<i>N</i>‐Methyl peptides

Abstract

The natural occurrence of N ‐methyl peptides in various plant metabolites has made N ‐methylation a subtle and attractive possible modification for structure‐activity relationship studies of endogeneous peptides. However, little is known about the conformational specificity induced by the N ‐methylation of a given peptide, and particularly concerning the β‐turn conformation. A spectroscopic investigation (i.r., n.m.r., CD) and X‐ray diffraction experiments have been carried out on tBuCO‐X‐Me‐Y‐NHMe blocked dipeptides (X = Gly, L‐Ala, L‐Pro, and Y = Gly, and L‐ or D‐Ala, Leu, Phe) with reference to the homologous desmethylated species. The influence of the N ‐methylation on conformation depends to a large extent on the chirality of the X and Y residues. Homochiral sequences are the most affected, with a strong preference for the βVI‐folded conformation containing a middle cis amide bond. Heterochiral sequences are essentially unaffected and retain the βII‐folded conformation with a trans middle amide bond. Glycine‐containing sequences undergo a more complex perturbation according to the X or Y position of the Gly residue. The available data for larger N ‐methyl peptides are consistent with our observations, suggesting that these simple dipeptides well reflect the conformational perturbations induced by N ‐methylation on the β‐turn conformation.