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N-Methylated Amino Acids for Preparing Peptides with Enhanced Proteolytic Stability

Substitution of natural amino acids by the corresponding N-methyl amino acids is an important strategy for improving the pharmacokinetic properties of bioactive peptides. N-methylation dramatically increases the proteolytic stability of amide bonds, increasing in vivo half life and intestinal permeability of peptides.

Backbone methylation can also dramatically increase peptide solubility by reducing interchain aggregation, and can be used to enhance the propensity of the peptide to adopt turn conformations with a cis-amide bond.

Introduction of these derivatives is best achieved using HATU/DIPEA. Preactivation times should be kept to a minimum to avoid racemization. For peptides incorporating contiguous N-methyl amino acids the triphosgene coupling method of Gilon has been found effective.

Fmoc-N-Me-Cys(Trt)-OH has been used as a tool to prepare peptide thioesters.Under acidic conditions, the residue attached to the amino group of N-methylcysteine can migrate to the cysteinyl thiol group, resulting in the formation of a peptide thioester. This N- to S-migration can be reversed by dissolution of the peptide in pH 8 buffer. Addition of a thiol compound to an acidic solution of the peptide will result in cleavage at the N-methylcysteine with formation of a peptide thioester derived from the N-terminal fragment.

Fmoc-N-Me-His(Trt)-OH is poorly soluble in DMF or NMP. However, it does dissolve upon activation with HBTU/DIPEA.

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