title: Synthesis and structure-activity relationships of amino acid conjugates of cholanic acid as antagonists of the EphA2 receptor.
abstract: The Eph-ephrin system plays a critical role in tumor growth and vascular functions during carcinogenesis. We had previously identified cholanic acid as a competitive and reversible EphA2 antagonist able to disrupt EphA2-ephrinA1 interaction and to inhibit EphA2 activation in prostate cancer cells. Herein, we report the synthesis and biological evaluation of a set of cholanic acid derivatives obtained by conjugation of its carboxyl group with a panel of naturally occurring amino acids with the aim to improve EphA2 receptor inhibition. Structure-activity relationships indicate that conjugation of cholanic acid with linear amino acids of small size leads to effective EphA2 antagonists whereas the introduction of aromatic amino acids reduces the potency in displacement studies. The b-alanine derivative 4 was able to disrupt EphA2-ephrinA1 interaction in the micromolar range and to dose-dependently inhibit EphA2 activation on PC3 cells. These findings may help the design of novel EphA2 antagonists active on cancer cell lines.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze 27/A, Parma I-43124, Italy. alessio.lodola@unipr.it.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Russo
authors.forename: Matteo
authors.initials: M
authors.lastname: Incerti
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Tognolini
authors.forename: Riccardo
authors.initials: R
authors.lastname: Castelli
authors.forename: Daniele
authors.initials: D
authors.lastname: Pala
authors.forename: Iftiin
authors.initials: I
authors.lastname: Hassan-Mohamed
authors.forename: Carmine
authors.initials: C
authors.lastname: Giorgio
authors.forename: Francesca
authors.initials: F
authors.lastname: De Franco
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.forename: Paola
authors.initials: P
authors.lastname: Vicini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002793:Cholic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017433:Protein Structure, Secondary; D036082:Receptor, EphA1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002793:Cholic Acids; D036082:Receptor, EphA1; D036104:Receptor, EphA2; C007036:cholanic acid