Synthesis and Structure-activity Relationships of Amino Acid Conjugates of Cholanic Acid As Antagonists of the EphA2 Receptor

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2013 Oct 25

PMID 24152675

Citations 9

Authors

Simonetta Russo

Matteo Incerti

Massimiliano Tognolini

Riccardo Castelli

Daniele Pala

Iftiin Hassan-Mohamed

Carmine Giorgio

Francesca De Franco

Antimo Gioiello

Paola Vicini

Elisabetta Barocelli

Silvia Rivara

Marco Mor

Alessio Lodola

Affiliations

Soon will be listed here.

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.

Citing Articles

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Prostate Cancer Metastases Are Strongly Inhibited by Agonistic Epha2 Ligands in an Orthotopic Mouse Model.

Salem A, Gambini L, Billet S, Sun Y, Oshiro H, Zhao M Cancers (Basel). 2020; 12(10).

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Therapeutic Targeting of Pancreatic Cancer via EphA2 Dimeric Agonistic Agents.

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