Untitled

Funder

Organizational Unit

Publications

Synthesis of new N-[3-(thieno[3,2-b]pyridine-7-ylthio)phenyl]benzamides as potential inhibitors the tyrosine kinase domain of VEGFR2

Publication . Campos, Joana F.; Begouin, Agathe; Peixoto, Daniela; Froufe, Hugo J.C.; Abreu, Rui M.V.; Ferreira, Isabel C.F.R.; Queiroz, Maria João R.P.

Angiogenesis, the growth of new vessels from preexisting vasculature, is a critical step in tumor progression [1]. The tyrosine kinase Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) is a crucial mediator in angiogenesis since the VEGF, excreted by the tumor cells, binds to it activating several signaling pathways involved in cell survival and proliferation [2]. Recently thienopyridine derivatives showed to be promising inhibitors of the tyrosine kinase domain of VEGFR2 [3,4]. In this work new N-[3-(thieno[3,2-b]pyridine-7-ylthio)phenyl]benzamides were prepared as potential VEGFR2 inhibitors suggested by rational design, as presented below.

2013Conference object

Open access

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

Publication . Queiroz, Maria João R.P.; Begouin, Agathe; Campos, Joana F.; Peixoto, Daniela; Froufe, Hugo J.C.; Calhelha, Ricardo C.; Abreu, Rui M.V.; Ferreira, Isabel C.F.R.

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).

2013Conference object

Open access

Virtual screening of thieno[3,2-b]pyridine arylthioether (hetero)aryltriazole derivatives as potential tyrosine kinase VEGFR2 inhibitors.

Publication . Calhelha, Ricardo C.; Begouin, Agathe; Campos, Joana F.; Ferreira, Isabel C.F.R.; Queiroz, Maria João R.P.; Abreu, Rui M.V.

Recently we presented a series of thieno[3,2-d]pyrimidinc ether I ,3-diaryl ureas with potent VEGFR2 inhibit ion activity. The binding mode was analyzed and the compounds showed a type-11 tyrosine kinase inhibition mode, with the thienopyrimidine moiety forming a Hydrogen Bond (H-bond) with CYS919 residue and the urea moiety forming a H-bonds with key residues G LU885 and ASP I 046 of the kinase domain. In this study, the potential of changing the more widely used urea moiety to a triazole moiety now in thieno[3,2-b)pyridine a rylthioethers, was analyzed. A number of 3D thieno[3.2-b ]pyrid ine arylthioethers (hetero )aryltriazole derivatives (Figure I) were designed and then molecular docking studies, using AutoDock4, were performed against a VEGFR2 crystal.

2013Conference object

Open access