Tetrazine‐Responsive Self‐immolative Linkers

Neumann, Kevin; Jain, Sarthak; Gambardella, Alessia; Walker, Sarah E.; Valero, Elsa; Lilienkampf, Annamaria; Bradley, Mark

doi:10.1002/cbic.201600560

Cited by 47 publications

(51 citation statements)

References 36 publications

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“…All this leads to an efficient prodrug system, while the water acceleration effect remains substantial . Thus, linking doxorubucin through a vinyl ether‐based, self‐immolative (safety‐catch) linker to a polymer backbone allowed generation of an amphiphilic block‐copolymer (DOX‐ b ‐PEG) and formation of tetrazine‐responsive polymeric nanoparticles (Scheme ) . This new concept of using tetrazines as a small‐molecule trigger was validated in in vitro studies using HEK and PC3 cells; a selective switch‐on of cytotoxicty upon triggering with tetrazines was observed.…”

Section: Tetrazines As Activators For Prodrugsmentioning

confidence: 99%

“…[20] After Devaraj reported vinyl ether as as uitable bioorthogonal dienophile for DA INV , [21] our group and that of Bernardes independently reported tetrazine-responsive prodrug systems that use vinyl ether masking of phenols( Scheme 1B). [22,23] Vinyl ethers are rapidly incorporated onto phenols by readily scalable methods and are bench stable andb iocompatible, thus overcoming someo ft he disadvantages of the previouslyr eported TCO moiety.H owever,t heir rates in the DA INV reaction are several orders of magnitude lower than those of TCO (k 2 = 7.2 10 À4 m À1 s À1 ), [21] although in vitro resultsh aved emonstrated their high stabilities and biocompatibility.A ll this leads to an efficient prodrug system,w hile the water acceleration effect remains substantial. [5] Thus, linking doxorubucin through a vinyl ether-based, self-immolative( safety-catch) linker to a polymer backbone allowed generation of an amphiphilic block-copolymer (DOX-b-PEG) and formation of tetrazine-responsivep olymericn anoparticles (Scheme 2).…”

Section: Tetrazines As Activators For Prodrugsmentioning

confidence: 99%

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The Emerging Role of Tetrazines in Drug‐Activation Chemistries

2019

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Traditionally, prodrug activation has been limited to enzymatic triggers or gross physiological aberrations, such as pH, that offer low selectivity and control over dosage. In recent years, the field of prodrug activation chemistry has been transformed by the use of bioorthogonal reactions that can be carried out under biological conditions at sub‐millimolar concentrations, with the tetrazine‐mediated inverse electron demand Diels–Alder reaction amongst the most recognised. Their high reaction rates, chemoselectivity and excellent biocompatibility make tetrazines ideal small molecules for activating prodrugs. Recently the tetrazine moiety has been used as a prodrug for a pyridazine thus broadening the scope of prodrug systems. This article discusses the concept of using tetrazines as small‐molecule activators for prodrugs, and provides an overview of tetrazine‐based prodrug systems, with a particular focus on the recently reported prodrug–prodrug activation strategy.

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Section: Tetrazines As Activators For Prodrugsmentioning

confidence: 99%

Section: Tetrazines As Activators For Prodrugsmentioning

confidence: 99%

The Emerging Role of Tetrazines in Drug‐Activation Chemistries

2019

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“…[54] Finally,d AC and related drugs could be modified with photoswitches that regulate bioactivity through photo-isomerable conformation changes rather than photolysis. [61][62][63] In the case of thicker tissues or organs, high-wavelength photocages active in the optical window need to be devised. Areas of interest include regenerative medicine, [55] developmental biology, [4] development and progression of cancer, [56] and the development of therapeutic routes [18,38,[57][58][59] to treat surface-accessible tissues.…”

Section: Angewandte Chemiementioning

confidence: 99%

A Photo‐responsive Small‐Molecule Approach for the Opto‐epigenetic Modulation of DNA Methylation

et al. 2019

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Controlling the functional dynamics of DNAwithin living cells is essential in biomedical research. Epigenetic modifications such as DNAmethylation play akey role in this endeavour.D NA methylation can be controlled by genetic means.Y et there are few chemical tools available for the spatial and temporal modulation of this modification. Herein, we present as mall-molecule approach to modulate DNAm ethylation with light. The strategy uses aphoto-tuneable version of ac linically used drug (5-aza-2'-deoxycytidine) to alter the catalytic activity of DNAmethyltransferases,the enzymes that methylate DNA. After uptake by cells,t he photo-regulated molecule can be light-controlled to reduce genome-wide DNA methylation levels in proliferating cells.T he chemical tool complements genetic,b iochemical, and pharmacological approaches to study the role of DNAm ethylation in biology and medicine.The methylation of DNAatposition 5ofcytosine residues is chemically av ery simple but biologically one of the most important modifications of DNA. It influences many biological processes in humans such as the regulation of cell function, cellular reprogramming,a nd organismal development. [1][2][3][4][5][6][7] Biological effects of higher methylation levels at promoters are mediated by lowering the transcription of genes either by blocking the binding of transcription factors or by recruiting unique methyl-recognizing proteins that lower gene expression. Altered levels of methylation are also associated with several diseases [8][9][10][11] including cancer. [8,[12][13][14][15][16] Driven by the growing importance of DNAmethylation in biomedical research, there is as trong interest to experimentally lower or increase methylation levels [17][18][19][20][21][22][23] to study,f or example,t he role of epigenetic reprogramming in tissue development or regenerative medicine. [24,25] Optical control is of particular relevance given the high spatial and temporal resolution of light. Often, the approach is implemented with photosensitive small molecules of tuneable bioactivity. [26][27][28][29][30][31] These can be used without the need for genetic engineering of cells leading to powerful applications within cell biology. [32] Yet, despite the importance of DNAm ethylation in biology, no light-tuneable small-molecule tool has been developed to manipulate methylation levels in cells.Herein, we present ap hoto-mediated small-molecule strategy that modulates methylation in light-exposed cells. At the approachsc entre is an inhibitor that interferes with DNAmethyltransferases (DNMTs), the enzymes responsible for DNAm ethylation [33] including the maintenance DNA methyltransferase 1( DNMT1). [34] Thei nhibitorsb ioactivity becomes tuneable with light by the chemical derivatization with ap hotocage.A ss chematically illustrated in Figure 1a, the attached photocage renders the inhibitor biologically inactive.However, light exposure cleaves off the photocage to restore the original inhibitory effect (Figure 1a). Thep hotocaged molecule is hence expected...

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“…[16] They then applied this "click-to-release" strategy to successfullytrigger the release of Dox and monomethyl auristatin E( MMAE) from an antibody-drug conjugate (ADC). Our group [22] and the groups of Bradley [23] and Devaraj [24] independently reported using the vinyl ether protecting group, which could be cleaved by reaction with tetrazines to release alcohols ( Figure 1B). [19] Al imitation of the click-toreleases trategy is the need for delivery,a nd therefore optimisation of the pharmacokinetic properties, of both the prodrug and the tetrazine.…”

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confidence: 99%

“…Our group [22] and the groups of Bradley [23] and Devaraj [24] independently reported using the vinyl ether protecting group, which could be cleaved by reaction with tetrazines to release alcohols ( Figure 1B). Our group [22] and the groups of Bradley [23] and Devaraj [24] independently reported using the vinyl ether protecting group, which could be cleaved by reaction with tetrazines to release alcohols ( Figure 1B).…”

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confidence: 99%

Tetrazine‐Triggered Release of Carboxylic‐Acid‐Containing Molecules for Activation of an Anti‐inflammatory Drug

et al. 2019

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In addition to its use for the study of biomolecules in living systems, bioorthogonal chemistry has emerged as ap romising strategyt oe nable protein or drug activation in as patially and temporally controlled manner.T his study demonstrates the application of ab ioorthogonal inverse electron-demand Diels-Alder (iEDDA) reaction to cleave trans-cyclooctene (TCO) and vinyl protecting groups from carboxylic acid-containing molecules. The tetrazine-mediated decaging reactionp roceeded under biocompatiblec onditions with fast reaction kinetics (< 2min). The anti-inflammatory activity of ketoprofen was successfully reinstated after decaging of the nontoxic TCOprodrug in live macrophages. Overall, this work expandst he scope of functional groups and the application of decaging reactions to an ew class of drugs.Early research in the fieldo fb ioorthogonal chemistry focused on ligation reactions such as the Staudinger reaction, [1] coppercatalysed azide-alkyne 1,3-dipolar cycloaddition (CuAAC), [2,3] palladium-catalysed cross-couplings, [4] ruthenium-catalysed olefin metatheses, [5] strain-promoted azide-alkyne cycloaddition (SPAAC), [6] tetrazole photoinduced 1,3-dipolar cycloadditions, [7,8] and inverse electron-demandD iels-Alder (iEDDA) tetrazine ligation. [9,10] Of these, the iEDDA reactionb etween transcyclooctene (TCO) and at etrazine is one of the more selective and fastestb ioorthogonal reactions to date. [11] Since it was first introduced by Fox et al., [9] this reactionh as been used in numerous biological applicationss uch as cell and in vivo pretargeting imaging. [12][13][14] Recently,b ioorthogonal cleavage reactions have emerged as promising strategies to control the activation of caged proteins,f luorophores, and small-molecule drugs in living systems. [15] The TCO-tetrazine iEDDA ligation can be re-engineered into ac leavage reaction by placing a leaving group at the allylic positiono fT CO. After the initial cycloaddition and elimination of nitrogen, the 4,5-dihydropyridazine now contains an appropriatelyp laced substituent that eliminates upon tautomerisation. [10] Robillard'sg roup reported the first use of the TCO-tetrazine reaction for bioorthogonal decaging to release amine-containing drugs ( Figure 1A), in which they demonstrated the release of doxorubicin (Dox) from aT CO carbamate prodrug in vitro. [16] They then applied this "click-to-release" strategy to successfullytrigger the release of Dox and monomethyl auristatin E( MMAE) from an antibody-drug conjugate (ADC). [17,18] Mejia Oneto and co-workers also reported targeted in vivo activation of aD ox-TCO carbamate prodrug by injecting an alginate hydrogel modified with tetrazines near the tumour site. [19] Al imitation of the click-toreleases trategy is the need for delivery,a nd therefore optimisation of the pharmacokinetic properties, of both the prodrug and the tetrazine. [20,21] However,t he previously mentioned approaches demonstrate the potential of bioorthogonal decaging reactions for targeted drug activation in vivo.Bioorthogonal chemist...

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Tetrazine‐Responsive Self‐immolative Linkers

Cited by 47 publications

References 36 publications

The Emerging Role of Tetrazines in Drug‐Activation Chemistries

The Emerging Role of Tetrazines in Drug‐Activation Chemistries

A Photo‐responsive Small‐Molecule Approach for the Opto‐epigenetic Modulation of DNA Methylation

Tetrazine‐Triggered Release of Carboxylic‐Acid‐Containing Molecules for Activation of an Anti‐inflammatory Drug

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