2. Academic Validation
  3. Synthesis and biological evaluation of 2,6-disubstituted-9H-purine, 2,4-disubstitued-thieno[3,2-d]pyrimidine and -7H-pyrrolo[2,3-d]pyrimidine analogues as novel CHK1 inhibitors

Synthesis and biological evaluation of 2,6-disubstituted-9H-purine, 2,4-disubstitued-thieno[3,2-d]pyrimidine and -7H-pyrrolo[2,3-d]pyrimidine analogues as novel CHK1 inhibitors

  • Eur J Med Chem. 2018 May 10:151:836-848. doi: 10.1016/j.ejmech.2018.03.075.
Chao Tian 1,  Zifei Han 2,  Yuanxin Li 2,  Meng Wang 2,  Jiajia Yang 2,  Xiaowei Wang 2,  Zhili Zhang 2,  Junyi Liu 3
Affiliations

Affiliations

  • 1 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: tianchao@bjmu.edu.cn.
  • 2 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
  • 3 Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China. Electronic address: jyliu@bjmu.edu.cn.
PMID: 29684894 DOI: 10.1016/j.ejmech.2018.03.075
Abstract

Checkpoint kinase 1 (Chk1) inhibitors can potentiate the effectiveness of deoxyribonucleic acid (DNA) damaging agents in the treatment of Cancer. A novel series of 2,6-disubstituted-9H-purine (3a-p, 5a and 5b), 2,4-disubstituted-thieno[3,2-d]pyrimidine (8a-c) and 2,4-disbustituted-7H-pyrrolo[2,3-d]pyrimidine (11a-c) analogues were designed and synthesized as potent Chk1 inhibitors. Compounds (3a, 3d, 3f and 3j-l) with 9H-purine core displayed more potent inhibition against Chk1. The most potent compound (3l) also exhibited low anti-proliferative effects towards HT29 and Hek293 cell lines. In addition, 3l showed strong potentiating effect (7-fold) on the anti-proliferative activity of gemcitabine towards HT29 cells. The results of cell cycle assay indicated that 3l could strikingly affect the cell cycle distribution of the gemcitabine-treated HT29 cells and induce a significant S phase accumulation. The kinase selectivity profile of 3l displayed acceptable selectivity against Other kinases. These results rendered 3l a potent lead compound of Chk1 Inhibitor for further investigation.

Keywords

9H-purine; Anti-proliferative effects; CHK1 inhibitors; Potentiating effect.

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