2. Academic Validation
  3. Δ(5)-Cholenoyl-amino acids as selective and orally available antagonists of the Eph-ephrin system

Δ(5)-Cholenoyl-amino acids as selective and orally available antagonists of the Eph-ephrin system

  • Eur J Med Chem. 2015 Oct 20:103:312-24. doi: 10.1016/j.ejmech.2015.08.048.
Riccardo Castelli 1,  Massimiliano Tognolini 2,  Federica Vacondio 1,  Matteo Incerti 1,  Daniele Pala 1,  Donatella Callegari 1,  Simona Bertoni 1,  Carmine Giorgio 1,  Iftiin Hassan-Mohamed 1,  Ilaria Zanotti 1,  Antonella Bugatti 3,  Marco Rusnati 3,  Claudio Festuccia 4,  Silvia Rivara 1,  Elisabetta Barocelli 1,  Marco Mor 1,  Alessio Lodola 5
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
  • 2 Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy. Electronic address: [email protected].
  • 3 Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Viale Europa 11, 25123, Brescia, Italy.
  • 4 Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università degli Studi dell'Aquila, Via Vetoio, Coppito 2, 67100, L'Aquila, Italy.
  • 5 Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy. Electronic address: [email protected].
PMID: 26363867 DOI: 10.1016/j.ejmech.2015.08.048
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.

Keywords

Anti-angiogenic agents; Bile acids; EphA2; Eph–ephrin antagonists; Oral bioavailability; Protein–protein interaction inhibitors.

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