Esterase-Activated Perthiocarbonate Persulfide Donors Provide Insights into Persulfide Persistence and Stability.

Persulfides (RSSH) are important reactive sulfur species (RSS) that are intertwined with the biological functions of hydrogen sulfide (HS). The direct study of persulfides is difficult, however, due to their both nucleophilic and electrophilic character, which leads to the generation of an equilibrium of different RSS. To investigate the effects of persulfides directly, especially in biological systems, persulfide donors are needed to generate persulfides .

HS donors with optical responses.

Reactive sulfur species, including hydrogen sulfide (HS), are important biological mediators and play key roles in different pathophysiological conditions. Small molecules that release HS on demand, often referred to as "HS donors," constitute a key investigative tool for HS-related research. A significant challenge, however, is correlating the rate of HS release from such donors in complex systems with biological outcomes, because release rates are commonly perturbed by different biological environments.

Progress toward colorimetric and fluorescent detection of carbonyl sulfide.

We report here that a fluorescent benzobisimidazolium salt (TBBI) can be used for the fluorescent and colorimetric detection of carbonyl sulfide (COS) over related heterocumulenes including CO2 and CS2 in wet MeCN. The reaction between TBBI and COS in the presence of fluoride yields a highly fluorescent (λem = 354 nm) and colored product (λmax = 321, 621 nm), that is readily observed by the naked eye. We view these results as a first step toward developing activity-based probes for COS detection.

Use of Dithiasuccinoyl-Caged Amines Enables COS/H S Release Lacking Electrophilic Byproducts.

The enzymatic conversion of carbonyl sulfide (COS) to hydrogen sulfide (H S) by carbonic anhydrase has been used to develop self-immolating thiocarbamates as COS-based H S donors to further elucidate the impact of reactive sulfur species in biology. The high modularity of this approach has provided a library of COS-based H S donors that can be activated by specific stimuli. A common limitation, however, is that many such donors result in the formation of an electrophilic quinone methide byproduct during donor activation.

Activatable Small-Molecule Hydrogen Sulfide Donors.

Hydrogen sulfide (HS) is an important biological signaling molecule involved in many physiological processes. These diverse roles have led researchers to develop contemporary methods to deliver HS under physiologically relevant conditions and in response to various stimuli. Different small-molecule donors have been developed that release HS under various conditions.

Development and Application of Carbonyl Sulfide-Based Donors for HS Delivery.

In addition to nitric oxide and carbon monoxide, hydrogen sulfide (HS) has been recently recognized as an important biological signaling molecule with implications in a wide variety of processes, including vasodilation, cytoprotection, and neuromodulation. In parallel to the growing number of reports highlighting the biological impact of HS, interest in developing HS donors as both research tools and potential therapeutics has led to the growth of different HS-releasing strategies. Many HS investigations in model systems use direct inhalation of HS gas or aqueous solutions of NaSH or NaS; however, such systems do not mimic endogenous HS production.

Fluorogenic hydrogen sulfide (HS) donors based on sulfenyl thiocarbonates enable HS tracking and quantification.

Hydrogen sulfide (HS) is an important cellular signaling molecule that exhibits promising protective effects. Although a number of triggerable HS donors have been developed, spatiotemporal feedback from HS release in biological systems remains a key challenge in HS donor development. Herein we report the synthesis, evaluation, and application of caged sulfenyl thiocarbonates as new fluorescent HS donors.

Dithioesters: simple, tunable, cysteine-selective HS donors.

Dithioesters have a rich history in polymer chemistry for RAFT polymerizations and are readily accessible through different synthetic methods. Here we demonstrate that the dithioester functional group is a tunable motif that releases HS upon reaction with cysteine and that structural and electronic modifications enable the rate of cysteine-mediated HS release to be modified. In addition, we use (bis)phenyl dithioester to carry out kinetic and mechanistic investigations, which demonstrate that the initial attack by cysteine is the rate-limiting step of the reaction.

Effects of sulfane sulfur content in benzyl polysulfides on thiol-triggered HS release and cell proliferation.

Investigations into hydrogen sulfide (HS) signaling pathways have demonstrated both the generation and importance of persulfides, which are reactive sulfur species that contain both reduced and oxidized sulfur. These observations have led researchers to suggest that oxidized sulfur species, including sulfane sulfur (S), are responsible for many of the physiological phenomena initially attributed to HS. A common method of introducing S to biological systems is the administration of organic polysulfides, such as diallyl trisulfide (DATS).

Thionoesters: A Native Chemical Ligation-Inspired Approach to Cysteine-Triggered HS Donors.

Native chemical ligation (NCL) is a simple, widely used, and powerful synthetic tool to ligate N-terminal cysteine residues and C-terminal α-thioesters via a thermodynamically stable amide bond. Building on this well-established reactivity, as well as advancing our interests in the chemical biology of reactive sulfur species including hydrogen sulfide (HS), we hypothesized that thionoesters, which are constitutional isomers of thioesters, would undergo a similar NCL reaction in the presence of cysteine to release HS under physiological conditions. Herein, we report mechanistic and kinetic investigations into cysteine-mediated HS release from thionoesters.

S Marks the Spot: Linking the Antioxidant Activity of N-Acetyl Cysteine to HS and Sulfane Sulfur Species.

N-Acetyl cysteine (NAC) is commonly used as an antioxidant and cytoprotectant, yet a broadly applicable mechanism of these activities has remained elusive. In this issue of Cell Chemical Biology, Ezeriņa et al. (2018) report an alternative mechanism for NAC cytoprotection and antioxidant activity by demonstrating that NAC treatment increases sulfane sulfur production via intermediate HS generation.

Bis(aryl) Tetrasulfides as Cathode Materials for Rechargeable Lithium Batteries.

An organotetrasulfide consists of a linear chain of four sulfur atoms that could accept up to 6 e in reduction reactions, thus providing a promising high-capacity electrode material. Herein, we study three bis(aryl) tetrasulfides as cathode materials in lithium batteries. Each tetrasulfide exhibits two major voltage regions in the discharge.

Applications of Synthetic Organic Tetrasulfides as HS Donors.

In an effort to expand the availability of simple polysulfides for HS donation, we report here the synthesis and HS release profiles of bis(aryl) and bis(alkyl) tetrasulfides. The tetrasulfide donors release HS in a first-order dependence on reduced glutathione (GSH) and release more HS than the commonly used trisulfide DATS.

A Bright Fluorescent Probe for H2S Enables Analyte-Responsive, 3D Imaging in Live Zebrafish Using Light Sheet Fluorescence Microscopy.

Hydrogen sulfide (H2S) is a critical gaseous signaling molecule emerging at the center of a rich field of chemical and biological research. As our understanding of the complexity of physiological H2S in signaling pathways evolves, advanced chemical and technological investigative tools are required to make sense of this interconnectivity. Toward this goal, we have developed an azide-functionalized O-methylrhodol fluorophore, MeRho-Az, which exhibits a rapid >1000-fold fluorescence response when treated with H2S, is selective for H2S over other biological analytes, and has a detection limit of 86 nM.