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

Molecules

Simonetta Russo²  Matteo Incerti²  Massimiliano Tognolini²  Riccardo Castelli²  Daniele Pala²  Iftiin Hassan-Mohamed²  Carmine Giorgio²  Francesca De Franco¹  Antimo Gioiello³  Paola Vicini²  Elisabetta Barocelli²  Silvia Rivara²  Marco Mor² 

[1] TES Pharma S.r.l., Via P. Togliatti, 20, Loc Taverne, Corciano 06073, Italy;Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze 27/A, Parma I-43124, Italy;Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1, Perugia 06123, Italy

关键词: cholanic acid;    amino acid conjugates;    EphA2 antagonists;    structure-activity relationships;   

DOI  :  10.3390/molecules181013043

来源: mdpi

【 摘 要 】

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 β-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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.