title: Antiangiogenic effect of dual/selective alpha(5)beta(1)/alpha(v)beta(3) integrin antagonists designed on partially modified retro-inverso cyclotetrapeptide mimetics.
abstract: Recent evidence highlighted the role of alpha(5)beta(1) integrin in angiogenesis and in regulating alpha(v)beta(3) integrin function. As a consequence, selective alpha(5)beta(1) integrin inhibitors or dual alpha(5)beta(1)/alpha(v)beta(3) integrin inhibitors are considered promising candidates for the development of cancer therapeutic agents. In this paper, we describe the synthesis and pharmacological characterization of a minilibrary of cyclotetrapeptide mimetics containing a PMRI Arg-Gly-Asp sequence. In particular, c[(R)-betaPhepsi(NHCO)Asppsi(NHCO)Gly-Arg] (3) displayed a good activity in inhibiting the alpha(v)beta(3) integrin-mediated cell adhesion of fibronectin or vitronectin, as well as the adhesion of fibronectin to the alpha(5)beta(1) integrin. Interestingly, the diastereomeric compound c[(S)-betaPhepsi(NHCO)Asppsi(NHCO)Gly-Arg] (2) maintained a good efficacy in inhibiting alpha(5)beta(1) integrin while gaining a certain selectivity over alpha(v)beta(3) integrin. These two integrin antagonists significantly inhibited bFGF-induced human endothelial cell tube formation at submicromolar concentrations. Conformational analysis and Molecular Docking calculations suggest that the different alpha(5)beta(1) versus alpha(v)beta(3) selectivity of 2 and 3 can be rationalized on the basis of the alternative display of the aromatic side chain adjacent to Asp.
authors.affiliation: Department of Chemistry "G. Ciamician", Universita degli Studi di Bologna, via Selmi 2, 40126 Bologna, Italy. luca.gentilucci@unibo.it
authors.forename: Luca
authors.initials: L
authors.lastname: Gentilucci
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cardillo
authors.forename: Santi
authors.initials: S
authors.lastname: Spampinato
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tolomelli
authors.forename: Federico
authors.initials: F
authors.lastname: Squassabia
authors.forename: Rossella
authors.initials: R
authors.lastname: De Marco
authors.forename: Andrea
authors.initials: A
authors.lastname: Bedini
authors.forename: Monica
authors.initials: M
authors.lastname: Baiula
authors.forename: Laura
authors.initials: L
authors.lastname: Belvisi
authors.forename: Monica
authors.initials: M
authors.lastname: Civera
mesh_terms: D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008956:Models, Chemical; D008968:Molecular Conformation; D018716:Molecular Mimicry; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D019151:Peptide Library; D010456:Peptides, Cyclic; D016222:Fibroblast Growth Factor 2