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. 2016 Sep 26;55(40):12243-7.
doi: 10.1002/anie.201605271. Epub 2016 Sep 8.

Vinylboronic Acids as Fast Reacting, Synthetically Accessible, and Stable Bioorthogonal Reactants in the Carboni-Lindsey Reaction

Selma Eising  1 , Francis Lelivelt  1 , Kimberly M Bonger  2
Affiliations

Vinylboronic Acids as Fast Reacting, Synthetically Accessible, and Stable Bioorthogonal Reactants in the Carboni-Lindsey Reaction

Selma Eising et al. Angew Chem Int Ed Engl. .

Abstract

Bioorthogonal reactions are widely used for the chemical modification of biomolecules. The application of vinylboronic acids (VBAs) as non-strained, synthetically accessible and water-soluble reaction partners in a bioorthogonal inverse electron-demand Diels-Alder (iEDDA) reaction with 3,6-dipyridyl-s-tetrazines is described. Depending on the substituents, VBA derivatives give second-order rate constants up to 27 m(-1) s(-1) in aqueous environments at room temperature, which is suitable for biological labeling applications. The VBAs are shown to be biocompatible, non-toxic, and highly stable in aqueous media and cell lysate. Furthermore, VBAs can be used orthogonally to the strain-promoted alkyne-azide cycloaddition for protein modification, making them attractive complements to the bioorthogonal molecular toolbox.

Keywords: bioorthogonal reactions; cycloadditions; protein modification; tetrazines; vinylboronic acid.

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Figures

Figure 1
Figure 1
A) Labeling of the protein of interest (POI) using the CL reaction. B) Reagents of the CL reaction. Tetrazine I, trans‐cyclooctene II, norbornene III, cyclopropene IV, N‐acylazetine V, terminal alkene VI, vinylboronic acid VII, and the borate form VIII.
Figure 2
Figure 2
The reaction of tetrazine with vinylboronic acids A) Scheme of the reaction of 3,6‐dipyridyl‐s‐tetrazine 10 with VBA 8. B) 1H NMR study of the reaction between 3,6‐dipyridyl‐s‐tetrazine 10 (▪) and VBA 8 (•). C) Proposed reaction mechanism.
Figure 3
Figure 3
Evaluation of the CL reaction with HSA functionalized with VBA probe 13. A) The structure of the molecules used for the protein modifications. B) The route used for individual HSA modification steps using 12, 13, and 16. C) Fluorescent image (top) and Coomassie stain (bottom) of SDS‐PAGE gels showing a) the individual modification steps of HSA (50 μm) as shown in B with 12, 13, and 16 (respectively 2, 10, and 10 equiv), b) the time range of the CL reaction of HSA‐VBA (50 μm) and tetrazine 16 (10 equiv), c) the stability of HSA‐VBA (0.5 μm) in cell lysate, and d) a concentration range of HSA‐VBA followed by the CL reaction with tetrazine 16 (10 equiv) in cell lysate. [a] At t=0 min, 1 % labeling is expected because a premix of fluorescent tetrazine 16 and tetrazine 10 (1000 equiv) is added.
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