Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Nat Chem Biol. 2011 Sep 25;7(11):810-7. doi: 10.1038/nchembio.664.

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

Author information

  • 1Department of Chemistry, University of California Santa Cruz, Santa Cruz, California, USA.

Abstract

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.

PMID:
21946276
[PubMed - indexed for MEDLINE]
PMCID:
PMC3210067
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Write to the Help Desk