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

A dynamic combinatorial analysis of carbohydrate/aromatic complexes clarifies the structural determinants and origins of these important interactions in water.

A dynamical combinatorial approach for the study of weak carbohydrate/aromatic interactions is presented. This methodology has been employed to dissect the subtle structure−stability relationships that govern facial selectivity in these supramolecular complexes.

Electrostatic and charge‐transfer contributions to CH–π complexes can be modulated by attaching electron‐withdrawing substituents to the carbon atom. While clearly stabilizing in the gas phase, the outcome of this chemical modification in water is more difficult to predict. Herein we provide a definitive and quantitative answer to this question employing a simple strategy based on dynamic combinatorial chemistry.

We have developed [2.2.1]azabicyclic vinyl sulfone reagents that simultaneously enable cysteine-selective protein modification and introduce a handle for further bioorthogonal ligation.

An anti-cancer vaccine based on an unnatural antigen with an sp2-iminosugar fragment.

Site-selective protein modification strategies can be used to insert non-natural functional groups into protein structures. Herein, we report on the use of the bis-electrophile 3-bromo-2-bromomethyl-1-propene as a reagent to introduce an electrophilic handle at cysteine residues under mild conditions. This method is demonstrated on a variety of proteins containing a solvent-exposed cysteine residue, including an anti-HER2 nanobody. Chemically distinct protein conjugates are then efficiently formed through further reaction of the electrophilic site with various nucleophiles, including thiols and amines. The resulting chemically-defined conjugates are highly stable in the presence of glutathione or human plasma and retain both the structure and function of the native protein.

The cleavage of a protecting group from a protein 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 alcohol‐containing molecules and as reagents for bioorthogonal bond‐cleavage reactions. A vinyl ether moiety was installed in a range of molecules, including amino acids, a monosaccharide, a fluorophore, and an analogue of the cytotoxic drug duocarmycin. Tetrazine‐mediated decaging proceeded under biocompatible conditions with good yields and reasonable kinetics. Importantly, the 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.