汀类药物更容易接受取代，氰基和羟亚胺甲基取代基的效率最高，TPI值在亚微摩尔范围内，细胞毒性在亚纳摩尔范围内。3,4,5-三甲氧基苯基环通常比2,3,4-三甲氧基苯基环提供更强效的衍生物。
Colchicine site ligands with indole B rings are potent tubulin polymerization inhibitors. Structural modifications at the indole 3-position of 1-methyl-5-indolyl-based isocombretastatins (1,1-diarylethenes) and phenstatins endowed them with anchors for further derivatization and resulted in highly potent compounds. The substituted derivatives displayed potent cytotoxicity against several human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies and promoted cell killing mediated by caspase-3 activation. Binding at the colchicine site was confirmed by means of fluorescence measurements of MTC displacement. Molecular modeling suggests that the tropolone-binding region of the colchicine site of tubulin can adapt to hosting small polar substituents. Isocombretastatins accepted substitutions better than phenstatins, and the highest potencies were achieved for the cyano and hydroxyiminomethyl substituents, with TPI values in the submicromolar range and cytotoxicities in the subnanomolar range. A 3,4,5-trimethoxyphenyl ring usually afforded more potent derivatives than a 2,3,4-trimethoxyphenyl ring.