Δ5-Cholenoyl-amino acids as selective and orally available antagonists of the Epheephrin system

6533b82efe1ef96bd12928d0

RESEARCH PRODUCT

Δ5-Cholenoyl-amino acids as selective and orally available antagonists of the Epheephrin system

Antonella Bugatti Ilaria Zanotti Marco Rusnati Riccardo Castelli Silvia Rivara Iftiin Hassan-mohamed Daniele Pala Alessio Lodola Donatella Callegari Federica Vacondio Marco Mor Simona Bertoni Carmine Giorgio Claudio Festuccia Matteo Incerti Massimiliano Tognolini Elisabetta Barocelli

subject

Male Models Molecular Anti-angiogenic agents Angiogenesis Inhibitors Epheephrin antagonists Pharmacology EphA2 Mice Structure-Activity Relationship In vivo Cell Line Tumor Oral bioavailability Proteineprotein interaction inhibitors Drug Discovery Animals Humans Structure–activity relationship Ephrin Amino Acids Receptor Receptors Eph Family chemistry.chemical_classification Pharmacology Dose-Response Relationship Drug Molecular Structure Anti-angiogenic agents; Bile acids; EphA2; Epheephrin antagonists; Oral bioavailability; Proteineprotein interaction inhibitors; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Pharmacology Drug Discovery3003 Pharmaceutical Science Organic Chemistry Erythropoietin-producing hepatocellular (Eph) receptor Endothelial Cells Biological activity General Medicine EPH receptor A2 biological factors Bile acids Amino acid chemistry Biochemistry Ephrins

description

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.

year	journal	country	edition	language
2015-01-01

10.1016/j.ejmech.2015.08.048 http://hdl.handle.net/11379/463063