On-Resin Synthesis and Late-Stage Functionalization of Macrocyclic Atosiban Mimetics via 5-Iodo-1,4-triazoles

We report an on-resin strategy for synthesizing 5-iodo-1,4-disubstituted-1,2,3-triazole-containing macrocyclic peptides as multifunctional disulfide bridge mimetics. Optimized Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and Suzuki–Miyaura conditions enabled late-stage arylation at the triazole 5-position. This approach offers a novel strategy for the fluorescent and biotin functionalization of peptides. Structural analysis revealed that the 5-iodo substituent influences the peptide conformation. These findings establish 5-iodo-1,4-triazoles as versatile, tunable motifs for macrocyclization and functionalization, expanding the chemical space accessible to macrocyclic peptide chemical biology tools and therapeutics.