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

作者：Incerti Matteo; Tognolini Massimiliano^*; Russo Simonetta; Pala Daniele; Giorgio Carmine; Hassan Mohamed Iftiin; Noberini Roberta; Pasquale Elena B; Vicini Paola; Piersanti Silvia; Rivara Silvia; Barocelli Elisabetta; Mor Marco; Lodola Alessio

来源：Journal of Medicinal Chemistry, 2013, 56(7): 2936-2947.

DOI：10.1021/jm301890k

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 (5 beta)-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 a-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 mu M concentrations, thus being significantly more potent than LCA. Compound 20 is among the most potent small-molecule antagonists of the EphA2 receptor.

• 出版日期2013-4-11