There has been a renewed interest in bioactive cyclic peptides and peptidomimetics, and new synthesis and screening technologies have enabled the discovery of potent macrocycles against a wide variety of biological targets. But while many cyclic peptides found in nature have suprisingly good cell permeability and even oral bioavailability, endowing synthetic cyclic peptides with �drug-like� permeability and pharmacokinetic properties has been relatively hit-or-miss. Cyclic peptide natural products often share a common chemical feature, backbone N-methylation, which serves to enhance lipophilicity and proteolytic stability, and our group has been interested in uncovering the relationship between N-methylation and membrane permeability.  I will present new chemical methods for the selective, on-resin N-methylation of cyclic peptides to generate compounds with improved membrane permeability. I will also show unpublished results detailing the interplay of N-methylation and side chain functionality on cell permeability in cyclic octapeptides with molecular weights over 1000.

Effect of N-methylation on pharmacokinetics of cyclic peptides: Implications for design of orally bioavailable scaffolds

245th National Meeting (2013)

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