The CuI-catalyzed alkyne–azide cycloaddition as direct conjugation/cyclization method of peptides to steroids

Abstract

The CuI-catalyzed azide–alkyne 1,3-dipolar cycloaddition is implemented as a direct conjugation method of alkynyl peptides to azidosteroids, enabling the preparation of novel triazole-linked peptide–steroid conjugates in good to excellent yields. The process comprised the solution-phase synthesis of oligopeptides featuring varied chain length and amino acid sequence as well as the preparation of a small library of azidosteroids bearing the azido group either at the side chain or the steroidal nucleus. An alternative strategy relying on a sequential peptide coupling/CuAAC-based macrocyclization procedure was also developed to afford macrocyclic peptide–steroid conjugates featuring different sizes and topologies. Both methods showed great chemical efficiency and versatility, thus showing promise toward the future preparation of conjugates with potential pharmaceutical and biological applications.