One-pot synthesis of spiro(indoline-3,4′-pyrazolo[3,4-b]pyridine)-5′-carbonitriles as p53-MDM2 interaction inhibitors

Aim: Inhibition of P53-mdm2 interaction will lead to cancer cell apoptosis. This strategy was achieved by reported spiro-oxindole derivatives. Materials & methods: Spiro(indoline-3,4′-pyrazolo[3,4-b]pyridine)-5′-carbonitrile derivatives (4a-i and 9a, b) were synthesized and screened for their in vitro anticancer activity. The most active compounds were subjected to P53-MDM2 inhibitory activity, apoptotic and molecular docking studies. Results & discussion: Compound 4d exhibited potent and broad spectrum of antiproliferative activity with full panel GI 50 (MG-MID) value of 3.97 μM. Compounds 4d and 4i inhibited p53-MDM2 protein-protein interaction with IC 50 = 52.1 and 95.2 nM, respectively. Compound 4d inhibits the expression of wild p53 in MCF-7 more than mutant p53 in MDA-MB231 at the molecular level. Molecular docking studies illustrated the possible interaction of the target spiro-oxindoles with the p53 binding site on MDM2.