RESUMEN
We describe the development of a small-molecule mimic of Xaa-trans-Pro dipeptide in poly-l-proline type II helix conformation, based upon a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane core structure. Stereoselective synthesis of the mimic from l-pyroglutamic acid is achieved in twelve linear steps and 9.9% yield. Configurational and conformational analyses are conducted using a combination of (1)H NMR spectroscopy, X-ray crystallography and circular dichroism spectroscopy; and evaluation of the mimic as a promising surrogate dipeptide, in a protein-protein interaction between the SH3 domain of human Fyn kinase (Fyn SH3) and peptidomimetics of its biological ligand, are conducted by (1)H-(15)N HSQC NMR titration experiments.
Asunto(s)
Compuestos de Azabiciclo/síntesis química , Dipéptidos/química , Péptidos/química , Peptidomiméticos/síntesis química , Secuencia de Aminoácidos , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Cristalografía por Rayos X , Dipéptidos/síntesis química , Dipéptidos/farmacología , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Péptidos/síntesis química , Péptidos/farmacología , Peptidomiméticos/química , Peptidomiméticos/farmacología , Estructura Secundaria de Proteína , Proteínas Proto-Oncogénicas c-fyn/química , Proteínas Proto-Oncogénicas c-fyn/metabolismo , Dominios Homologos srcRESUMEN
The efficient asymmetric synthesis of unnatural alkenyl amino acids required for peptide 'stapling' has been achieved using alkylation of a fluorine-modified Ni(II) Schiff base complex as the key step.