Optimized spirooxindole-pyrazole hybrids targeting the p53-MDM2 interplay induce apoptosis and synergize with doxorubicin in A549 cells

Recently, cancer research protocols have introduced clinical-stage spirooxindole-based MDM2 inhibitors. However, several studies reported tumor resistance to the treatment. This directed efforts to invest in designing various combinatorial libraries of spirooxindoles. Herein, we introduce new series of spirooxindoles via hybridization of the chemically stable core spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one and the pyrazole motif inspired by lead pyrazole-based p53 activators, the MDM2 inhibitor BI-0252 and promising molecules previously reported by our group. Single crystal X-ray diffraction analysis confirmed the chemical identity of a representative derivative. Fifteen derivatives were screened for cytotoxic activities via MTT assay against a panel of four cancer cell lines expressing wild-type p53 (A2780, A549, HepG2) and mutant p53 (MDA-MB-453). The hits were 8h against A2780 (IC(50) = 10.3 µM) and HepG2 (IC(50) = 18.6 µM), 8m against A549 (IC(50) = 17.7 µM), and 8k against MDA-MB-453 (IC(50) = 21.4 µM). Further MTT experiments showed that 8h and 8j potentiated doxorubicin activity and reduced its IC(50) by at least 25% in combinations. Western blot analysis demonstrated that 8k and 8m downmodulated MDM2 in A549 cells. Their possible binding mode with MDM2 were simulated by docking analysis.