Targeting apoptotic pathways in cancer: design, synthesis, and molecular docking studies of 1,3,5-trisubstituted-1H-pyrazole derivatives with Bcl-2 inhibition and DNA damage potential

Abstract

The search for new anticancer agents targeting apoptotic and autophagic pathways is crucial due to their roles in cellular homeostasis and cancer cell elimination. In this study, we synthesized and evaluated a series of 1,3,5-trisubstituted-1H-pyrazole derivatives as potential inhibitors of Bcl-2, a key regulator of apoptosis and autophagy. Several compounds activated pro-apoptotic proteins Bax, p53, and Caspase-3. Structure–activity relationship (SAR) studies assessed the cytotoxic effects of the compounds on MCF-7, A549, and PC-3 cancer cell lines. Compounds 4, 5, 6b, 6c, 7, 8, 10b, 10c, and 12b showed significant cytotoxicity against MCF-7 cells (IC₅₀: 3.9–35.5 μM), with similar activity observed against A549 and PC-3 cell lines. Compounds 6c, 8, 10b, and 10c also induced DNA damage, as evidenced by increased comet tail length, suggesting they cause genotoxic stress through DNA strand breaks. SAR analysis highlighted the importance of chlorophenyl, thiazole, and sulfonamide groups in enhancing cytotoxicity. Molecular docking confirmed high binding affinity of compounds 10b and 10c to Bcl-2 through key hydrogen bonding interactions. These findings suggest that the 1,3,5-trisubstituted-1H-pyrazole derivatives effectively target Bcl-2, activate apoptotic pathways, and induce DNA damage, making them promising candidates for further anticancer investigation.