Rational design, synthesis and evaluation of tyrosine kinase inhibitory effects of novel diaryl urea sorafenib-based derivatives

Abstract

Introduction: Cancer, a complex of diseases, is one of the main public health concerns worldwide. Angiogenesis as a critical step in the growth and metastasis of cancer is regulated by many growth factors such as the vascular endothelial growth factors (VEGFs) and receptor (VEGFR-2). Developing novel inhibitors blocking VEGFR2 and the Raf/MEK/ERK mitogen-activated protein kinase signaling pathway using in silico design aprroch is one of the research hotspot. Aims: The aims of this work were to synthesis and biological evaluation of diaryl urea derivatives designed as potential anticancer agents using de novo structure-based lead optimization approach Methods: Using in silico design method, a library of new ligand molecules was generated. After considering in silico binding affinity towards VEGFR2, some of the designed ligands were selected for synthesis. In vitro antiproliferative activities of synthesized compounds against two cancer cell lines (HT-29 and A549) were evaluated. Induction cell cycle arrest, induction apoptosis, ROS generation, VEGF2 and Raf/MEK/ERK pathway phosphorylation bloking in HT-29 cells treated with the most active compound were tested. Molecular docking were comducted for prediction of binding mode of generated compounds towards VEGFR2 receptor. Results: Antiproliferative activity showed four compounds exhibited stronger compared to those of the positive reference drug sorafenib against both cell lines. Notably, the most active compound, demonstrated the highest activity, and induced HT-29 apoptosis, increased intracellular reactive oxygen species level, arrested cell cycle at G0/G1 phase, and influenced the expression of apoptosis and cell cycle-related proteins. This compound can effectively block the Raf/MEK/ERK pathway and inhibit VEGFR2 phosphorylation. Molecular docking revealed that some of generated compounds could bind well to the active site of VEGFR2 receptor. Conclusions: Collectively, in the current study in silico drug design, synthesise of novel compounds and biological evaluation conducted to get insight into identified new anticancer agents based on sorafenib related diarylurea compounds.