Double-Click Strategy Combining CuAAC and (Thia-) Diels-Alder Reactions; Application towards Peptide Labeling.

Fiche publication

Date publication

juin 2025

Journal

Chemistry (Weinheim an der Bergstrasse, Germany)

Auteurs

Membres identifiés du Cancéropôle Est :
Dr BONNET Dominique

Tous les auteurs :
Maujean T, Van Wesemael C, Tual L, Le Berruyer V, Rodriguez-Noguer B, Girard N, Bonnet D, Gulea M

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/40560157

Résumé

We report an efficient double-click strategy combining copper-catalyzed azide-alkyne cycloaddition (CuAAC) with (thia-)Diels-Alder (DA) reactions, enabled by newly designed heterobifunctional platforms bearing orthogonal clickable groups: alkyne-dithioester, alkyne-maleimide, or azide-diene. These platforms were evaluated through both one-pot sequential protocols (CuAAC/DA or CuAAC/thia-DA) and three-component reactions (3CR), using model substrates with complementary functionalities. The use of a highly reactive s-cis-constrained exocyclic diene, enabled rapid cycloadditions with maleimide or phosphonodithioester dienophiles. All reactions were performed under mild, biocompatible conditions (37 °C, 1:1 H₂O/iPrOH, 1-2 h), and most afforded the desired conjugates in good isolated yields. The methodology was further validated through the successful bioconjugation of three small peptides with either a fluorophore or biotin, demonstrating its efficiency, versatility, and compatibility with biologically relevant functional groups.