title: Neighbor-directed histidine N (τ)-alkylation: A route to imidazolium-containing phosphopeptide macrocycles.
abstract: Our recently discovered, selective, on-resin route to N(τ)-alkylated imidazolium-containing histidine residues affords new strategies for peptide mimetic design. In this, we demonstrate the use of this chemistry to prepare a series of macrocyclic phosphopeptides, in which imidazolium groups serve as ring-forming junctions. Interestingly, these cationic moieties subsequently serve to charge-mask the phosphoamino acid group that directed their formation. Neighbor-directed histidine N(τ)-alkylation opens the door to new families of phosphopeptidomimetics for use in a range of chemical biology contexts.
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, 21702.
authors.forename: Wen-Jian
authors.initials: WJ
authors.lastname: Qian
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: Department of Biology and Biological Engineering, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139.
authors.forename: Robert
authors.initials: R
authors.lastname: Grant
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, 21702.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lai
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, 21702.
authors.forename: James A
authors.initials: JA
authors.lastname: Kelley
authors.affiliation: Department of Biology and Biological Engineering, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yaffe
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892.
authors.forename: Kyung S
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, 21702.
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D000478:Alkylation; D018360:Crystallography, X-Ray; D006639:Histidine / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry*; D047028:Macrocyclic Compounds / Q000737:chemistry*; D010748:Phosphopeptides / Q000737:chemistry*
chemical_list: D007093:Imidazoles; D047028:Macrocyclic Compounds; D010748:Phosphopeptides; D006639:Histidine
keywords: Plk1; cationic dialkyl histidine; crystal structure; peptide macrocycles, phosphopeptides; polo kinase; polo-box domain