Hydrogen sulfide (H 2 S) is an important endogenous gasotransmitter,b ut the targeted delivery and real-time feedbacko fe xogenous H 2 Sa re still challenging. With the aid of density functional theory (DFT) calculations,w ed esigned an ew 1,3-dithiolium-4-olate (DTO) compound, which can react with as trained alkyne via the 1,3-dipolar cycloaddition and the retro-Diels-Alder reaction to generate carbonyl sulfide (COS) as the precursor of H 2 S, and athiophene derivative with turn-on fluorescence.Moreover,the diphenylamino substituent in DTOg reatly increases the mitochondrial targeting of this H 2 Sd elivery system. Suchabioorthogonal click-and-release reaction has integrated three functions in one system for the first time:(1) in situ controllable H 2 Srelease,(2) concomitant fluorescence response,and (3) mitochondria-targeted delivery. In addition, we investigated the mitochondrial membrane potential loss alleviation by using this system in H9c2 cells under oxidative stress.

The amidated peptides are an important class of biologically active compounds due to their unique biological properties and wide applications as potential peptide drugs and biomarkers. Despite the abundance of free amide motifs (Asn, Gln, and C-terminal amide) in native peptides, late-stage modification of the amide unit in naturally occurring peptides remains very rare because of the intrinsically weak nucleophilicity of amides and the interference of multiple competing nucleophilic residues, which generally lead to undesired side reactions. Herein, chemoselective arylation of amides in unprotected polypeptides has been developed under an air atmosphere to afford the N-aryl amide peptides bearing various functional motifs. Its success relies on the combination of gold catalysis and silver salt to differentiate the relative inert amide among a collection of reactive nucleophilic amino acid residues (e.g., −NH 2 , −OH, and −COOH), favoring the C−N bond coupling toward amides over other more nucleophilic groups. Experimental and DFT studies reveal a crucial role of the silver cation, which serves as a transient coordination mask of the more reactive reaction sites, overcoming the inherently low reactivity of amides. The excellent biocompatibility of this strategy has been applied to functionalize a wide range of peptide drugs and complex peptides. The application could be further extended to peptide labeling and peptide stapling.

Hydrogen sulfide (H2S) is an important endogenous gasotransmitter, but the targeted delivery and real‐time feedback of exogenous H2S are still challenging. With the aid of density functional theory (DFT) calculations, we designed a new 1,3‐dithiolium‐4‐olate (DTO) compound, which can react with a strained alkyne via the 1,3‐dipolar cycloaddition and the retro‐Diels–Alder reaction to generate carbonyl sulfide (COS) as the precursor of H2S, and a thiophene derivative with turn‐on fluorescence. Moreover, the diphenylamino substituent in DTO greatly increases the mitochondrial targeting of this H2S delivery system. Such a bioorthogonal click‐and‐release reaction has integrated three functions in one system for the first time: (1) in situ controllable H2S release, (2) concomitant fluorescence response, and (3) mitochondria‐targeted delivery. In addition, we investigated the mitochondrial membrane potential loss alleviation by using this system in H9c2 cells under oxidative stress.

A FRET-based fluorescence turn-on probe is designed, which employs a sydnonimine as the linker to match specific fluorophore and quencher pairs and releases the fluorescence after the “click-and-release” reaction. Furthermore,...

Despite the tetrazine bioorthogonal reaction holding immense potential in biomedical research and drug discovery, its in vivo performance has been strongly challenged by the inverse correlation between the physiological stability and reactivity of tetrazines. Moreover, the preparation of tetrazine is typically complex and requires restricted reagents. To overcome these challenges, we describe a scalable approach to synthesize a range of shelf-stable ethynyl-tetrazines. By using ethynyl-tetrazine as a clickable precursor, we can modularly access a new type of highly reactive functionalized triazolyl-tetrazines with improved stability for use in biomedical applications. We demonstrate the efficacy of this approach by efficiently constructing 18F-labeled tetrazine derivatives with radiochemical yields of up to 84%, and tunable biodistribution patterns for PET (positron emission tomography) imaging. This approach will significantly facilitate the application of tetrazine bioorthogonal chemistry in biomedical research, theranostics, and materials science.