Synthesis of new N-[3-(thieno[3,2-b]pyridine-7-ylthio)phenyl]benzamides as potential inhibitors of VEGFR2 using rational design

Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) is the major receptor of the angiogenic effects when linked to VEGF released by tumors. It has a well known role as a transmembrane receptor activating multiple signaling pathways of proliferation and migration of endothelial cells [1], thus leading to the formation and the expansion of new blood vessels (vasculogenesis and angiogenesis) towards the tumor [2]. Therefore, several approaches have been developed to inhibit VEGFR activation and signaling [3]. Some thienopyridine derivatives have already been shown to be inhibitors of the tyrosine kinase domain of VEGFR2 preventing its activation [4]. Herein, we describe the synthesis of new N-[3-(thieno[3,2-b]pyridine-7 -ylthio )phenyl]benzamides, suggested by rational design as potential inhibitors of this domain, either through a Cu-catalyzed C-N coupling of a brominated di(hetero)arylthioether thieno[3,2-b]pyridine with benzamides, or through a reaction of an aminated di(hetero )arylthioether thieno[3,2-b ]pyridine with benzoyl chlorides, as presented below. The inhibition of the tyrosine kinase domain of VEGFR2 by the synthesized compounds will be evaluated by enzymatic and biomolecular assays using VEGF-stimulated Human Umbilical Vein Endothelial Cells (HUVECs).