VEGFR-2 inhibiting effect and molecular modeling of newly synthesized coumarin derivatives as anti-breast cancer agents

Twenty five newly synthesized coumarin scaffold based derivatives were assayed for their in vitro Anticancer activity against MCF-7 breast and PC-3 prostate Cancer cell lines and were further assessed for their in vitro VEGFR-2 kinase inhibitory activity. The in vitro cytotoxic studies revealed that most of the synthesized compounds possessed very promising cytotoxicity against MCF-7, particularly; compounds 4a (IC₅₀ = 1.24 µM) and 3d (IC₅₀ = 1.65 µM) exhibited exceptional activities superior to the positive control staurosporine (IC₅₀ = 8.81 µM). Similarly, the majority of the compounds exhibited higher antiproliferative activities compared to the reference standard with IC₅₀ values ranging from 2.07 to 8.68 µM. The two cytotoxic derivatives 4a and 3d were selected to evaluate their inhibitory potencies against VEGFR-2 kinase. Remarkably, compound 4a, exhibited significant IC₅₀ of 0.36 µM comparable to staurosporine (IC₅₀; 0.33 µM). Moreover, it was capable of inducing preG1 Apoptosis, cell growth arrest at G2/M phase and activating caspase-9. On the Other hand, insignificant cytotoxic activity was observed for all compounds towards PC-3 cell line. Molecular docking study was carried out for the most active anti-VEGFR-2 derivative 4a, which demonstrated the ability of the tested compound to interact with the key Amino acids in the target VEGFR-2 kinase binding site. Additionally, the ADME parameters and physicochemical properties of compound 4a were examined in silico.

Coumarin; MCF-7; Molecular modeling; VEGFR-2 kinase.