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European journal of medicinal chemistry v.143, 2018년, pp.48 - 65   SCI SCIE
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Discovery and structure-activity relationship of novel 4-hydroxy-thiazolidine-2-thione derivatives as tumor cell specific pyruvate kinase M2 activators

Li, Ridong (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) ; Ning, Xianling (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) ; Zhou, Shuo (Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentuchy, 789 South Lime-stone Street, Lexington, KY 40536, USA ) ; Lin, Zhiqiang (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) ; Wu, Xingyu (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) ; Chen, Hong (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) ; Bai, Xinyu (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) ; Wang, Xin (State Key Laboratory of Natural and Biomimet ) ; Ge, Zemei ; Li, Runtao ; Yin, Yuxin ;
  • 초록  

    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 IC 50 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. Highlights Discovery of 4-hydroxy-thiazolidine-2-thione derivatives as PKM2 activators. Most compounds showed significant antiproliferative activities. Compound 5w exhibited potent activities against four types of tumor cells at nanomolar concentration. Compound 5w arrests the cell cycle at the G2/M phase in HCT116 cell line. Graphical abstract [DISPLAY OMISSION]


  • 주제어

    PKM2 activators .   4-Hydroxy-Thiazolidine-2-thione derivatives .   Anti-tumor activity .   Structure-activity relationship.  

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