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.