Synthesis and In Vitro Anticancer Activity of Novel 4-Aryl-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridines Arrest Cell Cycle and Induce Cell Apoptosis by Inhibiting CDK2 and/or CDK9

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 mu M against Hela when compared with doxorubicin (IC50 = 2.35 mu M). Compound 14g revealed cytotoxicity IC50 = 4.66 and 1.98 mu M towards MCF7 and HCT-116 compared to doxorubicin with IC50 = 4.57 and 2.11 mu M, 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 mu M) and 14g (IC50 = 21.81 +/- 2.96 mu M) 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 mu M, 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 mu M, 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.