Steric impact of aza-amino acid on solid-phase aza-peptide bond synthesis

Abstract

Aza-peptides are metabolically more stable in living organisms than their parent peptides. Despite the properties of these peptidomimetics as promising drug leads, synthesizing them is challenging and, therefore, their biological activity has been studied relatively little. Previously, we determined that the steric hindrance of the side group of an activated amino acid coupled to the semicarbazide moiety of an aza-amino acid contributes to a decreased rate of formation of the aza-peptide bond. In the current work, we identified the influence of aza-amino acid side chain bulkiness for the synthesis of a model aza-peptide, H-Ala-AzAA-Phe-NH2, using COMU as a coupling reagent. The results indicated that the aza-amino acid steric hindrance controls the aza-peptide bond formation reaction rate and yield. This effect was found to be more substantial than the influence of the amino acid coupled to the semicarbazide moiety. While the rate of the reaction of activated Ala with the N-terminus of AzGly was found to be comparable with the rates of typical peptide bond formation reactions, the reaction with the sterically most demanding AzVal did not proceed at all when COMU was used as an activator.