Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University , Corrensstraße 48, D-48149 Münster, Germany.
Leibniz Institute on Aging-Fritz Lipmann Institute (FLI) , Beutenbergstrasse 11, D-07745 Jena, Germany.
J Med Chem. 2017 Jan 26;60(2):749-766. doi: 10.1021/acs.jmedchem.6b01591. Epub 2017 Jan 13.
We report here a series of 27 10-(4-phenylpiperazin-1-yl)methanones derived from tricyclic heterocycles which were screened for effects on tumor cell growth, inhibition of tubulin polymerization, and induction of cell cycle arrest. Several analogues, among them the 10-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-10H-phenoxazine-3-carbonitrile (16o), showed excellent antiproliferative properties, with low nanomolar GI values (16o, mean GI of 3.3 nM) against a large number (93) of cancer cell lines. Fifteen compounds potently inhibited tubulin polymerization. Analysis of cell cycle by flow cytometry revealed that inhibition of tumor cell growth was related to an induction of G2/M phase cell cycle blockade. Western blotting and molecular docking studies suggested that these compounds bind efficiently to β-tubulin at the colchicine binding site. Our studies demonstrate the suitability of the phenoxazine and phenothiazine core and also of the phenylpiperazine moiety for the development of novel and potent tubulin polymerization inhibitors.
我们在此报告了一系列 27 种源自三环杂环的 10-(4-苯基哌嗪-1-基)甲酮，它们被筛选用于对肿瘤细胞生长、微管蛋白聚合抑制和细胞周期阻滞的影响。其中一些类似物，包括 10-(4-(3-甲氧基苯基)哌嗪-1-羰基)-10H-苯并恶嗪-3-甲腈（16o），表现出优异的抗增殖特性，对大量（93）种癌细胞系的 GI 值低至纳摩尔（16o，平均 GI 为 3.3 nM）。15 种化合物能强烈抑制微管蛋白聚合。通过流式细胞术分析细胞周期显示，肿瘤细胞生长的抑制与 G2/M 期细胞周期阻滞的诱导有关。Western 印迹和分子对接研究表明，这些化合物能有效地与微管蛋白结合在秋水仙碱结合部位。我们的研究表明，苯并恶嗪和苯并噻嗪核心以及苯并哌嗪部分适合开发新型有效的微管蛋白聚合抑制剂。
