title: Synthesis and evaluation of a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane scaffold as a mimic of Xaa-trans-Pro in poly-L-proline type II helix conformation.
abstract: 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.
authors.affiliation: Chemistry, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, SO17 1BJ, UK. S.Bloodworth@soton.ac.uk.
authors.forename: Boris
authors.initials: B
authors.lastname: Aillard
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Kilburn
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Blaydes
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Tizzard
authors.forename: Stuart
authors.initials: S
authors.lastname: Findlow
authors.forename: Jörn M
authors.initials: JM
authors.lastname: Werner
authors.forename: Sally
authors.initials: S
authors.lastname: Bloodworth
mesh_terms: D000595:Amino Acid Sequence; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D051076:Proto-Oncogene Proteins c-fyn / Q000737:chemistry / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D053961:Azabicyclo Compounds; D004151:Dipeptides; D010455:Peptides; D057786:Peptidomimetics; C011083:polyproline; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn