Development of certain benzylidene coumarin derivatives as anti-prostate cancer agents targeting EGFR and PI3Kβ kinases

Abstract

Novel coumarin derivatives were synthesised and tested for their cytotoxicity against human cancer cells (PC-3 and MDA-MB-231). Compounds 5, 4b, and 4a possessed potent cytotoxic activity against PC-3 cells with IC₅₀ 3.56, 8.99, and 10.22 µM, respectively. Compound 4c displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC₅₀ 8.5 µM. Moreover, compound 5 exhibited potent inhibitory activity on EFGR with IC₅₀ 0.1812 µM, as well as PI3Kβ inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kβ inhibiting activity. Docking aligns with the in vitro results and sheds light on the molecular mechanisms underlying dual targeting. Furthermore, compound 5 decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound 5 caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways.

Keywords:

• Coumarins
• PC-3
• cytotoxicity
• apoptosis
• docking

Acknowledgements

Authors Aknowledge with thanks The Deanship of Scientific Research (DSR) at King Abdulaziz University (KAU), Jeddah, Saudi Arabia for technical and financial support.

Author contributions

The strategy was designed by Lina Amin, Noha Ryad, and Abdulrahman Salim Alharbi; experimental work was performed by Lina Amin, Noha Ryad, and Abdulrahman Salim Alharbi; biological studies were discussed by Noha Ryad, Lina Amin, Tarek S. Ibrahim, Mohamed Elagawany, and Mohamed S. Abdel-Aziz docking studies were performed by Eman El-labbad. All of the authors discussed the results and revised the manuscript. All authors approved the final version of the manuscript.

Disclosure statement

The authors report no conflicts of interest.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The Deanship of Scientific Research (DSR) at King Abdulaziz University (KAU), Jeddah, Saudi Arabia has funded this project, under Grant No. KEP-MSc-25-166-42.