Amino Acid Conjugates of Lithocholic Acid As Antagonists of the EphA2 Receptor

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2013 Mar 16

PMID 23489211

Citations 28

Authors

Matteo Incerti

Massimiliano Tognolini

Simonetta Russo

Daniele Pala

Carmine Giorgio

Iftiin Hassan-Mohamed

Roberta Noberini

Elena B Pasquale

Paola Vicini

Silvia Piersanti

Silvia Rivara

Elisabetta Barocelli

Marco Mor

Alessio Lodola

Affiliations

Soon will be listed here.

Abstract

The Eph receptor-ephrin system is an emerging target for the development of novel antiangiogenetic agents. We recently identified lithocholic acid (LCA) as a small molecule able to block EphA2-dependent signals in cancer cells, suggesting that its (5β)-cholan-24-oic acid scaffold can be used as a template to design a new generation of improved EphA2 antagonists. Here, we report the design and synthesis of an extended set of LCA derivatives obtained by conjugation of its carboxyl group with different α-amino acids. Structure-activity relationships indicate that the presence of a lipophilic amino acid side chain is fundamental to achieve good potencies. The l-Trp derivative (20, PCM126) was the most potent antagonist of the series disrupting EphA2-ephrinA1 interaction and blocking EphA2 phosphorylation in prostate cancer cells at low μM concentrations, thus being significantly more potent than LCA. Compound 20 is among the most potent small-molecule antagonists of the EphA2 receptor.

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