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 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.
Highlights
The erythropoietin-producing hepatocellular carcinoma (Eph) receptors form the largest family of receptor tyrosine kinases (RTKs) and, together with their ephrin ligands, are involved in the processes of cellular communication by virtue of the membrane localization of both Eph receptors and ephrins [1]
Cholanic acid (1) and methyl ester hydrochlorides of amino acids are commercially available, while compounds 2–4, 6–9 were synthesized according to known procedures or minor modifications to those described in ref. [16] (Schemes 1 and 2)
The pivotal role of the Eph-ephrin system in tumor growth and angiogenesis makes increasingly necessary the development of pharmacological tools to better clarify the cellular functions regulated by this system, as well as to investigate the potential antitumor action resulting from the blockage of the
Summary
The erythropoietin-producing hepatocellular carcinoma (Eph) receptors form the largest family of receptor tyrosine kinases (RTKs) and, together with their ephrin ligands, are involved in the processes of cellular communication by virtue of the membrane localization of both Eph receptors and ephrins [1]. As a result of this investigation, the L-Trp conjugate of LCA (known as PCM126/UniPR126) resulted the most potent derivative, able to disrupt the EphA2-ephrin-A1 interaction with a pIC50 of 5.69 (Figure 1). LCA is a rather potent agonist of both FXR and TGR5 receptors [17,18] PCM126/UniPR126 does not interact with FXR while it is endowed with activity on TGR5 receptor in the micromolar range (data from an unpublished study). All together, these findings prompted us to prepare and characterize some α and β-amino acid conjugates of the reference EphA2 antagonist cholanic acid. The newly synthetized compounds were tested on the EphA2 receptor and the gathered SAR data were rationalized through molecular docking simulations
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