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, U1-6, 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 IC50 concentrations against MCF-7, MDA-MB-231, and A549 cell lines. Notably, U2 and U3 demonstrated the highest activity, particularly against MCF-7 cells. Respectively, both U2 and U3 showed potential BCL-2 inhibition activity with IC50 values of 1.2 +/- 0.02 and 11.10 +/- 0.07 mu M using an ELISA binding assay compared with 0.62 +/- 0.01 mu M for gossypol, employed as a positive control. Molecular docking analysis suggested stable interactions of compound U2 at the Bcl-2 binding site through hydrogen bonding, pi-pi stacking, and hydrophobic interactions. Furthermore, U2 demonstrated significant induction of apoptosis and cell cycle arrest at the G1/S phase. Importantly, U2 displayed a favourable safety profile on HDF human dermal normal fibroblast cells at 10-fold greater IC50 values compared with MDA-MB-231 cells. These findings underscore the therapeutic potential of compound U2 as a Bcl-2 inhibitor and provide insights into its molecular mechanisms of action.

Automated summary

This study designed and synthesized a series of indole-based compounds, and found that U2 and U3 exhibited the highest anticancer activity against MCF-7 cells and potential BCL-2 inhibition activity. Molecular docking analysis suggested stable interactions between U2 and Bcl-2 through multiple mechanisms. In addition, U2 induced apoptosis and cell cycle arrest. U2 also showed a favorable safety profile.