title: Click-chemistry-derived triazole ligands of arginine-glycine-aspartate (RGD) integrins with a broad capacity to inhibit adhesion of melanoma cells and both in vitro and in vivo angiogenesis.
abstract: A click chemistry approach was applied for the discovery of triazole-based arginine-glycine-aspartate (RGD) mimetics by Cu(I)-catalyzed 1,3-dipolar alkyne-azide coupling reaction, which showed binding affinity properties toward α(v)β(3)/α(v)β(5) integrins. Biological assays showed compound 18 capable of binding α(v)β(3) integrin with nanomolar affinity according to a two-sites model, and molecular modeling studies revealed a peculiar π-stacking interaction between the triazole ring and Tyr178 side chain. Accordingly, compound 18 inhibited the adhesion of integrin-expressing human melanoma cells to RGD-containing proteins of the extracellular matrix, such as vitronectin, fibronectin, and osteopontin, and also angiogenesis in in vitro and in vivo experimental models. The relevant biological effects exerted by compound 18 suggest its potential application as an antiangiogenic agent in the diagnosis and therapy of tumors where α(v)β(3) integrin expression is up-regulated.
authors.affiliation: Department of Chemistry Ugo Schiff, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Trabocchi
authors.forename: Gloria
authors.initials: G
authors.lastname: Menchi
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Cini
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchini
authors.forename: Silvia
authors.initials: S
authors.lastname: Raspanti
authors.forename: Anna
authors.initials: A
authors.lastname: Bottoncetti
authors.forename: Alberto
authors.initials: A
authors.lastname: Pupi
authors.forename: Lido
authors.initials: L
authors.lastname: Calorini
authors.forename: Antonio
authors.initials: A
authors.lastname: Guarna
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008024:Ligands; D008545:Melanoma / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D018716:Molecular Mimicry; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology*; D009842:Oligopeptides / Q000378:metabolism*; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D019030:Receptors, Vitronectin / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C553292:3-(2-(4-(3-guanidinopropyl)(1,2,3)triazol-1-yl)acetylamino)-3-phenylpropionic acid; D000480:Alkynes; D020533:Angiogenesis Inhibitors; D001386:Azides; D016326:Extracellular Matrix Proteins; D039302:Integrin alphaVbeta3; D008024:Ligands; D009842:Oligopeptides; D010666:Phenylpropionates; D019030:Receptors, Vitronectin; D014230:Triazoles; C064660:integrin alphaVbeta5; C047981:arginyl-glycyl-aspartic acid