Almehdi, A.M.; Soliman, S.S.M.; El-Shorbagi, A.-N.A.; Westwell, A.D.; Hamdy, R. Design, Synthesis, and Potent Anticancer Activity of Novel Indole-Based Bcl-2 Inhibitors. Int. J. Mol. Sci.2023, 24, 14656.
Almehdi, A.M.; Soliman, S.S.M.; El-Shorbagi, A.-N.A.; Westwell, A.D.; Hamdy, R. Design, Synthesis, and Potent Anticancer Activity of Novel Indole-Based Bcl-2 Inhibitors. Int. J. Mol. Sci. 2023, 24, 14656.
Almehdi, A.M.; Soliman, S.S.M.; El-Shorbagi, A.-N.A.; Westwell, A.D.; Hamdy, R. Design, Synthesis, and Potent Anticancer Activity of Novel Indole-Based Bcl-2 Inhibitors. Int. J. Mol. Sci.2023, 24, 14656.
Almehdi, A.M.; Soliman, S.S.M.; El-Shorbagi, A.-N.A.; Westwell, A.D.; Hamdy, R. Design, Synthesis, and Potent Anticancer Activity of Novel Indole-Based Bcl-2 Inhibitors. Int. J. Mol. Sci. 2023, 24, 14656.
Abstract
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 µM using an ELISA binding assay compared to 0.62 ± 0.01 µM for gossypol, employed as 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 G1/S phase. Importantly, U2 displayed a favorable safety profile on HDF human dermal normal fibroblast cells at 10-fold greater IC50 compared to 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.
Keywords
Bcl-2; Anti-apoptotic protein; Indole; Cancer drug discovery
Subject
Biology and Life Sciences, Life Sciences
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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