N‐allyl quinoxaline derivative exhibited potent and selective cytotoxicity through EGFR/VEGFR‐mediated apoptosis: In vitro and in vivo studies

Abstract

AbstractThe cytotoxic activity, EGFR/VEGFR2 target inhibition, apoptotic activity, RT‐PCR gene expression, in vivo employing a solid‐Ehrlich carcinoma model, and in silico investigations for highlighting the binding affinity of eight quinoxaline derivatives were tested for anticancer activities. The results showed that compound 8 (N‐allyl quinoxaline) had potent cytotoxicity against A594 and MCF‐7 cancer cells with IC50 values of 0.86 and 1.06 µM, respectively, with noncytotoxic activity against WISH and MCF‐10A cells having IC50 values more than 100 µM. Furthermore, it strongly induced apoptotic cell death in A549 and MCF‐7 cells by 43.13% and 34.07%, respectively, stopping the cell cycle at S and G1‐phases. For the molecular target, the results showed that compound 8 had a promising EGFR inhibition activity with an IC50 value of 0.088 µM compared to Sorafenib (IC50 = 0.056 µM), and it had a promising VEGFR2 inhibition activity with an IC50 value of 0.108 µM compared to Sorafenib (IC50 = 0.049 µM). Treatment with compound 8 ameliorated biochemical and histochemical parameters near normal in the in vivo investigation, with a tumor inhibition ratio of 68.19% compared to 64.8% for 5‐FU treatment. Finally, the molecular docking study demonstrated the binding affinity through binding energy and interactive binding mode inside the EGFR/VEGFR2 proteins. Potent EGFR and VEGFR2 inhibition of compound 8 suggests its potential for development as a selective anticancer drug.