Design, synthesis and biological evaluation of new classes of thieno[3,2-d]pyrimidinone and thieno[1,2,3]triazine as inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2)

Enrico Perspicace; Valérie Jouan-Hureaux; Rino Ragno; Flavio Ballante; Stefania Sartini; Concettina La Motta; Federico Da Settimo; Binbin Chen; Gilbert Kirsch; Serge Schneider; Béatrice Faivre; Stéphanie Hesse

doi:10.1016/j.ejmech.2013.03.022

Design, synthesis and biological evaluation of new classes of thieno[3,2-d]pyrimidinone and thieno[1,2,3]triazine as inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2)

Eur J Med Chem. 2013 May:63:765-81. doi: 10.1016/j.ejmech.2013.03.022. Epub 2013 Mar 19.

Authors

Enrico Perspicace¹, Valérie Jouan-Hureaux, Rino Ragno, Flavio Ballante, Stefania Sartini, Concettina La Motta, Federico Da Settimo, Binbin Chen, Gilbert Kirsch, Serge Schneider, Béatrice Faivre, Stéphanie Hesse

Affiliation

¹ Laboratoire d'Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.

PMID: 23583911
DOI: 10.1016/j.ejmech.2013.03.022

Abstract

Driven by a multidisciplinary approach combination (Structure-Based (SB) Three-Dimensional Quantitative Structure-Activity Relationships (3-D QSAR), molecular modeling, organic chemistry and various biological evaluations) here is reported the disclosure of new thienopyrimidines 1-3 as inhibitors of KDR activity and human umbilical vein endothelial cell (HUVEC) proliferation. More specifically, compound 2f represents a new lead compound that inhibits VEGFR-2 and HUVEC at μM concentration. Moreover by the mean of an endothelial cell tube formation in vitro model 2f tartaric acid salt proved to block angiogenesis of HUVEC at μM level.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding, Competitive
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Design
Human Umbilical Vein Endothelial Cells / cytology
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Models, Chemical
Models, Molecular
Molecular Conformation
Molecular Structure
Neovascularization, Physiologic / drug effects
Protein Structure, Tertiary
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacology*
Quantitative Structure-Activity Relationship
Triazines / chemical synthesis
Triazines / chemistry
Triazines / pharmacology*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / chemistry
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Pyrimidinones
Triazines
Vascular Endothelial Growth Factor Receptor-2