AI Article Synopsis
- - Ring-closing metathesis (RCM) was used to link specific side chains in new pTyr mimetics, including a unique aza-containing version, to create macrocyclic tetrapeptides.
- - The resulting 15-member macrocyclic mimetics showed strong binding affinities for the Grb2 SH2 domain, indicating that variations in ring structure can still lead to effective interactions.
- - These findings suggest that understanding the structural flexibility of ring closure could aid in designing new drugs targeting Grb2 SH2 domain antagonists and potentially other biological targets.
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533429 | PMC |
| http://dx.doi.org/10.1021/jo701831q | DOI Listing |
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