Copper-Chelating Azides for Efficient Click Conjugation Reactions in Complex Media

• Published in: Angewandte Chemie International Edition Vol. 53; no. 23; pp. 5872 - 5876
• Main Authors: Bevilacqua, Valentina, King, Mathias, Chaumontet, Manon, Nothisen, Marc, Gabillet, Sandra, Buisson, David, Puente, Céline, Wagner, Alain, Taran, Frédéric
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 02-06-2014; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Alkynes; Azides - chemistry; Biocompatibility; bioconjugation; Catalysis; Chelating; chemical biology; Chemical reactions; Click Chemistry; Complex media; Copper; Copper - chemistry; Cycloaddition; Cycloaddition Reaction; Dilution; Position (location); Reactive Oxygen Species; bioconjugation; click chemistry; copper; chemical biology
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201310671

The concept of chelation‐assisted copper catalysis was employed for the development of new azides that display unprecedented reactivity in the copper(I)‐catalyzed azide–alkyne [3+2] cycloaddition (CuAAC) reaction. Azides that bear strong copper‐chelating moieties were synthesized; these functional groups allow the formation of azide copper complexes that react almost instantaneously with alkynes under diluted conditions. Efficient ligation occurred at low concentration and in complex media with only one equivalent of copper, which improves the biocompatibility of the CuAAC reaction. Furthermore, such a click reaction allowed the localization of a bioactive compound inside living cells by fluorescence measurements.
Chelating azides were designed to form clickable copper complexes for efficient ligation with alkynes in complex biological media. Among a series of azides that bear nitrogen heterocycles, a bis(triazole) azide allowed ultra‐fast click reactions with alkynes within seconds under diluted conditions. The reactivity and stability of this copper complex enabled efficient click reactions inside living cells.