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.
Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor / Incerti, Matteo; Tognolini, Massimiliano; Russo, Simonetta; Pala, Daniele; Giorgio, Carmine; HASSAN MOHAMED, Iftiin; Noberini, R; Pasquale, Eb; Vicini, Paola; Piersanti, Silvia; Rivara, Silvia; Barocelli, Elisabetta; Mor, Marco; Lodola, Alessio. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 56:7(2013), pp. 2936-2947. [10.1021/jm301890k]
Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor.
INCERTI, Matteo;TOGNOLINI, Massimiliano;RUSSO, Simonetta;PALA, Daniele;GIORGIO, Carmine;HASSAN MOHAMED, Iftiin;VICINI, Paola;PIERSANTI, Silvia;RIVARA, Silvia;BAROCELLI, Elisabetta;MOR, Marco;LODOLA, Alessio
2013-01-01
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.File | Dimensione | Formato | |
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