title: Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor.
abstract: The Eph receptor-ephrin system is an emerging target for the development of novel antiangiogenetic agents. We recently identified lithocholic acid (LCA) as a small molecule able to block EphA2-dependent signals in cancer cells, suggesting that its (5β)-cholan-24-oic acid scaffold can be used as a template to design a new generation of improved EphA2 antagonists. Here, we report the design and synthesis of an extended set of LCA derivatives obtained by conjugation of its carboxyl group with different α-amino acids. Structure-activity relationships indicate that the presence of a lipophilic amino acid side chain is fundamental to achieve good potencies. The l-Trp derivative (20, PCM126) was the most potent antagonist of the series disrupting EphA2-ephrinA1 interaction and blocking EphA2 phosphorylation in prostate cancer cells at low μM concentrations, thus being significantly more potent than LCA. Compound 20 is among the most potent small-molecule antagonists of the EphA2 receptor.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze 27/A, I-43124 Parma, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Incerti
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Tognolini
authors.forename: Simonetta
authors.initials: S
authors.lastname: Russo
authors.forename: Daniele
authors.initials: D
authors.lastname: Pala
authors.forename: Carmine
authors.initials: C
authors.lastname: Giorgio
authors.forename: Iftiin
authors.initials: I
authors.lastname: Hassan-Mohamed
authors.forename: Roberta
authors.initials: R
authors.lastname: Noberini
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
authors.forename: Paola
authors.initials: P
authors.lastname: Vicini
authors.forename: Silvia
authors.initials: S
authors.lastname: Piersanti
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000596:Amino Acids / Q000737:chemistry*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008095:Lithocholic Acid / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000596:Amino Acids; D008095:Lithocholic Acid; D036104:Receptor, EphA2