title: Development of isoxazoline-containing peptidomimetics as dual αvβ3 and α5β1 integrin ligands.
abstract: Isoxazoline-containing peptidomimetics, designed to be effective α(v)β(3) and α(5)β(1) integrin ligands, were synthesized through an original procedure involving N,O-bis(trimethylsilyl)hydroxyamine conjugate addition to alkylidene acetoacetates, followed by intramolecular hemiketalization. To mimic the RGD recognition sequence, basic and acidic terminal appendages were introduced, and the final products were tested in cell adhesion inhibition assays. All the synthesized compounds proved to be excellent ligands for both integrin receptors, and a strong influence on intracellular signaling and phosphorylation pathways was demonstrated by evaluation of fibronectin-induced phosphorylation of ERK. The molecular basis of the observed inhibitory activity was suggested on the results of docking experiments.
authors.affiliation: Department of Chemistry G. Ciamician, University of Bologna, Via Selmi 2, 40126 Bologna, Italy. alessandra.tolomelli@unibo.it
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tolomelli
authors.forename: Luca
authors.initials: L
authors.lastname: Gentilucci
authors.forename: Elisa
authors.initials: E
authors.lastname: Mosconi
authors.forename: Angelo
authors.initials: A
authors.lastname: Viola
authors.forename: Samantha Deianira
authors.initials: SD
authors.lastname: Dattoli
authors.forename: Monica
authors.initials: M
authors.lastname: Baiula
authors.forename: Santi
authors.initials: S
authors.lastname: Spampinato
authors.forename: Laura
authors.initials: L
authors.lastname: Belvisi
authors.forename: Monica
authors.initials: M
authors.lastname: Civera
mesh_terms: D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D003198:Computer Simulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007555:Isoxazoles / Q000737:chemistry*; D008024:Ligands; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D057786:Peptidomimetics; D010766:Phosphorylation; D017434:Protein Structure, Tertiary
chemical_list: D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D007555:Isoxazoles; D008024:Ligands; D009842:Oligopeptides; D057786:Peptidomimetics; C047981:arginyl-glycyl-aspartic acid; D048049:Extracellular Signal-Regulated MAP Kinases