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.     

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.     

Use of Dithiasuccinoyl-Caged Amines Enables COS/H2S Release Lacking Electrophilic Byproducts

The enzymatic conversion of carbonyl sulfide (COS) to hydrogen sulfide (H₂S) by carbonic anhydrase has been used to develop self-immolating thiocarbamates as COS-based H₂S 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 H₂S 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. As a mild alternative, we demonstrate here that dithiasuccinoyl groups can function as COS/H₂S donor motifs, and that these groups release two equivalents of COS/H₂S and uncage an amine payload under physiologically relevant conditions. Additionally, we demonstrate that COS/H₂S release from this donor motif can be altered by electronic modulation and alkyl substitution. These insights are further supported by DFT investigations, which reveal that aryl and alkyl thiocarbamates release COS with significantly different activation energies.     

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.     

Data‐Driven Identification of Hydrogen Sulfide Scavengers

Hydrogen sulfide (H₂S) is an important signaling molecule whose up‐ and down‐regulation have specific biological consequences. Although significant advances in H₂S up‐regulation, by the development of H₂S donors, have been achieved in recent years, precise H₂S down‐regulation is still challenging. The lack of potent/specific inhibitors for H₂S‐producing enzymes contributes to this problem. We expect the development of H₂S scavengers is an alternative approach to address this problem. Since chemical sensors and scavengers of H₂S share the same criteria, we constructed a H₂S sensor database, which summarizes key parameters of reported sensors. Data‐driven analysis led to the selection of 30 potential compounds. Further evaluation of these compounds identified a group of promising scavengers, based on the sulfonyl azide template. The efficiency of these scavengers in in vitro and in vivo experiments was demonstrated.     

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.     

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.     

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.     

o‐Fluorination of Aromatic Azides Yields Improved Azido‐Based Fluorescent Probes for Hydrogen Sulfide: Synthesis,Spectra, and Bioimaging

Hydrogen sulfide (H₂S) is an endogenously produced gaseous signaling molecule with multiple biological functions. To visualize the endogenous in situ production of H₂S in real time, new coumarin‐ and boron‐dipyrromethene‐based fluorescent turn‐on probes were developed for fast sensing of H₂S in aqueous buffer and in living cells. Introduction of a fluoro group in the ortho position of the aromatic azide can lead to a greater than twofold increase in the rate of reaction with H₂S. On the basis of o‐fluorinated aromatic azides, fluorescent probes with high sensitivity and selectivity toward H₂S over other biologically relevant species were designed and synthesized. The probes can be used to in situ to visualize exogenous H₂S and D ‐cysteine‐dependent endogenously produced H₂S in living cells, which makes them promising tools for potential applications in H₂S biology.     

A comparative experimental and theoretical investigation of hydrogen‐bond,halogen‐bond and π–π interactions in the solid‐state supramolecular assembly of 2‐ and 4‐formylphenyl arylsulfonates

To explore the operational role of noncovalent interactions in supramolecular architectures with designed topologies, a series of solid‐state structures of 2‐ and 4‐formylphenyl 4‐substituted benzenesulfonates was investigated. The compounds are 2‐formylphenyl 4‐methylbenzenesulfonate, C₁₄H₁₂O₄S, 3a , 2‐formylphenyl 4‐chlorobenzenesulfonate, C₁₃H₉ClO₄S, 3b , 2‐formylphenyl 4‐bromobenzenesulfonate, C₁₃H₉BrO₄S, 3c , 4‐formylphenyl 4‐methylbenzenesulfonate, C₁₄H₁₂O₄S, 4a , 4‐formylphenyl 4‐chlorobenzenesulfonate, 4b , C₁₃H₉ClO₄S, and 4‐formylphenyl 4‐bromobenzenesulfonate, C₁₃H₉BrO₄S, 4c . The title compounds were synthesized under basic conditions from salicylaldehyde/4‐hydroxybenzaldehydes and various aryl sulfonyl chlorides. Remarkably, halogen‐bonding interactions are found to be important to rationalize the solid‐state crystal structures. In particular, the formation of O…X (X = Cl and Br) and type I X…X halogen‐bonding interactions have been analyzed by means of density functional theory (DFT) calculations and characterized using Bader's theory of `atoms in molecules' and molecular electrostatic potential (MEP) surfaces, confirming the relevance and stabilizing nature of these interactions. They have been compared to antiparallel π‐stacking interactions that are formed between the arylsulfonates.     

Monitoring of Endogenous Hydrogen Sulfide in Living Cells Using Surface‐Enhanced Raman Scattering

Hydrogen sulfide (H₂S) has emerged as an important gasotransmitter in diverse physiological processes, although many aspects of its roles remain unclear, partly owing to a lack of robust analytical methods. Herein we report a novel surface‐enhanced Raman scattering (SERS) nanosensor, 4‐acetamidobenzenesulfonyl azide‐functionalized gold nanoparticles (AuNPs/4‐AA), for detecting the endogenous H₂S in living cells. The detection is accomplished with SERS spectrum changes of AuNPs/4‐AA resulting from the reaction of H₂S with 4‐AA on AuNPs. The SERS nanosensor exhibits high selectivity toward H₂S. Furthermore, AuNPs/4‐AA responds to H₂S within 1 min with a 0.1 μM level of sensitivity. In particular, our SERS method can be utilized to monitor the endogenous H₂S generated in living glioma cells, demonstrating its great promise in studies of pathophysiological pathways involving H₂S.     

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.     

Synthesis and structures of photoactive rhenium carbonyl complexes derived from 2‐(pyridin‐2‐yl)‐1,3‐benzothiazole, 2‐(quinolin‐2‐yl)‐1,3‐benzothiazole and 1,10‐phenanthroline

Carbon monoxide (CO) has recently been identified as a gaseous signaling molecule that exerts various salutary effects in mammalian pathophysiology. Photoactive metal carbonyl complexes (photoCORMs) are ideal exogenous candidates for more controllable and site‐specific CO delivery compared to gaseous CO. Along this line, our group has been engaged for the past few years in developing group‐7‐based photoCORMs towards the efficient eradication of various malignant cells. Moreover, several such complexes can be tracked within cancerous cells by virtue of their luminescence. The inherent luminecscent nature of some photoCORMs and the change in emission wavelength upon CO release also provide a covenient means to track the entry of the prodrug and, in some cases, both the entry and CO release from the prodrug. In continuation of the research circumscribing the development of trackable photoCORMs and also to graft such molecules covalently to conventional delivery vehicles, we report herein the synthesis and structures of three rhenium carbonyl complexes, namely, fac‐tricarbonyl[2‐(pyridin‐2‐yl)‐1,3‐benzothiazole‐κ²N ,N ′](4‐vinylpyridine‐κN )rhenium(I) trifluoromethanesulfonate, [Re(C₇H₇N)(C₁₂H₈N₂S)(CO)₃](CF₃SO₃), ( 1 ), fac‐tricarbonyl[2‐(quinolin‐2‐yl)‐1,3‐benzothiazole‐κ²N ,N ′](4‐vinylpyridine‐κN )rhenium(I) trifluoromethanesulfonate, [Re(C₇H₇N)(C₁₆H₁₀N₂S)(CO)₃](CF₃SO₃), ( 2 ), and fac‐tricarbonyl[1,10‐phenanthroline‐κ²N ,N ′](4‐vinylpyridine‐κN )rhenium(I) trifluoromethanesulfonate, [Re(C₇H₇N)(C₁₂H₈N₂)(CO)₃](CF₃SO₃), ( 3 ). In all three complexes, the Re^I center resides in a distorted octahedral coordination environment. These complexes exhibit CO release upon exposure to low‐power UV light. The apparent CO release rates of the complexes have been measured to assess their comparative CO‐donating capacity. The three complexes are highly luminescent and this in turn provides a convenient way to track the entry of the prodrug molecules within biological targets.     

Tetrakis(dimethyl sulfide)palladium(II) bis(tetrafluoroborate) and tetrakis(1,4‐oxathiane‐κS)palladium(II) bis(tetrafluoroborate)

Tetrakis(dimethyl sulfide)palladium(II) bis(tetrafluoroborate), [Pd(C₂H₆S)₄](BF₄)₂, (I), and tetrakis(1,4‐oxa­thiane‐κS)palladium(II) bis­(tetra­fluoro­borate), [Pd(C₄H₈OS)₄](BF₄)₂, (II), both crystallize as mononuclear square‐planar complexes with tetra­fluoro­borate as the counter‐ions. The Pd atom accepts four S‐donor atoms and is positioned at an inversion centre in both compounds. The two unique S atoms in the di­methyl sulfide complex, (I), are disordered. The Pd—S distances are in the range 2.3338 (12)–2.3375 (12) Å in (I), and the corresponding distances in the thio­xane complex, (II), are 2.3293 (17) and 2.3406 (17) Å. The anions in both compounds interact weakly with the Pd atom.     

Two polymorphs of tetraethylammonium [hydrogen tris(3,5‐dimethylpyrazolyl)borato]di‐μ2‐sulfido‐disulfido(η2‐tetrasulfido)ditungsten(V) with Z′ = 1 and 2

Two polymorphs of the title compound, (C₈H₂₀N)[W₂S₄(S₄)(C₁₅H₂₂BN₆)], have been obtained unexpectedly by attempted recrystallization of a mixed‐metal–sulfur cluster complex from different solvents. The dinuclear complex anion contains W^V in two different coordination environments, one of them distorted octahedral with a tris(pyrazolyl)borate anion, a terminal sulfide and two bridging sulfide ligands, the other distorted square‐pyramidal with a terminal sulfide, two bridging sulfide and a chelating tetrasulfide ligand. The three independent anions in the two polymorphs have essentially the same geometry. The central W₂S₂ ring is a slightly folded rhombus with acute angles at the S atoms, and the WS₄ chelate ring is an envelope with one noncoordinating S atom as the flap. The second polymorph, with Z′ = 2 and pseudo‐inversion symmetry relating the anions of the asymmetric unit, also displays pseudo‐translation features in its layer structure, and all examined crystals were found to be twinned, possibly as a consequence of this structural feature.     

Poly[μ4‐sulfido‐tris(thiocyanato‐κN)tris(μ3‐1,2,4‐triazolato‐κ3N1:N2:N4)tetrazinc(II)]: a three‐dimensional zinc sulfide coordination polymer

The title compound, [Zn₄(C₂H₂N₃)₃(NCS)₃S]_n, is a three‐dimensional coordination polymer consisting of tetrahedral SZn₄ clusters bridged by triazole ligands. In the tetrahedral unit, three Zn atoms are connected to six bridging triazolate ligands, whereas the fourth Zn atom (site symmetry 3m) is bonded to three terminal thiocyanate anions that protrude into the void space created by the Zn–triazolate network. The network prototype is simple cubic, but a strong distortion along a body diagonal and the imposition of a polar direction by the arrangement of the molecular constituents lead to the trigonal space group R3m. This study demonstrates the use of the 3‐mercapto‐1,2,4‐triazole ligand as an effective source for sulfide ions in the synthesis of sulfide‐based coordination polymers.     

On the Reaction of Dithioarsonites,L‐As(SPh)2 (L = Ar,R), with Octasulfur in the Presence of Triethylamine as an Activator. The Crystal Structure of the Sesquisulfide (2‐O2N‐C6H4‐As)2S3

Octasulfur (elemental sulfur) does not react at room temperature with a variety of As^III compounds of the type Ar‐As(SPh)₂ and R‐As(SPh)₂. However, in the presence of catalytic amounts of triethylamine, which probably acts as an activator of octasulfur, reactions do take place. The products isolated from the aromatic dithioarsonites are not the expected Ar‐As(S)(SPh)₂ but the sulfide, cyclo‐(PhAsS)₄, and the sesquisulfides, (ArAs)₂S₃, which are the same with those obtained by reduction of arylarsonic acids with hydrogen sulfide. The action of S₈/Et₃N on aliphatic dithioarsonites did not give any As^V products but gave mixtures of non‐separable oligomeric (RAsS)_x. Probable mechanistic routes for these reactions are proposed. The known cyclo‐(PhAsS)₄ and (PhAs)₂S₃ and the new (2‐O₂N‐C₆H₄‐As)₂S₃ have been structurally characterized: (2‐O₂N‐C₆H₄‐As)₂S₃, monoclinic, C2/c, a = 13.564(9)Å, b = 7.982(6)Å, c = 16.67(1)Å, β = 117.63(2)°, V = 1599(2)ų, Z = 4, wR2 0.0640. The 1, 4‐diarsa‐2, 3, 5‐trithiacyclopentane ring is puckered and the two As^III atoms are pseudo tetrahedral.     

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     

(Z)‐3‐(1H‐Indol‐3‐yl)‐2‐(3‐thienyl)­acrylo­nitrile and (Z)‐3‐[1‐(4‐tert‐butyl­benzyl)‐1H‐indol‐3‐yl]‐2‐(3‐thienyl)­acrylo­nitrile

(Z)‐3‐(1H‐Indol‐3‐yl)‐2‐(3‐thienyl)­acrylo­nitrile, C₁₅H₁₀N₂S, (I), and (Z)‐3‐[1‐(4‐tert‐butyl­benzyl)‐1H‐indol‐3‐yl]‐2‐(3‐thienyl)­acrylo­nitrile, C₂₆H₂₄N₂S, (II), were prepared by base‐catalyzed reactions of the corresponding indole‐3‐carbox­aldehyde with thio­phene‐3‐aceto­nitrile. ¹H/¹³C NMR spectral data and X‐ray crystal structures of compounds (I) and (II) are presented. The olefinic bond connecting the indole and thio­phene moieties has Z geometry in both cases, and the mol­ecules crystallize in space groups P2₁/c and C2/c for (I) and (II), respectively. Slight thienyl ring‐flip disorder (ca 5.6%) was observed and modeled for (I).     

Tetra­aqua(3,4,7,8‐tetra­methyl‐1,10‐phenanthroline‐κ2N,N′)­zinc(II) thio­sulfate

In the title complex of zinc(II) with 3,4,7,8‐tetra­methyl‐1,10‐phenanthroline (tmph), viz. [Zn(C₁₆H₁₆N₂)(H₂O)₄](S₂O₃), the metal atom has a monomeric octahedral ZnN₂O₄ complex environment comprising two N‐atom donors from the tmph group and four aqua O‐atom donors. The complex cation is connected to four thio­sulfate anions through a compact hydrogen‐bonding network involving all coordinated aqua H‐atom donors and all the outer acceptors (O and S) of the anion.