title: Investigation of unanticipated alkylation at the N(π) position of a histidyl residue under Mitsunobu conditions and synthesis of orthogonally protected histidine analogues.
abstract: We had previously reported that Mitsunobu-based introduction of alkyl substituents onto the imidazole N(π)-position of a key histidine residue in phosphothreonine-containing peptides can impart high binding affinity against the polo-box domain of polo-like kinase 1. Our current paper investigates the mechanism leading to this N(π)-alkylation and provides synthetic methodologies that permit the facile synthesis of histidine N(π)-modified peptides. These agents represent new and potentially important tools for biological studies.
authors.affiliation: Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Qian
authors.forename: Fa
authors.initials: F
authors.lastname: Liu
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D000478:Alkylation; D018797:Cell Cycle Proteins / Q000138:chemical synthesis* / Q000737:chemistry; D004583:Electrons; D006639:Histidine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry*; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry*; D010769:Phosphothreonine / Q000138:chemical synthesis* / Q000737:chemistry*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000138:chemical synthesis* / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000138:chemical synthesis* / Q000737:chemistry; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D006639:Histidine; D007093:Imidazoles; D010455:Peptides; D010769:Phosphothreonine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1