A Strain-Promoted [3 + 2] Azide−Alkyne Cycloaddition for Covalent Modification of Biomolecules in Living Systems

TLDR

Selective chemical reactions orthogonal to biological function are key in chemical biology; while the Staudinger ligation is biocompatible yet limited by phosphine oxidation and synthesis, Cu(I)-catalyzed click chemistry avoids phosphines but is cell‑toxic. The authors present a strain‑promoted [3+2] cycloaddition between cyclooctynes and azides that proceeds under physiological conditions without a catalyst. The reaction employs a catalyst‑free, strain‑promoted cycloaddition between cyclooctynes and azides that operates at physiological conditions. The method selectively modifies biomolecules in vitro and on living cells without detectable toxicity.

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.