Nitrogen Arylation for Macrocyclization of Unprotected Peptides

J Am Chem Soc. 2016 Jul 13;138(27):8340-3. doi: 10.1021/jacs.6b03757. Epub 2016 Jun 30.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cyclization
  • Hydrocarbons, Aromatic / chemistry*
  • Lysine / chemistry
  • Nitrogen / chemistry*
  • Peptides / chemistry*

Substances

  • Hydrocarbons, Aromatic
  • Peptides
  • Lysine
  • Nitrogen