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Review
, 21 (9), 1075-101

Click Chemistry in Complex Mixtures: Bioorthogonal Bioconjugation

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Review

Click Chemistry in Complex Mixtures: Bioorthogonal Bioconjugation

Craig S McKay et al. Chem Biol.

Abstract

The selective chemical modification of biological molecules drives a good portion of modern drug development and fundamental biological research. While a few early examples of reactions that engage amine and thiol groups on proteins helped establish the value of such processes, the development of reactions that avoid most biological molecules so as to achieve selectivity in desired bond-forming events has revolutionized the field. We provide an update on recent developments in bioorthogonal chemistry that highlights key advances in reaction rates, biocompatibility, and applications. While not exhaustive, we hope this summary allows the reader to appreciate the rich continuing development of good chemistry that operates in the biological setting.

Figures

Figure 1
Figure 1
Strategies for introducing and conjugating functionality to biomolecule targets. (A) The two-step bioorthogonal labeling strategy, in the first step exogenous functionality is introduced either genetically, metabolically or chemically, and the second step involves highly specific bioorthogonal reaction. (B) Site-specific bioconjugation based on native functionalities present in proteins.
Figure 2
Figure 2
Polar condensation reactions of carbonyl compounds.
Figure 3
Figure 3
Non-traceless and traceless Staudinger ligations.
Figure 4
Figure 4
Key features of the CuI-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. (A,B) Overall process and mechanistic overview of the CuAAC catalytic cycle. (C) Accelerating ligands commonly used in the CuAAC reaction. (D) Strategies to accelerate rates by chelation of the azide component. (E) Cu-promoted generation of reactive oxygen species. (F) Dehydroascorbic acid mediated cross-linking of protein side chains.
Figure 5
Figure 5
Strain-promoted 1,3-dipolar cycloaddition reactions useful for bioconjugation. (A) Strain-promoted azide-alkyne cycloaddition (SPAAC). (B) Common cyclooctyne reagents and associated rate constants for reaction with benzyl azide. (C,D) Side reactions of strain-promoted click chemistry reagents or products. (E) Alternative strain-promoted 1,3-dipolar cycloaddition reactions.
Figure 6
Figure 6
Strain-promoted cycloadditions of (A) azides and (B) nitriles oxides with strained alkenes; (C) quadricyclanes with a nickel complex.
Figure 7
Figure 7
Photo-induced 1,3-dipolar cycloadditions of 2,5-diaryltetrazoles and alkenes.
Figure 8
Figure 8
Examples of bioorthogonal reactions mediated by organometallic complexes.
Figure 9
Figure 9
Examples of responsive linkages enabled by bioorthogonal ligations.
Figure 10
Figure 10
Prodrug activation strategies using bioorthogonal chemistry. (A) Overall strategy. (B) Examples of traditional endogenous prodrug activation mechanisms. (C,D) Phosphine-based activation examples. (E) Activation assisted by tetrazine ligation.

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