期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 7, 页码 2936-2947出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm301890k
关键词
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资金
- Ministero dell'Universita e della Ricerca, Futuro in Ricerca program [RBFR10FXCP]
- My First AIRC Grant [MFAG 6181]
- National Institutes of Health [CA138390]
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.
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