Discovery and structure-activity relationship of novel 4-hydroxythiazolidine-2-thione derivatives as tumor cell specific pyruvate kinase M2 activators
Discovery and structure-activity relationship of novel 4-hydroxythiazolidine-2-thione derivatives as tumor cell specific pyruvate kinase M2 activators
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作为肿瘤细胞特异性丙酮酸激酶 M2 激活剂的新型 4-羟基噻唑烷-2-硫酮衍生物的发现及其构效关系
DOI：
10.1016/j.ejmech.2017.11.023
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发表时间：
2017
影响因子：
6.7
通讯作者：
Yuxin Yin
中科院分区：
文献类型：
--
作者：
Ridong Li;Xianling Ning;Shuo Zhou;Zhiqiang Lin;Xingyu Wu;Hong Chen;Xinyu Bai;Xin Wang;Zemei Ge;Runtao Li;Yuxin Yin
丙酮酸激酶M2亚型（PKM 2）是负责癌细胞有氧糖酵解的关键蛋白。PKM 2的活化可改变癌细胞中的异常代谢。在这项研究中，我们发现了一个4-羟基-噻唑烷-2-酮化合物2作为一个新的PKM 2激活剂从一个随机筛选的内部化合物库。设计并合成了一系列新型的4-羟基噻唑烷-2-酮衍生物，以筛选潜在的PKM 2激活剂。其中，一些化合物显示出比先导化合物2更高的PKM 2活化活性，并且在纳摩尔浓度下对人癌细胞系也显示出显著的抗增殖活性。化合物5 w对H1299、HCT 116、Hela和PC 3细胞的IC 50值在0.46 μM ~ 0.81 μM之间，对非肿瘤细胞株HELF的细胞毒活性低于癌细胞株。此外，初步药理学研究表明，5可使HCT 116细胞周期阻滞于G2/M期。化合物5的最佳PKM 2活化通过对接研究合理化。
Pyruvate kinase M2 isoform (PKM2) is a crucial protein responsible for aerobic glycolysis of cancer cells. Activation of PKM2 may alter aberrant metabolism in cancer cells. In this study, we discovered a 4-hydroxy-thiazolidine-2-thione compound2as a novel PKM2 activator from a random screening of an in-house compound library. Then a series of novel 4-hydroxy-thiazolidine-2-thione derivatives were designed and synthesized for screening as potent PKM2 activators. Among these, some compounds showed higher PKM2 activation activity than lead compound2and also exhibited significant anti-proliferative activities on human cancer cell lines at nanomolar concentration. The compound5wwas identified as the most potent antitumor agent, which showed excellent anti-proliferative effects with IC50values from 0.46 μM to 0.81 μM against H1299, HCT116, Hela and PC3 cell lines.5walso showed less cytotoxicity in non-tumor cell line HELF compared with cancer cells. In addition, Preliminary pharmacological studies revealed that5warrests the cell cycle at the G2/M phase in HCT116 cell line. The best PKM2 activation by compound5twas rationalized through docking studies.