Bioorthogonal reactions

Agard NJ, Baskin JM, Prescher JA, Lo A, Bertozzi CR. A comparative study of bioorthogonal reactions with azides. ACS Chem. Biol. 2006 1 644-648. 

To date, four bioorthogonal reactions have been used to label glycans on cells and in lysates hydrazone/oxime formation with ketones, thiol alkylation with maleimides, Staudinger ligation of azides with triaryl phosphines, and copper-catalyzed or strain-promoted [3+2] cycloadditions of alkynes and azides (Figure 5) (25, 26, 32, 34, 35). While each reaction has been used extensively, most recent applications have employed azido- or alkynyl-sugars due to their superior metabolic incorporation and efficient ligations. 

Figure 5. Bioorthogonal reactions on sugars, A. Ketones react with hydrazides to give hydrazones. B. Thiols undergo Michael Reaction with maleimides. C, Azides undergo Staudinger ligation with phosphines or D. strain-promoted or copper catalyzed [3 2] cycloaddition with all nes. E. Alkynes undergo copper-catalyzed [3- 2] cycloaddition with azides.

Keywords Bioorthogonal reactions Click chemistry Biomolecule labeling 1,3-dipolar cycloaddition Diels-Alder reaction... 

The following book chapters aim to recapitulate the recent advances in bioorthogonal reactions, with a focus on 1,3-dipolar cycloadditions and Diels-Alder reactions that were particularly influential in the field. Besides cycloaddition reactions, there are other types of chemical reactions that are selective and orthogonal to natural systems and were successfully used for various applications in chemical biology. We refer readers with broader interest on the topic to excellent reviews, published recently [97-100]. 

Merkel M, Peewasan K, Arndt S, Ploschik D, Wagenknecht HA (2015) Copper-free postsynthetic labeUng of nucleic acids by means of bioorthogonal reactions. ChemBioChem 16(11) 1541-1553. doi 10.1002/cbic.201500199... 

Keywords Bioorthogonal reaction Transition metal Cycloaddition reaction CuAAC reaction Unnatural amino acids... 

Lang K, Davis L, Tones-Kolbus J, Chou C, Deiters A, Chin JW (2012) Genetically encoded norbomene directs site-specific cellular protein labelling via a rapid bioorthogonal reaction. Nat Chem 4 298-304... 

Best MD (2009) Click chemistry and bioorthogonal reactions unprecedented selectivity in the labeling of biological molecules. Biochemistry 48 6571-6584... 

Zheng M, Zheng L, Zhang P, Li J, Zhang Y (2015) Development of bioorthogonal reactions and their applications in bioconjugation. Molecules 20 3190... 

Lang K, Chin JW (2014) Bioorthogonal reactions for labeling proteins. ACS Chem Biol 9 16-20... 

To study biological pathways in living system, it is often necessary to fluorescently label the biomolecules involved in the pathway so that their movement and function can be visualized directly inside a living cell. To this end, click chemistry [1] and many other bioorthogonal reactions have been developed in the last decade and a half, and they all share the following features (1) the reactants do not interfere with the native biochemical processes inside cells (2) the reaction rate is comparable to that of a biological process, and (3) the reactants are stable and nontoxic in living cells and animals [2, 3], Major efforts have been devoted to achieve a faster reaction rate, to improve the physicochemical properties of the reactants such as size, solubility and membrane permeability, and to demonstrate the utilities of these... 

Diels-Alder (DA) reaction is one of the most useful chemical transformations. This reaction typically proceeds slowly in the absence of a catalyst, but can be accelerated with the use of Lewis acids [75], It is characterized by high yield under various conditions, has less sensitivity against solvents, and does not produce byproducts. It is characterized by high yield under various conditions, insensitive toward solvent polarity, and little byproducts. Indeed, the tetrazine/trani-cy-clooctene based inverse electron-demand DA reaction has become the most popular bioorthogonal reaction in the literature because of its fast reaction kinetics [76]— second-order rate constant as high as 2.8 x 10 s has been reported [77], So... 

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