Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor

6533b7d1fe1ef96bd125c30d

RESEARCH PRODUCT

Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor

Matteo Incerti Elisabetta Barocelli Silvia Rivara Carmine Giorgio Massimiliano Tognolini Simonetta Russo Iftiin Hassan-mohamed Daniele Pala Alessio Lodola Antimo Gioiello Francesca De Franco Paola Vicini Marco Mor Riccardo Castelli

subject

EphA2 antagonists Stereochemistry Structure-activity relationship studies Pharmaceutical Science medicine.disease_cause Article Protein Structure Secondary Analytical Chemistry lcsh:QD241-441 Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound amino acid conjugates lcsh:Organic chemistry EphA2 anatgonists cholanic acid; amino acid conjugates; EphA2 antagonists; structure-activity relationships Cell Line Tumor Drug Discovery Aromatic amino acids medicine Humans Phosphorylation Physical and Theoretical Chemistry Receptor bile acids; EphA2 anatgonists; Structure-activity relationship studies; amino acid conjugates bile acids chemistry.chemical_classification Binding Sites Receptor EphA1 Receptor EphA2 structure-activity relationships Organic Chemistry Antagonist Cholic Acids Hydrogen Bonding EPH receptor A2 Amino acid Molecular Docking Simulation Cholanic acid cholanic acid chemistry Biochemistry Chemistry (miscellaneous)Molecular Medicine Carcinogenesis Protein Processing Post-Translational Protein Binding Conjugate

description

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.

year	journal	country	edition	language
2013-10-01	Molecules

https://doi.org/10.3390/molecules181013043