Design, Synthesis, and Potent Anticancer Activity of Novel Indole-Based Bcl-2 Inhibitors.

The Bcl-2 family plays a crucial role in regulating cell apoptosis, making it an attractive target for cancer therapy. In this study, a series of indole-based compounds, -, were designed, synthesized, and evaluated for their anticancer activity against Bcl-2-expressing cancer cell lines. The binding affinity, safety profile, cell cycle arrest, and apoptosis effects of the compounds were tested. The designed compounds exhibited potent inhibitory activity at sub-micromolar IC concentrations against MCF-7, MDA-MB-231, and A549 cell lines. Notably, and demonstrated the highest activity, particularly against MCF-7 cells. Respectively, both and showed potential BCL-2 inhibition activity with IC values of 1.2 ± 0.02 and 11.10 ± 0.07 µM using an ELISA binding assay compared with 0.62 ± 0.01 µM for gossypol, employed as a positive control. Molecular docking analysis suggested stable interactions of compound at the Bcl-2 binding site through hydrogen bonding, pi-pi stacking, and hydrophobic interactions. Furthermore, demonstrated significant induction of apoptosis and cell cycle arrest at the G1/S phase. Importantly, displayed a favourable safety profile on HDF human dermal normal fibroblast cells at 10-fold greater IC values compared with MDA-MB-231 cells. These findings underscore the therapeutic potential of compound as a Bcl-2 inhibitor and provide insights into its molecular mechanisms of action.