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Issue 4, 2006
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Utilization of 3′-carboxy-containing tyrosine derivatives as a new class of phosphotyrosyl mimetics in the preparation of novel non-phosphorylated cyclic peptideinhibitors of the Grb2–SH2 domain

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Abstract

A new class of phosphotyrosyl (pTyr) mimetics, distinct from the conventional pTyr mimetic design of adding non-hydrolyzable acidic functionalities to the 4′-position of phenylalanine, was created by introducing carboxy-containing groups to the 3′-position of tyrosine. The effect of the chain length of the carboxy substituent was examined. Reported herein is the chiral pool synthesis of the new pTyr mimetics, and their first use in a novel non-phosphorylated Grb2–SH2 domain binding motif with the 5-amino-acid sequence Xx1-Leu-(3′-substituted-Tyr)-Ac6c-Asn. The highest affinity was exhibited by the 3-L-(2-carboxyethyl)tyrosine-containing sulfoxide-cyclized peptide 3c, with an IC50 = 1.1 µM, providing a promising new template for further development of potent Grb2–SH2 domain inhibitors with reduced charge and peptidic nature, but improved selectivity and bioavailability.

Graphical abstract: Utilization of 3′-carboxy-containing tyrosine derivatives as a new class of phosphotyrosyl mimetics in the preparation of novel non-phosphorylated cyclic peptide inhibitors of the Grb2–SH2 domain

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Publication details

The article was received on 31 Oct 2005, accepted on 06 Dec 2005 and first published on 04 Jan 2006


Article type: Paper
DOI: 10.1039/B515432D
Org. Biomol. Chem., 2006,4, 659-666

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    Utilization of 3′-carboxy-containing tyrosine derivatives as a new class of phosphotyrosyl mimetics in the preparation of novel non-phosphorylated cyclic peptide inhibitors of the Grb2–SH2 domain

    Y. Song, J. Tan, X. Luo and Y. Long, Org. Biomol. Chem., 2006, 4, 659
    DOI: 10.1039/B515432D

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