title: Synthesis of Novel c(AmpRGD)-Sunitinib Dual Conjugates as Molecular Tools Targeting the αvβ3Integrin/VEGFR2 Couple and Impairing Tumor-Associated Angiogenesis.
abstract: On the basis of a previously discovered anti-αVβ3integrin peptidomimetic (c(AmpRGD)) and the clinically approved antiangiogenic kinase inhibitor sunitinib, three novel dual conjugates were synthesized (compounds 1-3), featuring the covalent and robust linkage between these two active modules. In all conjugates, the ligand binding competence toward αVβ3(using both isolated receptors and αVβ3-overexpressing endothelial progenitor EP cells) and the kinase inhibitory activity (toward both isolated kinases and EPCs) remained almost untouched and comparable to the activity of the single active units. Compounds 1-3 showed interesting antiangiogenesis properties in an in vitro tubulogenic assay; furthermore, dimeric-RGD conjugate 3 strongly inhibited in vivo angiogenesis in Matrigel plug assays in FVB mice. These results offer proof-of-concept of how the covalent conjugation of two angiogenesis-related small modules may result in novel and stable molecules, which impair tumor-related angiogenesis with equal or even superior ability as compared to the single modules or their simple combinations.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27A, 43124 Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartori
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27A, 43124 Parma, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Portioli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27A, 43124 Parma, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Battistini
authors.affiliation: Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze , Viale G. B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Lido
authors.initials: L
authors.lastname: Calorini
authors.affiliation: Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze , Viale G. B. Morgagni 50, 50134 Firenze, Italy.|Centro Interdipartimentale per lo Sviluppo Preclinico dell'Imaging Molecolare (CISPIM), Università degli Studi di Firenze , Viale G. B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pupi
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27A, 43124 Parma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.affiliation: Istituto di Scienze e Tecnologie Molecolari, Consiglio Nazionale delle Ricerche , Via Golgi 19, 20133 Milano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Arosio
authors.affiliation: Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze , Viale G. B. Morgagni 50, 50134 Firenze, Italy.|Centro Interdipartimentale per lo Sviluppo Preclinico dell'Imaging Molecolare (CISPIM), Università degli Studi di Firenze , Viale G. B. Morgagni 50, 50134 Firenze, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27A, 43124 Parma, Italy.
authors.forename: Franca
authors.identifier: 0000-0001-7451-781X
authors.initials: F
authors.lastname: Zanardi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D000077210:Sunitinib; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D011758:Pyrroles; C047981:arginyl-glycyl-aspartic acid; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib