Design and Synthesis of Highly Reactive Dienophiles for the Tetrazine–<i>trans-</i>Cyclooctene Ligation

Taylor, Michael T.; Blackman, Melissa L.; Dmitrenko, Olga; Fox, Joseph M.

doi:10.1021/ja201844c

Cited by 329 publications

(365 citation statements)

References 51 publications

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“…4b). Inspired by the work of Dommerholt et al 96 , it was found that trans-bicyclononene reacted at yet faster rates (while noting the caveats on rate determinations given above) 103 . In addition to allowing labelling of highly dynamic processes, such rapid and efficient reactions allow the concentrations of reactive partners to be lowered significantly, reducing background labelling particularly in cases where it is REVIEW implausible to wash away excess reagent, such as intracellularly or in animal models 104 .…”

Section: Review Nature Communications | Doi: 101038/ncomms5740mentioning

confidence: 99%

Selective chemical protein modification

2014

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Section: Review Nature Communications | Doi: 101038/ncomms5740mentioning

confidence: 99%

Selective chemical protein modification

2014

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“…This process was reported to take place via aminal formation as confirmed by 1 H-NMR. 13 Concise information on isomerisation from 3 to 4 as well as on the final oxidation step in terms of a systematic study is still missing. This may be the case due to two reasons: firstly, the initial [4+2] cycloaddition was identified to be the rate determining step and thus further reaction steps were neglected.…”

Section: Mechanismmentioning

confidence: 99%

Inverse electron demand Diels–Alder (iEDDA)-initiated conjugation: a (high) potential click chemistry scheme

2013

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Inverse electron demand Diels-Alder reactions (iEDDA) between 1,2,4,5-tetrazines and olefins have emerged into a state-of-the art concept for the conjugation of biomolecules. Now, this reaction is also increasingly being applied in polymer science and materials science. The orthogonality of this exciting reaction to other well-established click chemistry schemes, its high reaction speed and its biocompatibility are key features of iEDDA making it a powerful alternative to existing ligation chemistries. The intention of this tutorial review is to introduce the reader to the fundamentals of inverse electron demand Diels-Alder additions and to answer the question whether iEDDA chemistry is living up to the criteria for a ''click'' reaction and can serve as a basis for future applications in postsynthetic modification of materials. Key learning points(1) Electron-rich dienophiles and electron-poor dienes (e.g. tetrazines) react in an inverse electron demand Diels-Alder reaction (iEDDA).(2) iEDDA fulfils Sharpless' criteria for a ''click'' reaction while offering advantages over already established ''click'' chemistry schemes.

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“…However, many of these derivatives have low water solubility, require complex multistep synthesis, and possess suboptimal kinetics. Our search for alternative rapid, selective, and chemically accessible coupling reactions without need for a catalyst led us and others to investigate the [4 þ 2] inverse Diels-Alder cycloaddition (10)(11)(12)(13). We realized that this set of chemistries is more uniquely suited to biological applications and may indeed represent a universal platform technology ( Fig.…”

mentioning

confidence: 99%

Reactive polymer enables efficient in vivo bioorthogonal chemistry

Devaraj

Thurber

Keliher

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

179

187

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There has been intense interest in the development of selective bioorthogonal reactions or "click" chemistry that can proceed in live animals. Until now however, most reactions still require vast surpluses of reactants because of steep temporal and spatial concentration gradients. Using computational modeling and design of pharmacokinetically optimized reactants, we have developed a predictable method for efficient in vivo click reactions. Specifically, we show that polymer modified tetrazines (PMT) are a key enabler for in vivo bioorthogonal chemistry based on the very fast and catalyst-free [4 þ 2] tetrazine/trans-cyclooctene cycloaddition. Using fluorescent PMT for cellular resolution and 18 F labeled PMT for whole animal imaging, we show that cancer cell epitopes can be easily reacted in vivo. This generic strategy should help guide the design of future chemistries and find widespread use for different in vivo bioorthogonal applications, particularly in the biomedical sciences.in vivo chemistry | pharmacokinetics | PET imaging | intravital microscopy | pretargeting T he ability to perform selective chemistries in living systems such as single cells, 3D cultures, invertebrates, or mammals would have far reaching applications in tracking biomolecules, designing new therapeutic approaches, and in visualizing medically relevant biomarkers. To date, only a few practical bioorthogonal reactions have been reported, the most popular being the Staudinger ligation and the [3 þ 2] cycloaddition "click" reaction between azides and alkynes (1, 2). The latter click reaction involves copper(I) catalyzed coupling of an azide and terminal alkyne to generate a stable triazole (2). Until recently, the necessity of the copper catalyst precluded use of this reaction in biological systems due to toxicity concerns (3, 4). Bertozzi and others elegantly solved this problem by developing several new ring strained dienophile derivatives that do not require catalysts (5-9). However, many of these derivatives have low water solubility, require complex multistep synthesis, and possess suboptimal kinetics. Our search for alternative rapid, selective, and chemically accessible coupling reactions without need for a catalyst led us and others to investigate the [4 þ 2] inverse Diels-Alder cycloaddition (10-13). We realized that this set of chemistries is more uniquely suited to biological applications and may indeed represent a universal platform technology ( Fig. 1 A and B). Specifically we and others have shown that the cycloaddition between tetrazine (Tz) and trans-cyclooctene (TCO) can proceed orders of magnitude faster than previously studied azide and alkyne click reactions and importantly does not require the action of a catalyst. This reaction has also been adapted for single cell imaging using newer fluorogenic Tz probes (14).Although initial work focused on in vitro labeling there has been a surge of recent work applying this reaction for various in vivo applications (15-17). Despite the above progress, our results with initial TCO...

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Design and Synthesis of Highly Reactive Dienophiles for the Tetrazine–trans-Cyclooctene Ligation

Cited by 329 publications

References 51 publications

Selective chemical protein modification

Selective chemical protein modification

Inverse electron demand Diels–Alder (iEDDA)-initiated conjugation: a (high) potential click chemistry scheme

Reactive polymer enables efficient in vivo bioorthogonal chemistry

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