Click to Release: Instantaneous Doxorubicin Elimination upon Tetrazine Ligation

Versteegen, Ron M.; Rossin, Raffaella; Hoeve, Wolter ten; Janssen, Henk M.; Robillard, Marc S.

doi:10.1002/anie.201305969

Cited by 375 publications

(423 citation statements)

References 19 publications

Supporting

Mentioning

396

Contrasting

Unclassified

Order By: Relevance

“…Unlike tetrazine reactions with highly reactive strained alkenes, [8] our data indicate that the first step,t hat is,t he IEDDAcycloaddition, is the rate-limiting step of the reaction (TS1, DG°% 25 kcal mol À1 ;reaction time ca. 3days) followed by very fast retro-Diels Alder (TS2anti, DG°% 7kcal mol À1 ) and phenoxy group cleavage (TS3, DG°% 11 kcal mol À1 ).…”

mentioning

confidence: 66%

“…Once the 4-phenoxy-4,5-dihydropyridazine (int2)isobtained, it readily tautomerizes into 4-phenoxy-1,4-dihydropyridazine (int4), which can swiftly decage through an elimination reaction. Of note,o ther dihydropyridazine tautomers previously reported to undergo decaging (int3), [6,8] are unreactive in this reaction. To support the theoretical data, we mixed 1a The initial cycloaddition is the rate-limitingstep.…”

mentioning

confidence: 72%

“…[7] TheI EDDAr eaction between at etrazine and ac aged doxorubicin derivative efficiently releases the cytotoxic drug. [8] Strategies based on IEDDA elimination reactions with tetrazines are particularly attractive for decaging relevant molecules in cells and interrogating biology,b ecause of the favorable kinetics and the abiotic nature of tetrazines when compared to photo-and metalcatalyzed reactions.O ne limitation, however,h as been the breadth of protecting groups available for stable,y et conditionally reversible linkages.T ypically,I EDDAe limination reactions have been used with strained alkene protecting groups connected through ac arbamate,t hus resulting in ac ascade release of ap rimary amine (Figure 1a). [2,9] Furthermore,the reduced metabolic stability of strained alkenes constitutes am ajor caveat for its utility.F or instance, ciscyclooctene easily isomerizes to the non-reactive trans-cyclooctene,thus limiting the efficiencyofthe decaging process in cells.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Vinyl Ether/Tetrazine Pair for the Traceless Release of Alcohols in Cells

et al. 2016

View full text Add to dashboard Cite

The cleavage of aprotecting group from aprotein or drug under bioorthogonal conditions enables accurate spatiotemporal control over protein or drug activity.Disclosed herein is that vinyl ethers serve as protecting groups for alcoholcontaining molecules and as reagents for bioorthogonal bondcleavage reactions.Avinyl ether moiety was installed in arange of molecules,including amino acids,amonosaccharide,afluorophore,a nd an analogue of the cytotoxic drug duocarmycin. Tetrazine-mediated decaging proceeded under biocompatible conditions with good yields and reasonable kinetics.I mportantly,t he nontoxic, vinyl ether duocarmycin double prodrug was successfully decaged in live cells to reinstate cytotoxicity. This bioorthogonal reaction presents broad applicability and may be suitable for in vivo applications.Bioorthogonal chemistry for covalently conjugating synthetic molecules at ap redefined protein residue has been am ajor focus of research in the past two decades.[1] Very recently,focus has been placed on reactions which can instead cleave specific bonds under bioorthogonal conditions.[2] This strategy holds great potential for the precise spatiotemporal control of protein function in vivo. [1c,2] Fore xample,p hotodeprotection of agenetically encoded caged cysteinecould be used to reveal the active native protein in live cells.[3]Similarly,p alladium-mediated depropargylation, [4] phosphine-mediated Staudinger reduction, [5] and tetrazine-triggered inverse electron-demand Diels-Alder (IEDDA) elimination reactions [6] were successfully employed to restore the activity of proteins bearing acaged lysine residue in the active site.B ond-cleavage reactions are also attractive for drugdelivery applications.P alladium-catalyzed deprotection of a5 -fluoroacil prodrug was shown as am ethod for controlled drug release in vivo. [7] TheI EDDAr eaction between at etrazine and ac aged doxorubicin derivative efficiently releases the cytotoxic drug.[8] Strategies based on IEDDA elimination reactions with tetrazines are particularly attractive for decaging relevant molecules in cells and interrogating biology,b ecause of the favorable kinetics and the abiotic nature of tetrazines when compared to photo-and metalcatalyzed reactions.O ne limitation, however,h as been the breadth of protecting groups available for stable,y et conditionally reversible linkages.T ypically,I EDDAe limination reactions have been used with strained alkene protecting groups connected through ac arbamate,t hus resulting in ac ascade release of ap rimary amine (Figure 1a). [2,9] Furthermore,the reduced metabolic stability of strained alkenes constitutes am ajor caveat for its utility.F or instance, ciscyclooctene easily isomerizes to the non-reactive trans-cyclooctene,thus limiting the efficiencyofthe decaging process in cells. [10] Herein, we report the development of av inyl ether/ tetrazine system as IEDDAreaction partners for the traceless

show abstract

mentioning

confidence: 66%

mentioning

confidence: 72%

mentioning

confidence: 99%

See 1 more Smart Citation

Vinyl Ether/Tetrazine Pair for the Traceless Release of Alcohols in Cells

et al. 2016

View full text Add to dashboard Cite

show abstract

“…However, those reactions pass through a (thio)ester intermediate, so hydrolysis may compete with ligation (39,40). Artificial amino acids for bioorthogonal reaction would enable minimal modification but with some issues: the increased complexity of module expression and competing reactions [such as azide reduction (44), alkyne reaction with thiols (45), and spontaneous tetrazine degradation (46)] as well as competition from suppression of stop codons by normal amino acids (47). Recent work demonstrated the synthesis of ubiquitin homo-polymers by azide-alkyne (48), thiol-ene (49), or native chemical ligation reactions (50).…”

Section: Discussionmentioning

confidence: 99%

Programmable polyproteams built using twin peptide superglues

Veggiani

Nakamura

Brenner

et al. 2016

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

294

360

View full text Add to dashboard Cite

Programmed connection of amino acids or nucleotides into chains introduced a revolution in control of biological function. Reacting proteins together is more complex because of the number of reactive groups and delicate stability. Here we achieved sequenceprogrammed irreversible connection of protein units, forming polyprotein teams by sequential amidation and transamidation. SpyTag peptide is engineered to spontaneously form an isopeptide bond with SpyCatcher protein. By engineering the adhesin RrgA from Streptococcus pneumoniae, we developed the peptide SnoopTag, which formed a spontaneous isopeptide bond to its protein partner SnoopCatcher with >99% yield and no crossreaction to SpyTag/SpyCatcher. Solid-phase attachment followed by sequential SpyTag or SnoopTag reaction between building-blocks enabled iterative extension. Linear, branched, and combinatorial polyproteins were synthesized, identifying optimal combinations of ligands against death receptors and growth factor receptors for cancer cell death signal activation. This simple and modular route to programmable "polyproteams" should enable exploration of a new area of biological space.synthetic biology | protein engineering | nanobiotechnology | split protein | antibody

show abstract

“…A general strategy for the purification of bio-polymeric materials, such as RNA strands, synthesized by solid phase synthesis will be described. It is based on a recently developed concept involving bio-orthogonal inverse electron demand Diels-Alder (IEDDA) reaction between trans-cyclooctene and tetrazine, termed 'clickto-release' (Versteegen, Rossin, Hoeve, Janssen, & Robillard, 2013). The unique feature of this system is attachment of a releasable payload at the allylic position of the trans-cyclooctene.…”

mentioning

confidence: 99%