Affiliation:
1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
Abstract
Two series of pyrazolo[3,4-b]pyridine derivatives, 9a–h and 14a–h, are synthesized and evaluated for their anti-cancer potency towards Hela, MCF7, and HCT-116 cancer cell lines. Compound 9a showed the highest anticancer activity with IC50 = 2.59 µM against Hela when compared with doxorubicin (IC50 = 2.35 µM). Compound 14g revealed cytotoxicity IC50 = 4.66 and 1.98 µM towards MCF7 and HCT-116 compared to doxorubicin with IC50 = 4.57 and 2.11 µM, respectively. Compound 9a exhibited cell cycle arrest at the S phase for Hela, whereas 14g revealed an arresting cell cycle for MCF7 at G2/M phase and an arresting cell cycle at S phase in HCT-116. In addition, 9a induced a significant level of early and late apoptosis in Hela when compared with the control cells, whereas 14g induced an apoptosis in MCF7 and HCT-116, respectively. Compounds 9a (IC50 = 26.44 ± 3.23 µM) and 14g (IC50 = 21.81 ± 2.96 µM) showed good safety profiles on normal cell line WI-38. Compounds 9a and 14g showed good inhibition activity towards CDK2, with IC50 = 1.630 ± 0.009 and 0.460 ± 0.024 µM, respectively, when compared with ribociclib (IC50 = 0.068 ± 0.004). Furthermore, 9a and 14g showed inhibitory activity towards CDK9 with IC50 = 0.262 ± 0.013 and 0.801 ± 0.041 µM, respectively, related to IC50 of ribociclib = 0.050 ± 0.003. Docking study for 9a and 14g exhibited good fitting in the CDK2 and CDK9 active sites.
Funder
National Institute for Health Research
Subject
Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science