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

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

  • Eur J Med Chem. 2015 Oct 20:103:29-43. doi: 10.1016/j.ejmech.2015.08.027.
Silvia Salerno 1,  Anna Maria Marini 2,  Giacomo Fornaciari 1,  Francesca Simorini 1,  Concettina La Motta 1,  Sabrina Taliani 1,  Stefania Sartini 1,  Federico Da Settimo 1,  Aída Nelly García-Argáez 3,  Ornella Gia 3,  Sandro Cosconati 4,  Ettore Novellino 5,  Pilar D'Ocon 6,  Anna Fioravanti 7,  Paola Orlandi 7,  Guido Bocci 7,  Lisa Dalla Via 3
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
  • 2 Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy. Electronic address: marini@unipi.it.
  • 3 Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, I-35131 Padova, Italy.
  • 4 DiSTABiF, Seconda Università di Napoli, Via Vivaldi 43, I-81100 Caserta, Italy.
  • 5 Dipartimento di Farmacia, Università di Napoli Federico II, Via D. Montesano, 40, I-80131 Napoli, Italy.
  • 6 Departamento de Farmacologia, Universitat de València Av. Vicente Andrés s/n 46100 Burjassot, València, Spain.
  • 7 Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Scuola Medica - Via Roma 5, I-56126 Pisa, Italy.
PMID: 26318056 DOI: 10.1016/j.ejmech.2015.08.027
Abstract

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 (VEGFR2/KDR/Flk-1), 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.

Keywords

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

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