Olefin metathesis in the design and synthesis of a globally constrained Grb2 SH2 domain inhibitor.
One drawback frequently associated with olefin metathesis-mediated peptide macrocyclization, the loss of side chain functionality at sites of ring closure, may be circumvented by incorporation of side chain functionality within the ring-closing olefin segments. This approach is demonstrated in the preparation of a macrocyclic Grb2 SH2 domain antagonist designed as a conformationally constrained beta-bend mimic.
Gao
Y
Y
Laboratory of Medicinal Chemistry, DBS, NCI-FCRDC, National Institutes of Health, Frederick, MD 20892-4255, USA.
Wei
C Q
CQ
Burke
T R
TR
D048868:Adaptor Proteins, Signal Transducing; D000475:Alkenes / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D066246:ErbB Receptors / Q000737:chemistry*; D051380:GRB2 Adaptor Protein; D008968:Molecular Conformation; D011506:Proteins / Q000737:chemistry*; D012428:Ruthenium; D018909:src Homology Domains / Q000187:drug effects*
D048868:Adaptor Proteins, Signal Transducing; D000475:Alkenes; D051380:GRB2 Adaptor Protein; D011506:Proteins; D012428:Ruthenium; D066246:ErbB Receptors