Ferulic and p-coumaric acid derivatives as dual EGFR-VEGFR2 inhibitors: design, semi-synthesis, and biological investigations

Abstract

Since there is a great deal of interest in the examination of the potential role of herbal and complementary medicines in the treatment of different types of cancer, we report here the semi-synthesis of novel derivatives of the naturally occurring P-CA and FA as dual EGFR/VEGFR2 inhibitors and investigate their cytotoxicity through in vitro and in vivo studies, shedding light on their potential and mechanism of action. The synthesized compounds were evaluated for their cytotoxicity against MCF-7, HepG-2, A549 cell lines, and WISH normal cells. Compounds 3d, 3f, and 3h showed potent cytotoxicity against MCF-7 with IC₅₀ values of 1.16, 1.04, and 1.1 µM, respectively, compared to Sorafenib (IC₅₀ = 3.04 µM). Interestingly, compound 3f, the most active compound, exhibited potent EGFR and VEGFR2 inhibition with an IC₅₀ value of 75.4 nM and 36.2 nM, respectively, compared to Sorafenib with an EGFR and VEGFR2 inhibition IC₅₀ values of 69.8 nM and 30.1 nM. Additionally, compound 3f dramatically induced apoptotic cell death in MCF-7 cells, increasing the death rate by 32.9% compared to 0.95% in the untreated control. Furthermore, compound 3f treatment significantly increased the cell population at the G1-phase by 79.6% compared to control 53.3%, while cells in S and G2/M phases decreased and caused cell death in MCF-7 cells, stopping their growth in the G1 phase. In vivo studies revealed that compound 3f and Sorafenib decreased the mass of solid tumor to 132 mg and 116 mg, respectively. Accordingly, the tumor volume was reduced from 319 mm³ in the SEC-bearing model to 134 mm³ and 119.6 mm³, respectively. Hence, both treatments inhibited tumor proliferation by 57.9% and 62.5%, respectively. Ultimately, a histological evaluation was conducted to assess compound 3f's efficacy and safety. Finally, molecular docking revealed the bias of both EGFR and VEGFR2 pockets towards compound 3f compared to other synthesized compounds. The docking scores obtained for 3f against EGFR and VEGFR2 indicated comparable binding profiles at ΔG scores −9.48 and −10.12 kcal mol⁻¹, respectively, exhibiting a quite higher binding affinity than the other analogs. The results revealed that compound 3f had promising structural and functional properties, making it a promising candidate for further research into the design and development of more active analogs.