The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

Intramolecular N-to-O and O-to-N acyl migrations have been known for a century. Recent decades have witnessed a considerable number of applications of such chemical transformations in the fields of medicinal chemistry and peptide chemistry. The former has been focused on employing the isoacyl-mediated prodrug approach to improve the physicochemical properties of insoluble drug candidates. The latter involves multiple directions, including establishing new peptide segment ligation methods; facilitating sterically hindered amide-bond coupling; and enabling the synthesis, handling and investigation of difficult sequences. Notably, most of these cases can be achieved in a traceless manner. These successes are mainly attributed to the unique chemical and biophysical properties of the isoacyl structural motif. This review will summarize the historical achievements and highlight the recent advances in this topic.