Colorimetric Carbonyl Sulfide (COS)/Hydrogen Sulfide (H2S) Donation from γ‐Ketothiocarbamate Donor Motifs

Hydrogen sulfide (H₂S) is a biologically active molecule that exhibits protective effects in a variety of physiological and pathological processes. Although several H₂S‐related biological effects have been discovered by using H₂S donors, knowing how much H₂S has been released from donors under different conditions remains challenging. Now, a series of γ‐ketothiocarbamate (γ‐KetoTCM) compounds that provide the first examples of colorimetric H₂S donors and enable direct quantification of H₂S release, were reported. These compounds are activated through a pH‐dependent deprotonation/β‐elimination sequence to release carbonyl sulfide (COS), which is quickly converted into H₂S by carbonic anhydrase. The p‐nitroaniline released upon donor activation provides an optical readout that correlates directly to COS/H₂S release, thus enabling colorimetric measurement of H₂S donation.     

Hydrogen Sulfide Donors Activated by Reactive Oxygen Species

Hydrogen sulfide (H₂S) exhibits promising protective effects in many (patho)physiological processes, as evidenced by recent reports using synthetic H₂S donors in different biological models. Herein, we report the design and evaluation of compounds denoted PeroxyTCM, which are the first class of reactive oxygen species (ROS)‐triggered H₂S donors. These donors are engineered to release carbonyl sulfide (COS) upon activation, which is quickly hydrolyzed to H₂S by the ubiquitous enzyme carbonic anhydrase (CA). The donors are stable in aqueous solution and do not release H₂S until triggered by ROS, such as hydrogen peroxide (H₂O₂), superoxide (O₂^?), and peroxynitrite (ONOO^?). We demonstrate ROS‐triggered H₂S donation in live cells and also demonstrate that PeroxyTCM‐1 provides protection against H₂O₂‐induced oxidative damage, suggesting potential future applications of PeroxyTCM and similar scaffolds in H₂S‐related therapies.     

Carbonyl Sulfide (COS) Donor Induced Protein Persulfidation Protects against Oxidative Stress

The emergence of hydrogen sulfide (H₂S) as an important signalling molecule in redox biology with therapeutic potential has triggered interest in generating this molecule within cells. One strategy that has been proposed is to use carbonyl sulfide (COS) as a surrogate for hydrogen sulfide. Small molecules that generate COS have been shown to produce hydrogen sulfide in the presence of carbonic anhydrase, a widely prevalent enzyme. However, other studies have indicated that COS may have biological effects which are distinct from H₂S. Thus, it would be useful to develop tools to compare (and contrast) effects of COS and H₂S. Here we report enzyme‐activated COS donors that are capable of inducing protein persulfidation, which is symptomatic of generation of hydrogen sulfide. The COS donors are also capable of mitigating stress induced by elevated reactive oxygen species. Together, our data suggests that the effects of COS parallel that of hydrogen sulfide, laying the foundation for further development of these donors as possible therapeutic agents.     

A Persulfide Donor Responsive to Reactive Oxygen Species: Insights into Reactivity and Therapeutic Potential

Persulfides (RSSH) have been hypothesized as critical components in sulfur‐mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H₂S). Hindering the study of persulfides is a lack of persulfide‐donor compounds with selective triggers that release discrete persulfide species. Reported here is the synthesis and characterization of a ROS‐responsive (ROS=reactive oxygen species), self‐immolative persulfide donor. The donor, termed BDP‐NAC, showed selectivity towards H₂O₂ over other potential oxidative or nucleophilic triggers, resulting in the sustained release of the persulfide of N‐acetyl cysteine (NAC) over the course of 2 h, as measured by LCMS. Exposure of H9C2 cardiomyocytes to H₂O₂ revealed that BDP‐NAC mitigated the effects of a highly oxidative environment in a dose‐dependent manner over relevant controls and to a greater degree than common H₂S donors sodium sulfide (Na₂S) and GYY4137. BDP‐NAC also rescued cells more effectively than a non‐persulfide‐releasing control compound in concert with common H₂S donors and thiols.     

Esterase‐Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide

Prodrugs that release hydrogen sulfide upon esterase‐mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H₂S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H₂S donors. Additionally, such prodrugs can easily be conjugated to another non‐steroidal anti‐inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H₂S prodrugs, the anti‐inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS‐induced TNF‐α production in RAW 264.7 cells. This type of H₂S prodrugs shows great potential as both research tools and therapeutic agents.     

Development of a shape‐controlled H2S delivery system using epoxide‐functional nanoparticles

Hydrogen sulfide (H₂S), an endogenous modulator of signaling processes, has potential as a therapeutic drug or in combination drug therapies. Due to its broad biological impacts and malodorous nature, there is considerable interest in vehicles capable of delivering H₂S in a controlled manner. Herein, we report postpolymerization modification of polymers incorporating glycidyl methacrylate (GMA) units to form thiol‐triggered macromolecular H₂S donors. By combining this approach with polymerization‐induced self‐assembly, this methodology allows the facile preparation of polymeric nanoparticulate donors with either spherical or worm‐like morphology. The thiol‐reactive epoxide functional groups in poly(GMA) were chemically transformed into acyl‐protected perthiol groups using a three‐step procedure throughout which both morphologies remained intact. The H₂S releasing properties were subsequently studied, with both spherical and worm‐like nanoparticulate donors shown to successfully release H₂S in the presence of the model thiol, l ‐cysteine. In addition, the donor polymers were shown to effectively increase H₂S inside cells, upon exposure to biologically relevant endogenous thiol levels. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1982–1993     

Enzyme-Triggered Chemodynamic Therapy via a Peptide-H2S Donor Conjugate with Complexed Fe2+

Inducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe²⁺, CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide-H₂S donor conjugate, complexed with Fe²⁺, termed AAN - PTC – Fe²⁺ . The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H₂S, an inhibitor of catalase, an enzyme that detoxifies H₂O₂. Fe²⁺ and H₂S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe²⁺, the AAN sequence, or the ability to generate H₂S. AAN - PTC – Fe²⁺ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H₂S-amplified, enzyme-responsive platform for synergistic cancer treatment.     

Enol-mediated delivery of H2Se from γ-keto selenides: mechanistic insight and evaluation

Like hydrogen sulfide (H₂S), its chalcogen congener, hydrogen selenide (H₂Se), is an emerging molecule of interest given its endogenous expression and purported biological activity. However, unlike H₂S, detailed investigations into the chemical biology of H₂Se are limited and little is known about its innate physiological functions, cellular targets, and therapeutic potential. The obscurity surrounding these fundamental questions is largely due to a lack of small molecule donors that can effectively increase the bioavailability of H₂Se through their continuous liberation of the transient biomolecule under physiologically relevant conditions. Driven by this unmet demand for H₂Se-releasing moieties, we report that γ-keto selenides provide a useful platform for H₂Se donation via an α-deprotonation/β-elimination pathway that is highly dependent on both pH and alpha proton acidity. These attributes afforded a small library of donors with highly variable rates of release (higher alpha proton acidity = faster selenide liberation), which is accelerated under neutral to slightly basic conditions—a feature that is unique and complimentary to previously reported H₂Se donors. We also demonstrate the impressive anticancer activity of γ-keto selenides in both HeLa and HCT116 cells in culture, which is likely to stimulate additional interest and research into the biological activity and anticancer effects of H₂Se. Collectively, these results indicate that γ-keto selenides provide a highly versatile and effective framework for H₂Se donation.

Like hydrogen sulfide (H₂S), its chalcogen congener, hydrogen selenide (H₂Se), is an emerging biomolecule of interest. Therefore, small molecule donors that effectively increase its bioavailability are desired to further probe H₂Se chemical biology.     

Research Progress of H2S Donors Conjugate Drugs Based on ADTOH

H₂S is an endogenous gas signaling molecule and its multiple biological effects have been demonstrated. The abnormal level of H₂S is closely related to the occurrence and development of many diseases, and H₂S donors has important pharmacological implications. In recent years, H₂S donors represented by ADTOH (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione) are often used to synthesize new ‘conjugate’ compounds that can release H₂S and parent drugs. These hybrids retain the pharmacological activity of the parent drugs and H₂S and have a synergistic effect. ADTOH and parent drug hybrids have become one of the important strategies for the development of H₂S donor conjugate drugs. This review summarizes molecular hybrids between ADTOH and clinical drugs to provide new ideas for the study of H₂S donor drug design.     

A Single-Component Dual Donor Enables Ultrasound-Triggered Co-release of Carbon Monoxide and Hydrogen Sulfide

The development of dual gasotransmitter donors can not only provide robust tools to investigate their subtle interplay under pathophysiological conditions but also optimize therapeutic efficacy. While conventional strategies are heavily dependent on multicomponent donors, we herein report an ultrasound-responsive water-soluble copolymer ( PSHF ) capable of releasing carbon monoxide (CO) and hydrogen sulfide (H₂S) based on single-component sulfur-substituted 3-hydroxyflavone (SHF) derivatives. Interestingly, sulfur substitution can not only greatly improve the ultrasound sensitivity but also enable the co-release of CO/H₂S under mild ultrasound irradiation. The co-release of CO/H₂S gasotransmitters exerts a bactericidal effect against Staphylococcus aureus and demonstrates anti-inflammatory activity in lipopolysaccharide-challenged macrophages. Moreover, the excellent tissue penetration of ultrasound irradiation enables the local release of CO/H₂S in the joints of septic arthritis rats, exhibiting superior therapeutic efficacy without the need for any antibiotics.     

Decomposition of Gaseous Sulfide Compounds in Air by Pulsed Corona Discharge

The effectiveness of applying a pulsed corona discharge to the destruction of olfactory pollution in air was investigated. This paper presents a comparative study of the decomposition of three representative sulfide compounds in diluted concentrations: hydrogen sulfide (H₂S), dimethyl sulfide (DMS), and ethanethiol (C₂H₅SH), which could be completely removed when a sufficient but reasonable energy density was deposited in the gas. DMS showed the lowest energy cost (around 30 eV/molecules); C₂H₅SH and H₂S had an EC of respectively 45 eV and 115 eV. The efficiency of the non-thermal plasma process increased with decreasing the initial concentration of sulfide compounds, while the energy yield remained almost unchanged. SO₂ was the only identified byproduct of H₂S decomposition, but the sulfur balance suggests the formation of undetected SO₃. The byproducts analyzed during the degradation of DMS and C₂H₅SH enabled to propose a reaction mechanism, starting with radical attack and breaking of C–S bonds.     

Biocompatible metal–organic frameworks for the storage and therapeutic delivery of hydrogen sulfide

Hydrogen sulfide (H₂S) is an endogenous gasotransmitter with potential therapeutic value for treating a range of disorders, such as ischemia-reperfusion injury resulting from a myocardial infarction or stroke. However, the medicinal delivery of H₂S is hindered by its corrosive and toxic nature. In addition, small molecule H₂S donors often generate other reactive and sulfur-containing species upon H₂S release, leading to unwanted side effects. Here, we demonstrate that H₂S release from biocompatible porous solids, namely metal–organic frameworks (MOFs), is a promising alternative strategy for H₂S delivery under physiologically relevant conditions. In particular, through gas adsorption measurements and density functional theory calculations we establish that H₂S binds strongly and reversibly within the tetrahedral pockets of the fumaric acid-derived framework MOF-801 and the mesaconic acid-derived framework Zr-mes, as well as the new itaconic acid-derived framework CORN-MOF-2. These features make all three frameworks among the best materials identified to date for the capture, storage, and delivery of H₂S. In addition, these frameworks are non-toxic to HeLa cells and capable of releasing H₂S under aqueous conditions, as confirmed by fluorescence assays. Last, a cellular ischemia-reperfusion injury model using H9c2 rat cardiomyoblast cells corroborates that H₂S-loaded MOF-801 is capable of mitigating hypoxia-reoxygenation injury, likely due to the release of H₂S. Overall, our findings suggest that H₂S-loaded MOFs represent a new family of easily-handled solid sources of H₂S that merit further investigation as therapeutic agents. In addition, our findings add Zr-mes and CORN-MOF-2 to the growing lexicon of biocompatible MOFs suitable for drug delivery.

Metal–organic frameworks enable the delivery of hydrogen sulfide (H₂S), an endogenous gasotransmitter with potential therapeutic value for treating disorders such as ischemia-reperfusion injury.     

Hydrogen Sulfide: Novel Endogenous and Exogenous Modulator of Oxidative Stress in Retinal Degeneration Diseases

Oxidative stress (OS) damage can cause significant injury to cells, which is related to the occurrence and development of many diseases. This pathological process is considered to be the first step to trigger the death of outer retinal neurons, which is related to the pathology of retinal degenerative diseases. Hydrogen sulfide (H₂S) has recently received widespread attention as a physiological signal molecule and gas neuromodulator and plays an important role in regulating OS in eyes. In this article, we reviewed the OS responses and regulatory mechanisms of H₂S and its donors as endogenous and exogenous regulators in retinal degenerative diseases. Understanding the relevant mechanisms will help to identify the therapeutic potential of H₂S in retinal degenerative diseases.     

Alleviating Cellular Oxidative Stress through Treatment with Superoxide-Triggered Persulfide Prodrugs

Overproduction of superoxide anion (O₂^.−), the primary cellular reactive oxygen species (ROS), is implicated in various human diseases. To reduce cellular oxidative stress caused by overproduction of superoxide, we developed a compound that reacts with O₂^.− to release a persulfide (RSSH), a type of reactive sulfur species related to the gasotransmitter hydrogen sulfide (H₂S). Termed SOPD-NAC , this persulfide donor reacts specifically with O₂^.−, decomposing to generate N-acetyl cysteine (NAC) persulfide. To enhance persulfide delivery to cells, we conjugated the SOPD motif to a short, self-assembling peptide (Bz-CFFE-NH₂) to make a superoxide-responsive, persulfide-donating peptide ( SOPD-Pep ). Both SOPD-NAC and SOPD-Pep delivered persulfides/H₂S to H9C2 cardiomyocytes and lowered ROS levels as confirmed by quantitative in vitro fluorescence imaging studies. Additional in vitro studies on RAW 264.7 macrophages showed that SOPD-Pep mitigated toxicity induced by phorbol 12-myristate 13-acetate (PMA) more effectively than SOPD-NAC and several control compounds, including common H₂S donors.     

FRET‐Based Mitochondria‐Targetable Dual‐Excitation Ratiometric Fluorescent Probe for Monitoring Hydrogen Sulfide in Living Cells

Hydrogen sulfide (H₂S) is connected with various physiological and pathological functions. However, understanding the important functions of H₂S remains challenging, in part because of the lack of tools for detecting endogenous H₂S. Herein, compounds Ratio‐H₂S 1/2 are the first FRET‐based mitochondrial‐targetable dual‐excitation ratiometric fluorescent probes for H₂S on the basis of H₂S‐promoted thiolysis of dinitrophenyl ether. With the enhancement of H₂S concentration, the excitation peak at λ≈402 nm of the phenolate form of the hydroxycoumarin unit drastically increases, whereas the excitation band centered at λ≈570 nm from rhodamine stays constant and can serve as a reference signal. Thus, the ratios of fluorescence intensities at λ=402 and 570 nm (I₄₀₂/I₅₇₀) exhibit a drastic change from 0.048 in the absence of H₂S to 0.36 in the presence of 180 μM H₂S; this is a 7.5‐fold variation in the excitation ratios. The favorable properties of the probe include the donor and acceptor excitation bands, which exhibit large excitation separations (up to 168 nm separation) and comparable excitation intensities, high sensitivity and selectivity, and function well at physiological pH. In addition, it is demonstrated that the probe can localize in the mitochondria and determine H₂S in living cells. It is expected that this strategy will lead to the development of a wide range of mitochondria‐targetable dual‐excitation ratiometric probes for other analytes with outstanding spectral features, including large separations between the excitation wavelengths and comparable excitation intensities.     

Reactions of Group V Metal Atoms with Hydrogen Sulfide:Argon Matrix Infrared Spectra and Theoretical Calculations

The reaction of laser-ablated vanadium, niobium and tantalum atoms with hydrogen sulfide has been investigated using matrix isolation FTIR and theoretical calculations. The metal atoms inserted into the H-S bond of H₂S to form the HMSH molecules (M=V, Nb, Ta), which rearranged to H₂MS molecules on annealing for Nb and Ta. The HMSH molecule can also further react with another H₂S to form the H₂M(SH)₂ molecules. These new molecules were identified on the basis of the D₂S and H₂³⁴S isotopic substitutions. DFT (B3LYP and BPW91) theoretical calculations are used to predict energies, geometries, and vibrational frequencies for these novel metal dihydrido complexes and molecules. Reaction mechanism for formation of group V dihydrido complex was investigated by DFT internal reaction coordinate calculations. The dissociation of HVSH gave VS+H₂ on broad band irradiation and reverse reaction happened on annealing. Based on B3LYP calculation releasing hydrogen from HVSH is endothermic only by 13.5 kcal/mol with lower energy barrier of 16.9 kcal/mol.     

Pharmacological Inhibition of Endogenous Hydrogen Sulfide Attenuates Breast Cancer Progression

Hydrogen sulfide (H₂S), a gaseous signaling molecule, is associated with the development of various malignancies via modulating various cellular signaling cascades. Published research has established the fact that inhibition of endogenous H₂S production or exposure of H₂S donors is an effective approach against cancer progression. However, the effect of pharmacological inhibition of endogenous H₂S-producing enzymes (cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MPST)) on the growth of breast cancer (BC) remains unknown. In the present study, DL-propargylglycine (PAG, inhibitor of CSE), aminooxyacetic acid (AOAA, inhibitor of CBS), and L-aspartic acid (L-Asp, inhibitor of 3-MPST) were used to determine the role of endogenous H₂S in the growth of BC by in vitro and in vivo experiments. An in silico study was also performed to confirm the results. Corresponding to each enzyme in separate groups, we treated BC cells (MCF-7 and MDA-MB-231) with 10 mM of PAG, AOAA, and L-Asp for 24 h. Findings reveal that the combined dose (PAG + AOAA + L-Asp) group showed exclusive inhibitory effects on BC cells’ viability, proliferation, migration, and invasion compared to the control group. Further, treated cells exhibited increased apoptosis and a reduced level of phospho (p)-extracellular signal-regulated protein kinases such as p-AKT, p-PI3K, and p-mTOR. Moreover, the combined group exhibited potent inhibitory effects on the growth of BC xenograft tumors in nude mice, without obvious toxicity. The molecular docking results were consistent with the wet lab experiments and enhanced the reliability of the drugs. In conclusion, our results demonstrate that the inhibition of endogenous H₂S production can significantly inhibit the growth of human breast cancer cells via the AKT/PI3K/mTOR pathway and suggest that endogenous H₂S may act as a promising therapeutic target in human BC cells. Our study also empowers the rationale to design novel H₂S-based anti-tumor drugs to cure BC.     

In Vivo Detection of Hydrogen Sulfide in Brain and Cell

Hydrogen sulfide (H₂S), is proposed as a cytoprotectant and gasotransmitter, involving in many physiological processes and regulating of some diseases. In addition, H₂S is a small molecular with a minimum of steric hindrance compared with other reactive sulfur species. In physiological atmosphere, H₂S is mainly existent in HS⁻, which has a strong nucleophilicity and reducing potency. It also can precipitate with some metal ions forming metallic sulfides with high precipitation coefficient. In recent years, the researchers have a desire to develop methods to achieve real-time detection of H₂S in vivo, further understanding the physiology and pathology of H₂S. In this minireview, we summarize recent progress for detecting of H₂S in brain or cell and briefly expound the principle of methods with the comparison of the different methods between performance and temporal resolution.     

Multi‐Fluorinated Azido Coumarins for Rapid and Selective Detection of Biological H2S in Living Cells

Hydrogen sulfide (H₂S) is an endogenously produced gaseous signaling molecule with multiple biological functions. In order to visualize the endogenous in situ production of H₂S in living cells in real time, here we developed multi‐fluorinated azido coumarins as fluorescent probes for the rapid and selective detection of biological H₂S. Kinetic studies indicated that an increase in fluorine substitution leads to an increased rate of H₂S‐mediated reduction reaction, which is also supported by our theoretical calculations. To our delight, tetra‐fluorinated coumarin 1 could react with H₂S fast (t_1/2≈1 min) and selectively, which could be further used for continuous enzymatic assays and for visualization of intracellular H₂S. Bioimaging results obtained with 1 revealed that d ‐Cys could induce a higher level of endogenous H₂S production than l ‐Cys in a time‐dependent manner in living cell.     

Removal of carbonyl sulfide from CO2 stream using AgNO3-modified NaZSM-5

Removal of carbonyl sulfide (COS) from CO₂ stream is significant for the production and utilization of food grade CO₂. This study investigates the adsorption performance of Ag/NaZSM-5 as adsorbent prepared by incipient wetness impregnation for the removal of COS from a CO₂ stream in a fixed-bed adsorption apparatus. Effects of various conditions on the preparation of adsorbent, adsorption and desorption were intensively examined. The results revealed that COS can be removed to below 1×10^?9 from a CO₂ stream (1000 ppm COS/CO₂) using Ag/NaZSM-5 (10 wt% AgNO₃) with an adsorption capacity of 12.86 mg-g^?1. The adsorbent can be fully regenerated using hot air at 450 °C. The adsorption ability remained stable even after eight cycles of regeneration.