Synthesis and evaluation of cell toxicity of new sorafenib derivatives

Abstract

Introduction: Cancer, is defined by abnormal cell growth and rapid proliferation. In spite of substantial advances in the recent years, the development of novel antitumor agents with high efficiency and low toxicity is currently one of the main interests in life science research. Aberrant angiogenesis as a critical step in the growth and metastasis of cancer has been widely observed in the great majority of solid tumors. Angiogenesis is regulated by many growth factors such as the vascular endothelial growth factors (VEGFs) and their receptors such as VEGFR-2. Therefore, the development of anticancer agents based on VEGFR-2 inhibitors (ATP analogues) have received considerable attention. Aims: The aims of current study are design, synthesis, characterization and anti-proliferative activity evaluation of some novel sorafenib analogues. Methods: In the current investigation, using sorafenib as a lead compound and taking into account the molecular hybridization drug design principle, a series of novel derivatives were designed and synthesized. Anti-proliferative activity of the generated compounds were evaluated by MTT assay against HT-29 cells. The possible modes of interactions established between the most active compound (12f) and tyrosinkinase receptor (PDB code: 4ASD) as the target of interest was investigated by molecular docking studies. Results: The structure of the synthesized compounds was characterized and approved by 1HNMR, 13CNMR, CHNS and FTIR methods. Among the synthesized compounds, 12f showed the highest activity (IC50 5.91 M). Docking of the most active compound into the ATP binding site of the tyrosinkinase receptor, revealed that the compound interacts with the binding site via multiple H-bonds, hydrophobic and electrostatic interactions. Conclusion: In present study novel deravatives based on sorafenib were synthesized and characterized. According to results of MTT evaluation and docking study, 12f superiour activity relative to the reference drug (sorafenib) and hence can be considered as a suitbale candidate for in-vivo studies.