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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.

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.
AuthorsChao Tian, Zifei Han, Yuanxin Li, Meng Wang, Jiajia Yang, Xiaowei Wang, Zhili Zhang, Junyi Liu
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 151 Pg. 836-848 (May 10 2018) ISSN: 1768-3254 [Electronic] France
PMID29684894 (Publication Type: Journal Article)
CopyrightCopyright © 2018 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Purines
  • Pyrimidines
  • CHEK1 protein, human
  • Checkpoint Kinase 1
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Cell Cycle (drug effects)
  • Cell Proliferation (drug effects)
  • Checkpoint Kinase 1 (antagonists & inhibitors, metabolism)
  • Colonic Neoplasms (drug therapy, metabolism)
  • Drug Screening Assays, Antitumor
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Models, Molecular
  • Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Purines (chemical synthesis, chemistry, pharmacology)
  • Pyrimidines (chemical synthesis, chemistry, pharmacology)
  • Structure-Activity Relationship

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