On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds

Nat Chem Biol. 2011 Sep 25;7(11):810-7. doi: 10.1038/nchembio.664.


Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biological Availability
  • Chemistry, Pharmaceutical
  • Combinatorial Chemistry Techniques
  • Computer Simulation
  • Drug Discovery / methods
  • Male
  • Methylation
  • Molecular Structure
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / metabolism*
  • Peptides, Cyclic / pharmacokinetics*
  • Rats
  • Structure-Activity Relationship


  • Peptides, Cyclic

Associated data

  • PubChem-Substance/125240910
  • PubChem-Substance/125240911
  • PubChem-Substance/125240912
  • PubChem-Substance/125240913
  • PubChem-Substance/125240914
  • PubChem-Substance/125240915
  • PubChem-Substance/125240916
  • PubChem-Substance/125240917
  • PubChem-Substance/125240918
  • PubChem-Substance/125240919