Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor.

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.

• 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 7 Pg. 2936-47 (Apr 11 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23489211 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Lithocholic Acid
• Receptor, EphA2

Topics

• Adenocarcinoma (pathology)
• Amino Acids (chemistry)
• Enzyme-Linked Immunosorbent Assay
• Humans
• Lithocholic Acid (chemistry, pharmacology)
• Male
• Models, Molecular
• Phosphorylation
• Prostatic Neoplasms (pathology)
• Receptor, EphA2 (antagonists & inhibitors, metabolism)