Synthesis and in vitro anticancer activity of some 2-oxindoline derivatives as potential CDK2 inhibitors

Novel series of 2-oxindoline hydrazones 6a-h, 3-hydroxy-2-oxoindolines 9a-d and 2-oxoindolin-3-ylidenes 10a-d were prepared and assessed for their anticancer activity towards breast cancer cell line (MCF7). Compounds 6c, 6d, 6g, 9d, 10a and 10b (IC50 = 14.0 +/- 0.7, 15.6 +/- 0.7, 13.8 +/- 0.7, 4.9 +/- 0.2, 6.0 +/- 0.3 and 10.8 +/- 0.5 mu M, respectively) showed the highest growth inhibition activity against MCF7 when compared to staurosporine (IC50 = 14.5 +/- 0.7 mu M). Cell cycle analysis exposed arrest at G1 phase for compounds 6c, 10 and 10b, at S phase for compounds 6d and 9d, and at G1/S phase for compound 6g. Apoptotic effect of compounds 6c, 6d, 6g, 9d, 10a and 10b was confirmed via their early and late apoptotic effects. A safety profile was revealed for compounds 6c, 6d, 6g, 9d, 10a and 10b on MCF10A treated normal cell. Also, compounds 6c and 10b displayed a promising CDK2 inhibition activity (IC50 = 0.22 +/- 0.01, 0.25 +/- 0.01 mu M, respectively). Also, docking study revealed comparable interactions with the native ligand (5-bromoindirubin). ADMET computational studies forecast the promising pharmacokinetic profile of the targeted compounds.Communicated by Ramaswamy H. Sarma