Hydrogen sulfide (H2S) is an important biological signaling agent that exerts action on numerous (patho)physiological processes. Once generated, H2S can be oxidized to generate reductant-labile sulfane sulfur pools, which include hydrodisulfides/persulfides. Despite the importance of hydrodisulfides in H2S storage and signaling, little is known about the physical properties or chemical reactivity of these compounds. We report here the synthesis, isolation, and characterization (NMR, IR, Raman, HRMS, X-ray) of a small-molecule hydrodisulfide and highlight its reactivity with reductants, nucleophiles, electrophiles, acids, and bases. Our experimental results establish that hydrodisulfides release H2S upon reduction and that deprotonation results in disproportionation to the parent thiol and S0, thus providing a mechanism for transsulfuration in the sulfane sulfur pool.

Hydrogen sulfide (H2S) is now recognized as an important biological regulator and signaling agent that is active in many physiological processes and diseases. Understanding the important roles of this emerging signaling molecule has remained challenging, in part due to the limited methods available for detecting endogenous H2S. Here we report two reaction-based ChemiLuminescent Sulfide Sensors, CLSS-1 and CLSS-2, with strong luminescence responses toward H2S (128-, 48-fold, respectively) and H2S detection limits (0.7 ± 0.3, 4.6 ± 2.0 μM, respectively) compatible with biological H2S levels. CLSS-2 is highly selective for H2S over other reactive sulfur, nitrogen, and oxygen species (RSONs) including GSH, Cys, Hcy, S2O32−, NO2−, HNO, ONOO−, and NO. Despite its similar chemical structure, CLSS-1 displays lower selectivity toward amino acid-derived thiols than CLSS-2. The origin of this differential selectivity was investigated using both computational DFT studies and NMR experiments. Our results suggest a model in which amino acid binding to the hydrazide moiety of the luminol-derived probes provides differential access to the reactive azide in CLSS-1 and CLSS-2, thus eroding the selectivity of CLSS-1 for H2S over Cys and GSH. Based on its high selectivity for H2S, we used CLSS-2 to detect enzymatically-produced H2S from isolated cystathionine γ-lyase (CSE) enzymes (p < 0.001) and also from C6 cells expressing CSE (p < 0.001). CLSS-2 can readily differentiate between H2S production in active CSE and CSE inhibited with β-cyano alanine (BCA) in both isolated CSE enzymes (p < 0.005) and in C6 cells (p < 0.005). In addition to providing a highly sensitive and selective reaction-based tool for chemiluminescent H2S detection and quantification, the insights into substrate-probe interactions controlling the selectivity for H2S over biologically-relevant thiols may guide the design of other selective H2S detection scaffolds.

Hydrogen sulfide (HS) and nitric oxide (NO) are important biosignaling molecules, and their biochemistries are increasingly recognized to be intertwined. Persulfides are an oxidized product of biological HS and have emerged as important species involved in the biological action of reactive sulfur species. Using isolated persulfides, we employed a combination of experimental and computational methods to investigate the contribution of persulfides to HS/NO crosstalk. Our studies demonstrate that isolated persulfides react with nitrite to produce NO via polysulfide and perthionitrite intermediates. These results highlight the importance of persulfides, polysulfides, and perthionitrite as intertwined reactive nitrogen and sulfur species.

Hydrogen sulfide is ubiquitous in biological systems and exerts function over a wide range of important physiological processes. Complementing free H2S, the reductant-labile sulfur pool plays significant roles in the translocation and action of sulfide, however the chemistry of reductant-labile sources of sulfide have not been studied systematically. Using a combination of NMR and UV-Vis spectroscopy, we investigated the spectroscopic properties and reactivity of three isolated organic persulfides and report a simple model for persulfide reactivity, including their roles as nucleophiles, electrophiles, and sulfide donors.

Hydrogen sulfide (H 2 S) is now recognized as an important biological molecule that plays diverse roles in various (patho)physiological conditions. Endogenous H 2 S, or its misregulation, has been associated with a variety of aspects of human health, including diabetes, hypertension, atherosclerosis, inflammation, neurodegeneration, sepsis, and asthma. Motivated by the potential use of H 2 S-donating molecules as both investigative and therapeutic tools, researchers are developing new types of slow-releasing H 2 S donor molecules that mimic the slow, continuous H 2 S release characteristic of enzymatic production. In addition to synthetic H 2 S donors, many natural products contain functional groups well known to release sulfide. Here we provide an overview of natural products that contain such functional groups, with an emphasis on organic polysulfides, to highlight the diversity of these structures and also to outline possible areas of future research on pharmacologically relevant H 2 S donors derived from natural products. 1 Introduction 2 Polysulfide-Containing Natural Products 2.1 Linear Polysulfides 2.2 Cyclic Polysulfides 2.3 Epidithiodioxopiperazines 2.4 Enediyne-Containing Trisulfides 3 Leinamycin 4 Other Disulfides and Thiols Implicated in Hydrogen Sulfide Generation 5 Conclusions and Prospects