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Eur J Med Chem. 2015 Oct 20;103:29-43. doi: 10.1016/j.ejmech.2015.08.027. Epub 2015 Aug 14.

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

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Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy. Electronic address:
Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, I-35131 Padova, Italy.
DiSTABiF, Seconda Università di Napoli, Via Vivaldi 43, I-81100 Caserta, Italy.
Dipartimento di Farmacia, Università di Napoli Federico II, Via D. Montesano, 40, I-80131 Napoli, Italy.
Departamento de Farmacologia, Universitat de València Av. Vicente Andrés s/n 46100 Burjassot, València, Spain.
Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Scuola Medica - Via Roma 5, I-56126 Pisa, Italy.


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.


Benzothiopyranopirimidines; Kinase inhibitors; Receptor tyrosine kinases; Tumor angiogenesis; VEGFR

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