Investigation of new 2-aryl substituted Benzothiopyrano[4,3-d[pyrimidines as kinase inhibitors targeting vascular endothelial growth factor receptor 2

6533b83afe1ef96bd12a7aaf

RESEARCH PRODUCT

Investigation of new 2-aryl substituted Benzothiopyrano[4,3-d[pyrimidines as kinase inhibitors targeting vascular endothelial growth factor receptor 2

Guido Bocci Silvia Salerno Ettore Novellino Sabrina Taliani Sandro Cosconati Stefania Sartini Concettina La Motta Lisa Dalla Via Paola Orlandi Federico Da Settimo Anna Fioravanti Anna Maria Marini Pilar D'ocon Ornella Gia Francesca Simorini Aída Nelly García-argáez G. Fornaciari

subject

Models Molecular Angiogenesis Receptor tyrosine kinase Cell Antineoplastic Agents Receptor tyrosine kinase Benzothiopyranopirimidines; Kinase inhibitors; Receptor tyrosine kinases; Tumor angiogenesis; VEGFR;Tumor angiogenesis Structure-Activity Relationship chemistry.chemical_compound VEGFR Benzothiopyranopirimidine Cell Line Tumor Receptor tyrosine kinases Drug Discovery Human Umbilical Vein Endothelial Cells medicine Humans Protein Kinase Inhibitors Cell Proliferation Pyrans Tumor angiogenesi Pharmacology Kinase inhibitor Dose-Response Relationship Drug Molecular Structure biology Kinase Cell growth Organic Chemistry Kinase insert domain receptor General Medicine Vascular Endothelial Growth Factor Receptor-2 Molecular biology Vascular endothelial growth factor Pyrimidines medicine.anatomical_structure Benzothiopyranopirimidines chemistry Benzothiopyranopirimidines; Kinase inhibitors; Receptor tyrosine kinases; Tumor angiogenesis; VEGFR Kinase inhibitors Cancer research biology.protein Drug Screening Assays Antitumor Ex vivo

description

Vascular Endothelial Growth Factor (VEGF) pathway has emerged as one of the most important positive modulators of Angiogenesis, a central process implicated in tumour growth and metastatic dissemination. This led to the design and development of anti-VEGF monoclonal antibodies and small-molecule ATP-competitive VEGFR-inhibitors. In this study, we describe the synthesis and the biological evaluation of novel 2-aryl substituted benzothiopyrano-fused pyrimidines 1a-i, 2a-i and 3a-i. The ability of the compounds to target the VEGF pathway was determined in vitro exploiting the compounds' antiproliferative efficacy against HUVEC cells. The VEGFR-2 inhibition was confirmed by enzymatic assays on recombinant human kinase insert domain receptor (KDR), by cell-based phospho-VEGFR-2 inhibition assays, and by ex vivo rat aortic ring tests. The selectivity profile of the best performing derivatives belonging to series 2 was further explored combining modeling studies and additional assays in a panel of human cell lines and other kinases.

year	journal	country	edition	language
2015-01-01

10.1016/j.ejmech.2015.08.027 http://hdl.handle.net/11591/195244