Design, synthesis, and potent anticancer activity of novel indole-based Bcl-2 inhibitors

Almehdi, Ahmed M., Soliman, Sameh S. M., El-Shorbagi, Abdel-Nasser A., Westwell, Andrew D. ORCID: https://orcid.org/0000-0002-5166-9236 and Hamdy, Rania 2023. Design, synthesis, and potent anticancer activity of novel indole-based Bcl-2 inhibitors. International Journal of Molecular Sciences 24 (19) , 14656. 10.3390/ijms241914656

PDF - Published Version Available under License Creative Commons Attribution. Download (3MB)

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 with 0.62 ± 0.01 µM 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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Pharmacy
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	MDPI
ISSN:	1661-6596
Date of First Compliant Deposit:	10 October 2023
Date of Acceptance:	20 August 2023
Last Modified:	11 Oct 2023 19:23
URI:	https://orca.cardiff.ac.uk/id/eprint/163100

Actions (repository staff only)

Edit Item