title: Δ(5)-Cholenoyl-amino acids as selective and orally available antagonists of the Eph-ephrin system.
abstract: The Eph receptor-ephrin system is an emerging target for the development of novel anti-angiogenic therapies. Research programs aimed at developing small-molecule antagonists of the Eph receptors are still in their initial stage as available compounds suffer from pharmacological drawbacks, limiting their application in vitro and in vivo. In the present work, we report the design, synthesis and evaluation of structure-activity relationships of a class of Δ(5)-cholenoyl-amino acid conjugates as Eph-ephrin antagonists. As a major achievement of our exploration, we identified N-(3β-hydroxy-Δ(5)-cholen-24-oyl)-L-tryptophan (UniPR1331) as the first small molecule antagonist of the Eph-ephrin system effective as an anti-angiogenic agent in endothelial cells, bioavailable in mice by the oral route and devoid of biological activity on G protein-coupled and nuclear receptors targeted by bile acid derivatives.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Castelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy. Electronic address: massimiliano.tognolini@unipr.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Tognolini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Incerti
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Pala
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Callegari
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Bertoni
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Giorgio
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Iftiin
authors.initials: I
authors.lastname: Hassan-Mohamed
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zanotti
authors.affiliation: Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Viale Europa 11, 25123, Brescia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bugatti
authors.affiliation: Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Viale Europa 11, 25123, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rusnati
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università degli Studi dell'Aquila, Via Vetoio, Coppito 2, 67100, L'Aquila, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy. Electronic address: alessio.lodola@unipr.it.
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D036342:Ephrins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D036081:Receptors, Eph Family / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D020533:Angiogenesis Inhibitors; D036342:Ephrins; D036081:Receptors, Eph Family
keywords: Anti-angiogenic agents; Bile acids; EphA2; Eph–ephrin antagonists; Oral bioavailability; Protein–protein interaction inhibitors