title: Cyclic isoDGR and RGD peptidomimetics containing bifunctional diketopiperazine scaffolds are integrin antagonists.
abstract: The cyclo[DKP-isoDGR] peptidomimetics 2-5, containing bifunctional diketopiperazine (DKP) scaffolds that differ in the configuration of the two DKP stereocenters and in the substitution at the DKP nitrogen atoms, were prepared and examined in vitro in competitive binding assays with purified αv β3 and αv β5 integrin receptors. IC50 values ranged from low nanomolar (ligand 3) to submicromolar with αv β3 integrin. The biological activities of ligands cyclo[DKP3-RGD] 1 and cyclo[DKP3-isoDGR] 3, bearing the same bifunctional DKP scaffold and showing similar αV β3 integrin binding values, were compared in terms of their cellular effects in human U373 glioblastoma cells. Compounds 1 and 3 displayed overlapping inhibitory effects on the FAK/Akt integrin activated transduction pathway and on integrin-mediated cell infiltration processes, and qualify therefore, despite the different RGD and isoDGR sequences, as integrin antagonists. Both compounds induced apoptosis in glioma cells after 72 hour treatment.
authors.affiliation: Università degli Studi dell'Insubria, Dipartimento di Scienza e Alta Tecnologia, Via Valleggio 11, 22100 Como (Italy).
authors.forename: Silvia
authors.initials: S
authors.lastname: Panzeri
authors.forename: Simone
authors.initials: S
authors.lastname: Zanella
authors.forename: Daniela
authors.initials: D
authors.lastname: Arosio
authors.forename: Leila
authors.initials: L
authors.lastname: Vahdati
authors.forename: Alberto
authors.initials: A
authors.lastname: Dal Corso
authors.forename: Luca
authors.initials: L
authors.lastname: Pignataro
authors.forename: Mayra
authors.initials: M
authors.lastname: Paolillo
authors.forename: Sergio
authors.initials: S
authors.lastname: Schinelli
authors.forename: Laura
authors.initials: L
authors.lastname: Belvisi
authors.forename: Cesare
authors.initials: C
authors.lastname: Gennari
authors.forename: Umberto
authors.initials: U
authors.lastname: Piarulli
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D054659:Diketopiperazines / Q000737:chemistry* / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D019030:Receptors, Vitronectin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D054659:Diketopiperazines; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5
keywords: cell adhesion; drug design; drug discovery; peptidomimetics; phosphorylation