A Strain-Promoted [3 + 2] Azide−Alkyne Cycloaddition for Covalent Modification of Biomolecules in Living Systems
2004/11/01 by Nicholas J. Agard, Jennifer A. Prescher, Carolyn R. Bertozzi · 2,967 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · Medicine · #Alkyne #Azide #Biochemistry #Biocompatibility #Biomolecule #Catalysis #Chemistry #Click Chemistry and Applications #Click chemistry #Combinatorial chemistry #Cycloaddition #Monoclonal and Polyclonal Antibodies Research #Organic chemistry #Protein Degradation and Inhibitors
paper · doi:10.1021/ja044996f
published in Journal of the American Chemical Society 126(46), 15046-15047 (American Chemical Society)
openalex publication_date 2004/11/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/05
Abstract
Selective chemical reactions that are orthogonal to the diverse functionality of biological systems have become important tools in the field of chemical biology. Two notable examples are the Staudinger ligation of azides and phosphines and the Cu(I)-catalyzed [3 + 2] cycloaddition of azides and alkynes ("click chemistry"). The Staudinger ligation has sufficient biocompatibility for performance in living animals but suffers from phosphine oxidation and synthetic challenges. Click chemistry obviates the requirement of phosphines, but the Cu(I) catalyst is toxic to cells, thereby precluding in vivo applications. Here we present a strain-promoted [3 + 2] cycloaddition between cyclooctynes and azides that proceeds under physiological conditions without the need for a catalyst. The utility of the reaction was demonstrated by selective modification of biomolecules in vitro and on living cells, with no apparent toxicity.
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