MEDI 120 |
| Global conformational constraint has been successfully applied in the development of macrocyclic Grb2-SH2 domain-binding ligands. However, our recent studies have shown that the chirality of certain stereogenic centers in the backbones of ring-closing metathesis (RCM)-derived macrocycles is not crucial for high binding affinity. Accordingly, a series of compounds were designed and synthesized to systematically examine the role of secondary conformational constraint in these macrocylces. First, a nitrogen was introduced in place of the phosphotyrosine (pTyr) mimetic beta-methylene in order to alter the orientation of both the pTyr benzyl ring and the macrocycle conformation (1a). Second, the stereochemistry at the beta-methylene of the pTyr mimetic was reversed (1b). Third, the double bond resulting from RCM-derived macrocyclization was shifted (1c and 1d) or reduced (1e) in order to alter the local conformation and provide increased flexibility. The effects of these changes on binding were determined by surface plasma resonance studies measuring the direct interaction of ligand with surface-bound Grb2-SH2 domain protein.
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Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |
