Design, synthesis and molecular modeling study of certain 4-Methylbenzenesulfonamides with CDK2 inhibitory activity as anticancer and radio-sensitizing agents.

Two series of 2-aminopyridine derivatives 6-17 and tyrphostin AG17 analogs 18-22 bearing 4-methylbenzenesulfonamide moiety were designed and synthesized as anticancer compounds. The synthesized compounds were biologically evaluated for their cytotoxic activity against human breast cancer cell line MCF-7. From 2-aminopyridine and tyrphostin AG17 series, compounds 14, 16 and 20 showed the best activities with IC values of 20.4, 18.3 and 26.3 µM, respectively compared to E7070 IC 36.3 µM. Further biological evaluation of 14, 16 and 20 against cyclin dependent kinase-2 (CDK2) revealed good inhibitory activity with IC of 2.53, 1.79 and 2.92 µM, respectively compared to roscovitine IC 0.43 µM. Additionally, capability of γ-radiation to augment the cytotoxic activity of 14, 16 and 20 was studied and showed a dramatic increase in the cell killing effect at lower concentrations after irradiation. Docking was used to investigate the possible binding modes of compounds 14, 16 and 20 inside the active site of CDK2 enzyme.