Design, Synthesis and Molecular Docking Studies of Novel Indole-Pyrimidine Hybrids as Tubulin Polymerization Inhibitors
Design, Synthesis and Molecular Docking Studies of Novel Indole-Pyrimidine Hybrids as Tubulin Polymerization Inhibitors
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新型吲哚-嘧啶杂化物作为微管蛋白聚合抑制剂的设计、合成和分子对接研究
DOI：
10.1111/cbdd.12616
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发表时间：
2015-12-01
影响因子：
3
通讯作者：
Zhao, Pei-Liang
中科院分区：
文献类型：
--
作者：
Hu, Meng-Jin;Zhang, Bei;Zhao, Pei-Liang
设计、合成了一系列含吲哚-嘧啶的哌嗪杂环化合物，并对其抗增殖和抑制微管蛋白聚合活性进行了评价。结果表明，大部分化合物对HT-29、A549、MDA-MB-231和MCF-7四种癌细胞株具有明显的细胞毒活性。特别是，最有前途的化合物34显示出更有效和广谱的细胞毒活性，其对A549、MDAMB-231和MCF-7细胞系的IC 50值范围为5.01至14.36 μ M。同时，34也显示出最强的微管蛋白聚合抑制活性，IC 50值为11.2 μ M。此外，分子对接分析表明，34相互作用，并有效地结合微管蛋白在秋水仙素结合位点。值得注意的是，该化合物不影响正常的人胚胎肾细胞HEK-293。这些结果表明，这类新的吲哚-嘧啶杂合物可能有潜力被开发为一类新的微管蛋白聚合抑制剂。
A series of novel hybrids of indole-pyrimidine-containing piperazine moiety were designed, synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. The results indicated that most of these compounds possessed significant cytotoxic potency against four cancer cell lines, HT-29, A549, MDA-MB-231 and MCF-7. Particularly, the most promising compound 34 showed more potent and broad-spectrum cytotoxic activities with the IC50 values ranged from 5.01 to 14.36 mu M against A549, MDAMB-231 and MCF-7 cell lines. Meanwhile, 34 also displayed the most potent tubulin polymerization inhibitory activity with IC50 value of 11.2 mu M. Furthermore, molecular docking analysis demonstrated 34 interacts and binds efficiently with the tubulin protein at the colchicine-binding site. It was worth noting that the compound did not affect the normal human embryonic kidney cells, HEK-293. These results suggest that this novel class of indole-pyrimidine hybrids may have potential to be developed as new a class of tubulin polymerization inhibitors.