title: Investigation of new 2-aryl substituted Benzothiopyrano[4,3-d]pyrimidines as kinase inhibitors targeting vascular endothelial growth factor receptor 2.
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 (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.
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors: Silvia
authors: S
authors: Salerno
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy. Electronic address: marini@unipi.it.
authors: Anna Maria
authors: AM
authors: Marini
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors: Giacomo
authors: G
authors: Fornaciari
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors: Francesca
authors: F
authors: Simorini
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors: Concettina
authors: C
authors: La Motta
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors: Sabrina
authors: S
authors: Taliani
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors: Stefania
authors: S
authors: Sartini
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy.
authors: Federico
authors: F
authors: Da Settimo
authors: Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, I-35131 Padova, Italy.
authors: Aída Nelly
authors: AN
authors: García-Argáez
authors: Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, I-35131 Padova, Italy.
authors: Ornella
authors: O
authors: Gia
authors: DiSTABiF, Seconda Università di Napoli, Via Vivaldi 43, I-81100 Caserta, Italy.
authors: Sandro
authors: S
authors: Cosconati
authors: Dipartimento di Farmacia, Università di Napoli Federico II, Via D. Montesano, 40, I-80131 Napoli, Italy.
authors: Ettore
authors: E
authors: Novellino
authors: Departamento de Farmacologia, Universitat de València Av. Vicente Andrés s/n 46100 Burjassot, València, Spain.
authors: Pilar
authors: P
authors: D'Ocon
authors: Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Scuola Medica - Via Roma 5, I-56126 Pisa, Italy.
authors: Anna
authors: A
authors: Fioravanti
authors: Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Scuola Medica - Via Roma 5, I-56126 Pisa, Italy.
authors: Paola
authors: P
authors: Orlandi
authors: Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Scuola Medica - Via Roma 5, I-56126 Pisa, Italy.
authors: Guido
authors: G
authors: Bocci
authors: Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, I-35131 Padova, Italy.
authors: Lisa
authors: L
authors: Dalla Via
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011714:Pyrans; D011743:Pyrimidines; C000607309:benzothiopyrano(4,3-d)pyrimidine; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Benzothiopyranopirimidines; Kinase inhibitors; Receptor tyrosine kinases; Tumor angiogenesis; VEGFR