An efficient and mild oxidant for the synthesis of s-tetrazines

Selvaraj, Ramajeyam; Fox, Joseph M.

doi:10.1016/j.tetlet.2014.07.012

Cited by 32 publications

(33 citation statements)

References 26 publications

(23 reference statements)

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“…Metal oxides MnO 2 96 and CrO 3 97 have also been explored for oxidation of dihydrotetrazines but the moderate yields and toxic chromium waste limit their applications. Other oxidants like peroxy acid, m-CPBA 98 and benzoyl peroxide 99 are being used for oxidation of dihydrotetrazines. DDQ (dichlorodicyanobenzoquinone) has recently been reported to oxidize amino dipyridinedihydrotetrazines where NaNO 2 fails.…”

Section: Synthesis Of Tetrazine Derivativesmentioning

confidence: 99%

Inverse electron demand Diels–Alder reactions in chemical biology

2017

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The emerging inverse electron demand Diels-Alder (IEDDA) reaction stands out from other bioorthogonal reactions by virtue of its unmatchable kinetics, excellent orthogonality and biocompatibility. With the recent discovery of novel dienophiles and optimal tetrazine coupling partners, attention has now been turned to the use of IEDDA approaches in basic biology, imaging and therapeutics. Here we review this bioorthogonal reaction and its promising applications for live cell and animal studies. We first discuss the key factors that contribute to the fast IEDDA kinetics and describe the most recent advances in the synthesis of tetrazine and dienophile coupling partners. Both coupling partners have been incorporated into proteins for tracking and imaging by use of fluorogenic tetrazines that become strongly fluorescent upon reaction. Selected notable examples of such applications are presented. The exceptional fast kinetics of this catalyst-free reaction, even using low concentrations of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are also discussed. Finally, IEDDA reactions have recently found use in bioorthogonal decaging to activate proteins or drugs in gain-of-function strategies. We conclude by showing applications of the IEDDA reaction in the construction of biomaterials that are used for drug delivery and multimodal imaging, among others. The use and utility of the IEDDA reaction is interdisciplinary and promises to revolutionize chemical biology, radiochemistry and materials science.

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Section: Synthesis Of Tetrazine Derivativesmentioning

confidence: 99%

Inverse electron demand Diels–Alder reactions in chemical biology

2017

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“…31 With strained trans -cyclooctenes, we have measured bimolecular rate constants as high as 3.3 × 10 6 M −1 s −1 in reactions with tetrazines (Tz), representing the fastest bioorthogonal reactions reported to date. 32,33 Tetrazines are typically synthesized through the chemical oxidation of dihydrotetrazine (DHTz) precursors, 34 and the electroactivity of tetrazines is well established. 35 Recently, Devaraj has demonstrated that electrochemistry can be used to control the redox state of pendant DHTz/Tz groups on the surface of microelectrodes, allowing selective bioconjugation to oxidized electrode surfaces.…”

Section: Introductionmentioning

confidence: 99%

Rapid Bioorthogonal Chemistry Turn-on through Enzymatic or Long Wavelength Photocatalytic Activation of Tetrazine Ligation

et al. 2016

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Rapid bioorthogonal reactivity can be induced by controllable, catalytic stimuli using air as the oxidant. Methylene blue (4 μM) irradiated with red light (660 nm) catalyzes the rapid oxidation of a dihydrotetrazine to a tetrazine thereby turning on reactivity toward trans-cyclooctene dienophiles. Alternately, the aerial oxidation of dihydrotetrazines can be efficiently catalyzed by nanomolar levels of horseradish peroxidase under peroxide-free conditions. Selection of dihydrotetrazine/tetrazine pairs of sufficient kinetic stability in aerobic aqueous solutions is key to the success of these approaches. In this work, polymer fibers carrying latent dihydrotetrazines were catalytically activated and covalently modified by trans-cyclooctene conjugates of small molecules, peptides and proteins. In addition to visualization with fluorophores, fibers conjugated to a cell adhesive peptide exhibited a dramatically increased ability to mediate contact guidance of cells.

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“…General Methods: See supporting information for full details. The synthesis and characterization of compounds 2 , 9 , 10 , 14 , 13 , 16 , 18 , and 20 – 23 were reported previously …”

Section: Methodsmentioning

confidence: 99%

“…General Methods: See supporting information for full details. The synthesis and characterization of compounds 2, [43] 9, [44] 10, [45] 14, [19] 13, 16, 18, and 20-23 were reported previously. [17] Vinylsilacyclopropane 11: The synthesis of trans-oxasilacycloheptene 11 was adapted from a reported procedure.…”

Section: Methodsmentioning

confidence: 99%