Convenient preparation of deuterium‐labeled analogs of peptides containing N ‐substituted glycines for a stable isotope dilution LC‐MS quantitative analysis

N ‐substituted glycines constitute mimics of natural amino acids that are of great interest in the peptide‐based drug development. Peptoids‐oligo( N ‐substituted glycines) have been recently demonstrated to be highly active peptidomimetics in biological systems, resistant to proteolytic degradation. We developed a method of the deuterium labeling of peptidomimetics containing N ‐substituted glycine residues via H/D exchange of their α ‐carbon hydrogen atoms. The labeling was shown to be easy, inexpensive, and without the use of derivatization reagents or the need for a further purification. The deuterons introduced at the α ‐carbon atoms do not undergo a back exchange under acidic conditions during liquid chromatography mass spectrometry (LC‐MS) analysis. The LC‐MS analysis of a mixture of isotopologues revealed a co‐elution of deuterated and nondeuterated forms of the peptidomimetics, which may be useful in the quantitative isotope dilution analysis of peptoids and other derivatives of N ‐substituted glycines. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.