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.
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Authors | Chao Tian, Zifei Han, Yuanxin Li, Meng Wang, Jiajia Yang, Xiaowei Wang, Zhili Zhang, Junyi Liu |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 151
Pg. 836-848
(May 10 2018)
ISSN: 1768-3254 [Electronic] France |
PMID | 29684894
(Publication Type: Journal Article)
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Copyright | Copyright © 2018 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Purines
- Pyrimidines
- CHEK1 protein, human
- Checkpoint Kinase 1
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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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