European Journal of Medicinal Chemistry p. 29 - 43 (2015)
Update date:2022-08-15
Topics:
Salerno, Silvia
Marini, Anna Maria
Fornaciari, Giacomo
Simorini, Francesca
La Motta, Concettina
Taliani, Sabrina
Sartini, Stefania
Da Settimo, Federico
Garciá-Argaéz, Aída Nelly
Gia, Ornella
Cosconati, Sandro
Novellino, Ettore
D'Ocon, Pilar
Fioravanti, Anna
Orlandi, Paola
Bocci, Guido
Dalla Via, Lisa
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.
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