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| - Structural Examination of Ring-Closing Metathesis-Derived15-Member Macrocycles as Grb2 SH2 Domain-Binding TetrapeptideMimetics
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| - Ring-closing metathesis (RCM) was employed to join carboxy-terminal alkenyl glycine side chains togetherwith vinyl- and allyl-functionality appended to the β-methylene of amino-terminal phosphotyrosyl (pTyr)mimetics. This required the synthesis of a variety of new pTyr mimetics, including a novel aza-containinganalogue. Many of the resulting 15-member macrocyclic tetrapeptide mimetics exhibited low nanomolarGrb2 SH2 domain-binding affinities in spite of the fact that differing ring junction stereochemistries andgeometries of the RCM-derived double bond were employed. The finding that significant latitude existsin the structural requirements for ring closure may facilitate the development of therapeutically relevantmacrocyle-based Grb2 SH2 domain-binding antagonists. The synthetic approaches used in this studymay also find application to peptide mimetics directed at other biological targets.
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