title: Dehydro-β-proline Containing α4β1 Integrin Antagonists: Stereochemical Recognition in Ligand-Receptor Interplay.
abstract: A novel class of dehydro-β-proline-containing peptidomimetics, designed to be effective as α4β1 integrin ligands, has been developed on the basis of the fundamental requirements for the interactions of these transmembrane receptors with bioactive ligands. Dehydro-β-proline ring has been synthesized through an original pathway, involving ring closing metathesis of a diallylamino derivative. The synthesized products showed to be effective and selective as α4β1 integrin antagonists and displayed IC50 values in the nanomolar range in cell adhesion inhibition assays and in VCAM-1-induced phosphorylation of extracellular-signal-regulated kinases. Significant activity was observed also toward the homologous integrin α4β7, while they did not display any activity toward selected members of β1, β2, and β3 families. A strong dependence on the stereochemistry of the heterocyclic central core could be observed. The great importance of α4β1 integrin in chronic inflammatory and autoimmune diseases suggests a possible exploitation of these ligands as lead compounds for therapeutic tools development.
authors.affiliation: Department of Chemistry "G. Ciamician", University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tolomelli
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna , Via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Baiula
authors.affiliation: Department of Chemistry "G. Ciamician", University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Viola
authors.affiliation: Department of Chemistry "G. Ciamician", University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ferrazzano
authors.affiliation: Department of Chemistry "G. Ciamician", University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gentilucci
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna , Via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Samantha Deianira
authors.initials: SD
authors.lastname: Dattoli
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna , Via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Santi
authors.initials: S
authors.lastname: Spampinato
authors.affiliation: Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional , Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco 07360, México.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Juaristi
authors.affiliation: Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional , Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco 07360, México.
authors.forename: Margarita
authors.initials: M
authors.lastname: Escudero
keywords: Small-molecule inhibitors; enantiomers; inflammation; integrin ligands; peptidomimetics