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

Eising, Selma; Lelivelt, Francis; Bonger, Kimberly M.

doi:10.1002/anie.201605271

Cited by 48 publications

(66 citation statements)

References 35 publications

(16 reference statements)

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“…Unstrained alkenes show low reaction rates with tetrazines, although the reaction rate can be enhanced by using electron‐donating substituents . Recently, we reported a large rate enhancement if boronic acid‐substituted alkenes were used instead of their corresponding unsubstituted alkenes in reactions with 3,6‐dipyridyl‐ s ‐tetrazines . These unstrained vinylboronic acids (VBAs) showed, depending on the substituents, second‐order rate constants ( k 2 ) up to 27 m −1 s −1 in 5 % MeOH/phosphate‐buffered saline (PBS).…”

Section: Methodsmentioning

confidence: 99%

Coordination‐Assisted Bioorthogonal Chemistry: Orthogonal Tetrazine Ligation with Vinylboronic Acid and a Strained Alkene

Eising¹,

Xin

Kleinpenning³

et al. 2018

ChemBioChem

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Bioorthogonal chemistry can be used for the selective modification of biomolecules without interfering with any other functionality that might be present. Recent developments in the field include orthogonal bioorthogonal reactions to modify multiple biomolecules simultaneously. During our research, we observed that the reaction rates for the bioorthogonal inverse-electron-demand Diels-Alder (iEDDA) reactions between nonstrained vinylboronic acids (VBAs) and dipyridyl-s-tetrazines were exceptionally higher than those between VBAs and tetrazines bearing a methyl or phenyl substituent. As VBAs are mild Lewis acids, we hypothesised that coordination of the pyridyl nitrogen atom to the boronic acid promoted tetrazine ligation. Herein, we explore the molecular basis and scope of VBA-tetrazine ligation in more detail and benefit from its unique reactivity in the simultaneous orthogonal tetrazine labelling of two proteins modified with VBA and norbornene, a widely used strained alkene. We further show that the two orthogonal iEDDA reactions can be performed in living cells by labelling the proteasome by using a nonselective probe equipped with a VBA and a subunit-selective VBA bearing a norbornene moiety.

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Section: Methodsmentioning

confidence: 99%

Coordination‐Assisted Bioorthogonal Chemistry: Orthogonal Tetrazine Ligation with Vinylboronic Acid and a Strained Alkene

Eising¹,

Xin

Kleinpenning³

et al. 2018

ChemBioChem

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“…The observed rate constant of VBA ether 6 was lower than expected as we previously observed rate enhancements of up to 100-fold compared to the unsubstituted alkene derivatives. 4 We hypothesize that the moderate rate enhancement is due to the ether on the vinylic position. Since this alcohol is slightly electron-donating, we assume that the alkene becomes more electron-rich, thereby lowering the acidity of the boronic acid, resulting in less favorable coordination to the pyridyl substituents of the tetrazine.…”

Section: Resultsmentioning

confidence: 99%

“…Our group has recently reported a new bioorthogonal tetrazine ligation utilizing vinylboronic acids (VBAs). [4][5][6][7] We showed that by introducing a boronic acid moiety on an alkene, reaction rates of an inverse electron-demand Diels-Alder (iEDDA) reaction with pyridyl-containing tetrazines improved by several orders of magnitude compared to the non-modified linear alkene. 4 The hydrophilic properties and the small size of VBAs compared to other bioorthogonal reactants make them attractive for use in biomolecular labeling experiments.…”

Section: Introductionmentioning

confidence: 99%

Vinylboronic acid-caged prodrug activation using click-to-release tetrazine ligation

et al. 2019

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Bioorthogonal reactions can be performed selectively in the presence of any biological functional group and are widely used to achieve site-selective chemical modifications of biomolecules. The click-to-release reaction is a bioorthogonal bond-cleavage variant that has gained much interest over the last few years. The bioorthogonal reaction between tetrazines and trans-cyclooctenes or vinyl ethers, for example, initiates the release of a small molecule immediately after the cycloaddition with tetrazines. Recently, our group reported that vinylboronic acids (VBAs) give exceptionally high reaction rates in the bioorthogonal inverse electrondemand Diels-Alder reaction with tetrazines that are substituted with boron-coordinating ligands. In the present study, we show that VBAs can be used in a click-to-release variant and demonstrate its bioorthogonality with a VBA-protected doxorubicin prodrug. We show that the cytotoxicity of doxorubicin is silenced by the attachment of the VBA, and activity can be largely restored upon the reaction with a tetrazine, inducing cell death. † Electronic supplementary information (ESI) available. See

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“…Introduction of a carbamate in allylic position to the double bond of a trans ‐cyclooctene allows for “click‐to‐release” reactions, opening up the possibility for targeted drug delivery . The use of vinylboronic acids can lead to high selectivity towards 2‐pyridyl or 2‐hydroxyphenyl substituted 1,2,4,5‐tetrazines, as recently shown by Bonger and co‐workers. Other bioorthogonal ligations based on aza‐Diels–Alder reactions include the 1,2,4‐triazine ligation introduced by Prescher and co‐workers and a variant of the Kondrat′eva reaction introduced by Jouanno et al.…”

Section: Introductionmentioning

confidence: 89%

Factors Controlling the Diels–Alder Reactivity of Hetero‐1,3‐Butadienes

et al. 2018

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We have quantum chemically explored the Diels–Alder reactivities of a systematic series of hetero‐1,3‐butadienes with ethylene by using density functional theory at the BP86/TZ2P level. Activation strain analyses provided physical insight into the factors controlling the relative cycloaddition reactivity of aza‐ and oxa‐1,3‐butadienes. We find that dienes with a terminal heteroatom, such as 2‐propen‐1‐imine (NCCC) or acrolein (OCCC), are less reactive than the archetypal 1,3‐butadiene (CCCC), primarily owing to weaker orbital interactions between the more electronegative heteroatoms with ethylene. Thus, the addition of a second heteroatom at the other terminal position (NCCN and OCCO) further reduces the reactivity. However, the introduction of a nitrogen atom in the backbone (CNCC) leads to enhanced reactivity, owing to less Pauli repulsion resulting from polarization of the diene HOMO in CNCC towards the nitrogen atom and away from the terminal carbon atom. The Diels–Alder reactions of ethenyl‐diazene (NNCC) and 1,3‐diaza‐butadiene (NCNC), which contain heteroatoms at both the terminal and backbone positions, are much more reactive due to less activation strain compared to CCCC.

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

Cited by 48 publications

References 35 publications

Coordination‐Assisted Bioorthogonal Chemistry: Orthogonal Tetrazine Ligation with Vinylboronic Acid and a Strained Alkene

Coordination‐Assisted Bioorthogonal Chemistry: Orthogonal Tetrazine Ligation with Vinylboronic Acid and a Strained Alkene

Vinylboronic acid-caged prodrug activation using click-to-release tetrazine ligation

Factors Controlling the Diels–Alder Reactivity of Hetero‐1,3‐Butadienes

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