title: Nitrogen Arylation for Macrocyclization of Unprotected Peptides.
abstract: We describe an efficient and mild method for the synthesis of macrocyclic peptides via nitrogen arylation from unprotected precursors. Various electrophiles and lysine-based nucleophiles were investigated and showed high-yielding product formation, even for a macrocyclization scan with 14 variants. We found that nitrogen-linked aryl products were more stable to base and oxidation when compared to thiol arylated species, thereby highlighting the utility of this methodology. Finally, N-aryl macrocyclization was performed on a p53 peptide inhibitor of MDM2 and resulted in identification of a nanomolar binder with improved proteolytic stability and cell permeability.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lautrette
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Fayçal
authors.initials: F
authors.lastname: Touti
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Hong Geun
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Dai
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Pentelute
mesh_terms: D000595:Amino Acid Sequence; D003500:Cyclization; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry; D009584:Nitrogen / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*
chemical_list: D006841:Hydrocarbons, Aromatic; D010455:Peptides; D008239:Lysine; D009584:Nitrogen