Design, synthesis and biological evaluation of sorafenib based compounds as potential anticancer agents using structure based approach

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-۲). Developing novel inhibitors blocking VEGFR۲ and the Raf/MEK/ERK mitogen-activated protein kinase signaling pathway using in silico design approach is one of the research hotspot. To this goal, new compounds based on sorafenib were designed, synthesized and biologically evaluated. Using de novo design method, a library of new ligands was generated and expanded. Considering in silico binding affinity towards VEGFR۲, synthetic feasibility, and drug-likeness property, some of the designed ligands were selected for synthesis and screening for their in vitro anti-proliferative activities against two cancer cell lines (HT-۲۹ and A۵۴۹). Induction cell cycle arrest, induction apoptosis, ROS generation, VEGF۲ and Raf/MEK/ERK pathway phosphorylation blocking in HT-۲۹ cells upon exposure by the most active compound were evaluated. Molecular docking were used for prediction of binding mode of generated compounds towardsVEGFR۲ receptor. 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.

کلیدواژه ها:

Lead optimization ، de novo drug design ، diaryl urea ، synthesis ، docking ، antiproliferative activity