New quinazoline sulfonamide derivatives as potential anticancer agents: Identifying a promising hit with dual EGFR/VEGFR-2 inhibitory and radiosensitizing activity

Abstract

Herein, we report the synthesis of a series of new quinazoline sulfonamide conjugates 2-16 and their evaluation as potential anticancer agents via dual targeting of EGFR^T790M and VEGFR-2. The newly synthesized compounds were designed based on the structure requirements of the target receptors and were confirmed using spectral data. The compounds were evaluated for their cytotoxicity against four cancer cell lines (HepG2, MCF-7, HCT116 and A549) using MTT assay. The most active compounds were further evaluated for their inhibitory activity against EGFR^T790M and VEGFR-2. Compound 15 showed the most significant cytotoxic activity with IC₅₀ = 0.0977 µM against MCF-7 and the most potent inhibitory activity against both EGFR and VEGFR with IC₅₀ = 0.0728 and 0.0523 µM, respectively. Compound 15 was able to induce apoptosis in MCF-7 cells and cell cycle arrest at the G2/M phase. The relative safety profile of 15 was assessed using HEK-293 normal cell line and an ADMET profile was carried out. Radiosensitizing evaluation of 15 proved its significant ability to sensitize the cancer cell to the effect of radiation after being subjected to a single dose of 8 Gy gamma irradiation. Molecular docking studies revealed that 15 could bind to the ATP-binding site of EGF and VEGF receptors, inhibiting their activity.

Keywords: ADMET; Anticancer; Quinazoline; Sulfonamide; Tyrosine kinase.