Mimicry of sorafenib: novel diarylureas as VEGFR2 inhibitors and apoptosis inducers in breast cancer

Abstract

Thirteen diarylurea derivatives were designed and synthesized as sorafenib mimetics. The cytotoxic activity of the newly synthesized entities towards human breast cancer cell lines, (MCF-7) and (MDA-MB-231), were evaluated in comparison with the reference drugs doxorubicin (DOX) and sorafenib using the MTT assay. Notably, pyrazoline 6 and N-pyrazoline carboxamide 7a were the most active cytotoxic drugs, and their cytotoxicity against human lung fibroblast cells (WI-38) was estimated to ensure their selectivity. Compounds 6 and 7a displayed higher selectivity indices (SI = 3.66–10.86) towards the breast cancer cell lines compared with dox (SI = 1.61–2.11). Afterward, the mechanistic study of compounds 6 and 7a was performed both in vitro (via VEGFR2 inhibition assay, apoptosis induction, and cell cycle analysis) and in silico (by molecular docking and physicochemical properties). Compound 7a exhibited a potent VEGFR-2 inhibitory effect with IC₅₀ equal to 0.136 ± 0.007μM and impressively downregulated the anti-apoptotic marker bcl-2 and upregulated the pro-apoptotic oncogene, Bax. Furthermore, compound 7a is expected to be an apoptosis inducer that arrests the cell cycle at the S phase. In silico prediction was accomplished to endorse the physicochemical and ADME characteristics, which confirmed that most compounds have good oral bioavailability, are free of side effects, and obey the Lipinski and Veber rules. The prospective mode of action was further investigated via molecular modeling simulation of compounds 6 and 7a, which revealed their binding affinities to the active site of VEGFR-2.