Advertisement

 

 

Discovery and structure-activity relationship of novel 4-hydroxy-thiazolidine-2-thione derivatives as tumor cell specific pyruvate kinase M2 activators.

Discovery and structure-activity relationship of novel 4-hydroxy-thiazolidine-2-thione derivatives as tumor cell specific pyruvate kinase M2 activators.
Author Information (click to view)

Li R, Ning X, Zhou S, Lin Z, Wu X, Chen H, Bai X, Wang X, Ge Z, Li R, Yin Y,


Li R, Ning X, Zhou S, Lin Z, Wu X, Chen H, Bai X, Wang X, Ge Z, Li R, Yin Y, (click to view)

Li R, Ning X, Zhou S, Lin Z, Wu X, Chen H, Bai X, Wang X, Ge Z, Li R, Yin Y,

Advertisement
Share on FacebookTweet about this on TwitterShare on LinkedIn

European journal of medicinal chemistry 2017 11 10143() 48-65 pii 10.1016/j.ejmech.2017.11.023

Abstract

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 compound 2 as 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 compound 2 and also exhibited significant anti-proliferative activities on human cancer cell lines at nanomolar concentration. The compound 5w was identified as the most potent antitumor agent, which showed excellent anti-proliferative effects with IC50 values from 0.46 μM to 0.81 μM against H1299, HCT116, Hela and PC3 cell lines. 5w also showed less cytotoxicity in non-tumor cell line HELF compared with cancer cells. In addition, Preliminary pharmacological studies revealed that 5w arrests the cell cycle at the G2/M phase in HCT116 cell line. The best PKM2 activation by compound 5t was rationalized through docking studies.

Submit a Comment

Your email address will not be published. Required fields are marked *

nine − four =

[ HIDE/SHOW ]