Orthogonal bioorthogonal chemistries

Patterson, David M.; Prescher, Jennifer A.

doi:10.1016/j.cbpa.2015.07.006

Cited by 126 publications

(129 citation statements)

References 79 publications

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“…3,4,6–8,17 Strain-activation—also termed distortion-acceleration 18 —has provided reagents for chemical biology, but those reagents have little selectivity between diazo and azido dipoles. 5 Although increased reactivity does not necessarily imply an inherent loss of selectivity, 19 retaining selectivity while increasing reactivity requires a thorough understanding of those factors that lead to increased reaction rates.…”

Section: Resultsmentioning

confidence: 99%

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Decreasing Distortion Energies without Strain: Diazo-Selective 1,3-Dipolar Cycloadditions

2016

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The diazo group has attributes that complement those of the azido group for applications in chemical biology. Here, we use computational analyses to provide insights into the chemoselectivity of the diazo group in 1,3-dipolar cycloadditions. Dipole distortion energies are responsible for ~80% of the overall energetic barrier for these reactions. Here, we show that diazo compounds, unlike azides, provide an opportunity to decrease that barrier substantially without introducing strain into the dipolarophile. The ensuing rate-enhancement is due to the greater nucleophilic character of a diazo group compared to that of an azido group, which can accommodate decreased distortion energies without pre-distortion. The tuning of distortion energies with substituents in a diazo compound or dipolarophile can enhance reactivity and selectivity in a predictable manner. Notably, these advantages of diazo groups are amplified in water. Our findings provide a theoretical framework that can guide the design and application of both diazo compounds and azides in “orthogonal” contexts, especially for biological investigations.

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Section: Resultsmentioning

confidence: 99%

“…In this regard, the diazo group is poised for application in chemical biology to meet the rising demand for “orthogonal–bioorthogonal” reactions in bioconjugation and chemical reporter strategies. 3 …”

Section: Resultsmentioning

confidence: 99%

Decreasing Distortion Energies without Strain: Diazo-Selective 1,3-Dipolar Cycloadditions

2016

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“…1f,8,9 However, many of the available chemistries are limited by their slow kinetics, the need for toxic catalysts, or a lack of compatibility with other chemistries to allow the simultaneous attachment of multiple distinct entities at different sites. 10 Consequently, there is continued interest in additional genetically encoded chemical functionalities that can be rapidly and chemoselectively labeled using catalyst-free conjugation reactions, and that are also compatible with other available chemistries to allow concurrent labeling at multiple sites.…”

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A Chemoselective Rapid Azo-Coupling Reaction (CRACR) for Unclickable Bioconjugation

et al. 2017

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Chemoselective modification of complex biomolecules has become a cornerstone of chemical biology. Despite the exciting developments of the past two decades, the demand for new chemoselective reactions with unique abilities, and those compatible with existing chemistries for concurrent multisite-directed labeling, remains high. Here we show that 5-hydroxyindoles exhibit remarkably high reactivity toward aromatic diazonium ions and this reaction can be used to chemoselectively label proteins. We have previously genetically encoded the noncanonical amino acid 5-hydroxytryptophan in both E. coli and eukaryotes, enabling efficient site-specific incorporation of 5-hydroxyindole into virtually any protein. The 5-hydroxytryptophan residue was shown to allow rapid, chemoselective protein modification using the azocoupling reaction, and the utility of this bioconjugation strategy was further illustrated by generating a functional antibody–fluorophore conjugate. Although the resulting azo-linkage is otherwise stable, we show that it can be efficiently cleaved upon treatment with dithionite. Our work establishes a unique chemoselective “unclickable” bioconjugation strategy to site-specifically modify proteins expressed in both bacteria and eukaryotes.

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“…[%] [c] 3/3' [c] tions,t he possibility of using both annulations in tandem in one pot is certainly promising. [27] Finally,a nd importantly,w ef ound that the RuAtACc an also be carried in the presence of bacteria (E. coli)w ithout compromising their viability.T herefore,i ncubation of PBS containing Ec oli with 1a (1 mm), 2a (2 mm), and Cp*Ru-(cod)Cl (100 mm)l ed to ar apid increase in the fluorescence. After 24 hours,centrifugation and analysis in aplate reader of both the extracellular supernatant and the methanol/water (8:2) extracts of the resulting bacteria pellet showed ac ombined increase in fluorescence of eight times with respect to controls (see Figure S29).…”

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confidence: 99%

“…[27] Gratifyingly, the engineered diyne 4 was quantitatively converted into the bis(triazole) 5,w ithout cross-reactivity,b yp erforming aC uAACw ith the dansyl azide 1f,a nd subsequent in situ addition of the ruthenium catalyst and the anthracenyl azide 1a (1 equiv with respect to thioalkyne;Scheme 2). Considering the scarcity of mutually compatible bioorthogonal reac- [a]…”

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Ruthenium‐Catalyzed Azide–Thioalkyne Cycloadditions in Aqueous Media: A Mild, Orthogonal, and Biocompatible Chemical Ligation

et al. 2017

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The development of efficient metal-promoted bioorthogonal ligations remains as am ajor scientific challenge. Demonstrated herein is that azides undergo efficient and regioselective room-temperature annulations with thioalkynes in aqueous milieu when treated with catalytic amounts of asuitable ruthenium complex. The reaction is compatible with different biomolecules,a nd can be carried out in complex aqueous mixtures such as phosphate buffered saline,c ell lysates,f etal bovine serum, and even living bacteria (E. coli). Importantly,t he reaction is mutually compatible with the classical CuAAC.The copper-catalyzed azide-alkyne cycloaddition (CuAAC), paradigm of "click" chemistry, [1] can be considered among the most relevant chemical transformations discovered in the last decades,w ith countless applications in many areas of science.[2] Theb iological relevance of this reaction stems from its robustness and compatibility with aqueous media, as well as from its good bioorthogonality.[3] However,t he transformation still presents important limitations.T hus,i n addition to being fairly incompatible with thiols,the reaction is essentially restricted to terminal alkynes,aconsequence of am echanism which requires the formation of copper acetylide intermediates (Scheme 1a). An important additional drawback has to do with the side reactivity and toxicity of copper ions in biological contexts.[4] Furthermore,toreach efficient conversions in typically diluted biological settings, the reactive copper(I) species need to be generated in situ using excess amounts of ac opper(II) source and sodium ascorbate,areductant which is not innocent in biological contexts.[5] These issues have been partially addressed by using copper-stabilizing ligands which enhance the biocompatibility and kinetic of the reactions. [6,7] Copper-free,s trainpromoted annulations have been shown to be an efficient alternative, [8] however, these reactions also present limitations associated to the side-reactivity of the reactants.T herefore,the development of new bioorthogonal and biocompatible reactions which address some of the above limitations remains as amajor challenge. [9] In particular, the discovery of robust and aqueous-compatible metal-catalyzed annulations, as alternatives to the CuAAC, represents ah ighly appealing goal. [10] Several azide-alkyne cycloadditions using metals other than copper have been described in recent years, [11] but only the ruthenium variant (RuAAC) [12] has shown am eaningful scope (Scheme 1b). [13] In contrast to the CuAAC, which encompasses dinuclear copper intermediates such as I and II, [14] the ruthenium-promoted reaction involves intermediate species like III,w hich evolve into IV by oxidative cyclometalation, and eventually to the triazole products.[15] In keeping with this scenario,the RuAAC, essentially developed in organic solvents,t olerates disubstituted alkynes but can produce mixtures of regioisomers.Probably,the notion that it is not compatible with water and air atmospheres has precluded more ...

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Orthogonal bioorthogonal chemistries

Cited by 126 publications

References 79 publications

Decreasing Distortion Energies without Strain: Diazo-Selective 1,3-Dipolar Cycloadditions

Decreasing Distortion Energies without Strain: Diazo-Selective 1,3-Dipolar Cycloadditions

A Chemoselective Rapid Azo-Coupling Reaction (CRACR) for Unclickable Bioconjugation

Ruthenium‐Catalyzed Azide–Thioalkyne Cycloadditions in Aqueous Media: A Mild, Orthogonal, and Biocompatible Chemical Ligation

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