Work

Structural Examination of Ring-Closing Metathesis-Derived 15-Member Macrocycles as Grb2 SH2 Domain-Binding Tetrapeptide Mimetics

Year: 2007

Type: article

Abstract: Ring-closing metathesis (RCM) was employed to join carboxy-terminal alkenyl glycine side chains together with vinyl- and allyl-functionality appended to the beta-methylene of amino-terminal phosphotyrosyl (pTyr) mimetics. This required the synthesis of a variety of new pTyr mimetics, including a novel aza-containing analogue. Many of the resulting 15-member macrocyclic tetrapeptide mimetics exhibited low nanomolar Grb2 SH2 domain-binding affinities in spite of the fact that differing ring junction stereochemistries and geometries of the RCM-derived double bond were employed. The finding that significant latitude exists in the structural requirements for ring closure may facilitate the development of therapeutically relevant macrocyle-based Grb2 SH2 domain-binding antagonists. The synthetic approaches used in this study may also find application to peptide mimetics directed at other biological targets.

Source: The Journal of Organic Chemistry

DOI: 10.1021/jo701831q

Authors: Fa Liu, Karen M. Worthy, Lakshman K. Bindu, Robert J. Fisher, Terrence R. Burke

Institutions: National Institutes of Health, National Cancer Institute, Center for Cancer Research

Language: English

Topic: Chemical Synthesis and Analysis

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: National Institutes of Health, National Cancer Institute

Awards: G1356092923, DCTD Computer Support, G1799052500, G9000330576