In recent years, the chemical modification of peptides has gained significant attention due to the increasing demand of peptide-based drugs. Peptide therapeutics often exhibit effective protein-target binding activity at low concentrations due to high selectivity. However, the value of peptide therapeutics is often overshadowed by their marked susceptibility to proteolytic degradation and subsequent failure to reach validated targets <i>in vivo</i>. The modification of bioactive linear peptides by cyclization has proven to be a successful strategy to address this issue. Inspired by Nature’s wide collection of modified peptides, specifically those comprising electron-rich aromatic moieties, we have developed a new strategy for the synthesis of cyclic peptides by leveraging the intrinsic reactivity of nucleophilic aromatic amino acid side chains. Due to their reactivity toward π-cloud type substrates, we have identified N-4-substituted azo reagents, namely, 1,2,4-triazoline-3,5-diones (TADs), as chemoselective electrophiles for the construction of peptide macrocycles. Here, the requisite 1,2,4-triazolidine-3,5-dione (aka urazole) moiety is readily prepared from any free amine revealed on a solid-supported peptide. Once prepared, the urazole moiety of an unprotected peptide is selectively oxidized to generate an electrophilic TAD moiety <i>in situ</i>. The reactive TAD moiety reacts chemoselectively with internal and terminal side chain nucleophiles to furnish stable peptidic macrocycles under aqueous conditions. This presentation will give an overview of recent progress concerning the development of this method wherein the TAD moiety has been successfully utilized to generate macrocyclic peptides.

Chemoselective peptide macrocyclization enabled by 1,2,4-triazoline-3,5-diones

ACS Spring 2022

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