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      Highly Stable and Selective Tetrazines for the Coordination-Assisted Bioorthogonal Ligation with Vinylboronic Acids

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          Abstract

          Bioorthogonal reactions are selective transformations that are not affected by any biological functional group and are widely used for chemical modification of biomolecules. Recently, we reported that vinylboronic acids (VBAs) gave exceptionally high reaction rates in the bioorthogonal inverse electron-demand Diels–Alder (iEDDA) reaction with tetrazines bearing a boron-coordinating pyridyl moiety compared to tetrazines lacking such a substituent. In this integrated experimental and theoretical study, we show how the reaction rate of the VBA-tetrazine ligation can be accelerated by shifting the equilibrium from boronic acid to the boronate anion in the reaction mixture. Quantum chemical activation strain analyses reveal that this rate enhancement is a direct consequence of the excellent electron-donating capability of the boronate anion in which the π HOMO is pushed to a higher energy due to the net negative potential of this species. We have explored the second-order rate constants of several tetrazines containing potential VBA-coordinating hydroxyl substituents. We observed an increase in rate constants of several orders of magnitude compared to the tetrazines lacking a hydroxyl substituent. Furthermore, we find the hydroxyl-substituted tetrazines to be more selective toward VBAs than toward the commonly used bioorthogonal reactant norbornene, and more stable in aqueous environment than the previously studied tetrazines containing a pyridyl substituent.

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          Chemistry with ADF

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            Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity.

            Described is a bioorthogonal reaction that proceeds with unusually fast reaction rates without need for catalysis: the cycloaddition of s-tetrazine and trans-cyclooctene derivatives. The reactions tolerate a broad range of functionality and proceed in high yield in organic solvents, water, cell media, or cell lysate. The rate of the ligation between trans-cyclooctene and 3,6-di-(2-pyridyl)-s-tetrazine is very rapid (k2 2000 M-1 s-1). This fast reactivity enables protein modification at low concentration.
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              Left-right correlation energy

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                Author and article information

                Journal
                Bioconjug Chem
                Bioconjug. Chem
                bc
                bcches
                Bioconjugate Chemistry
                American Chemical Society
                1043-1802
                1520-4812
                06 August 2018
                19 September 2018
                : 29
                : 9
                : 3054-3059
                Affiliations
                [1] Department of Biomolecular Chemistry, and Department of Theoretical Chemistry, Institute for Molecules and Materials, Radboud University Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
                [§ ]Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling (ACMM) , De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
                Author notes
                Article
                10.1021/acs.bioconjchem.8b00439
                6148442
                30080405
                e951292e-8887-4e6b-84f6-918da123b933
                Copyright © 2018 American Chemical Society

                This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.

                History
                : 20 June 2018
                : 22 July 2018
                Categories
                Article
                Custom metadata
                bc8b00439
                bc-2018-00439k

                Biochemistry
                Biochemistry

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