Nucleus-targeting Oxaplatin(IV) prodrug Amphiphile for enhanced chemotherapy and immunotherapy.

Platinum(II)-based drugs (PtII), which hinder DNA replication, are the most widely used chemotherapeutics. However, current PtII drugs often miss their DNA targets, leading to severe side effects and drug resistance. To overcome this challenge, we developed a novel oxaliplatin-based platinum(IV) (PtIV) prodrug amphiphile (C16-OPtIV-R8K), integrating a long-chain hydrophobic lipid and a nucleus-targeting hydrophilic peptide (R8K). This design allows the prodrug to self-assemble into highly uniform lipid nanoparticles (NTPtIV) for enhanced targeting chemotherapy and immunotherapy. Subsequently, NTPtIV's bioactivity and effects were examined at diverse levels, encompassing cancer cells, 3D tumor spheres, and in vivo. Our in vitro studies show a 74% cancer cell nucleus localization of platinum drugs-3.6 times higher than that of oxaliplatin, achieving more than a ten-fold increase in eliminating drug-resistant cancer cells. In vivo, NTPtIV shows efficient tumor accumulation, leading to suppressed tumor growth of murine breast cancer. Moreover, NTPtIV recruited more CD4+ and CD8+ T cells and reduced CD4+ Foxp3+ Tregs to synergistically enhance targeted chemotherapy and immunotherapy. Overall, this strategy presents a promising advancement in nucleus-targeted cancer therapy, synergistically boosting the efficacy of chemotherapy and immunotherapy.

Cobalt(III)-Macrocyclic Scaffolds with Anti-Cancer Stem Cell Activity.

Cobalt(III) compounds with tetradentate ligands have been widely employed to deliver cytotoxic and imaging agents into cells. A large body of work has focused on using cobalt(III)-cyclam scaffolds for this purpose. Here, we investigate the cytotoxic properties of cobalt(III) complexes containing 14-membered macrocycles related to cyclam. A breast cancer stem cell (CSC) in vitro model was used to gauge efficacy. Specifically, [Co(1,4,7,11-tetraazacyclotetradecane)Cl2]+ (1) and [Co(1-oxa-4,8,12-triazacyclotetradecane)Cl2]+ (2) were synthesised and characterised, and their breast CSC activity was determined. The cobalt(III) complexes 1 and 2 displayed micromolar potency towards bulk breast cancer cells and breast CSCs grown in monolayers. Notably, 1 and 2 displayed selective potency towards breast CSCs over bulk breast cancer cells (up to 4.5-fold), which was similar to salinomycin (an established breast CSC-selective agent). The cobalt(III) complexes 1 and 2 were also able to inhibit mammosphere formation at low micromolar doses (with respect to size and number). The mammopshere inhibitory effect of 2 was similar to that of salinomycin. Our studies show that cobalt(III) complexes with 1,4,7,11-tetraazacyclotetradecane and 1-oxa-4,8,12-triazacyclotetradecane macrocycles could be useful starting points for the development of new cobalt-based delivery systems that can transport cytotoxic and imaging agents into breast CSCs.

Au⋠⋠⋠H-X (X=N or C) Intramolecular Interactions in Gold (I)-NHC Carbene Complexes with Potential Anticancer Properties: A Quantum Mechanical Study with Two Basis Sets.

Three cationic Gold(I)-NHC complexes with potential anticancer properties were studied using DFT with B3LYP functional in combination with two basis sets, LanL2DZ and SDD. Obtained equilibrium geometries and computed IR spectra were found in excellent agreement with previously reported x-ray structures and experimental IR spectral data. NBO population analysis showed gold(I) has a charge deficiency of 0.26-0.30 e. All three complex cations are polar, with dipole moment values ranging from 6.8 to 7.4 Debye. Regardless of some structural differences in their co-ligands, all three complex cations have remarkably similar HOMO-LUMO energy gaps, with values ranging from 5.2 to 5.4 eV, confirming they are chemically stable and that they share an almost identical stability. Long-range intramolecular interactions Au ⋅⋅⋅H-X (X=N or C) in all three cationic complexes were identified. Both basis sets employed in this study were found equally effective in producing reliable results.

Synthetic Mn3Ce2O5-Cluster Mimicking the Oxygen-Evolving Center in Photosynthesis.

The photosynthetic oxygen-evolving center (OEC) is a unique Mn4CaO5-cluster that catalyses water splitting into electrons, protons, and dioxygen. Precisely structural and functional mimicking of the OEC is a long-standing challenge and pressingly needed for understanding the structure-function relationship and catalytic mechanism of O-O bond formation. Herein we report two simple and robust artificial Mn3Ce2O5-complexes that display a remarkable structural similarity to the OEC in regarding of the ten-atom core (five metal ions and five oxygen bridges) and the alkyl carboxylate peripheral ligands. This Mn3Ce2O5-cluster can catalyse the water-splitting reaction on the surface of ITO electrode. These results clearly show that cerium can structurally and functionally replace both calcium and manganese in the cluster. Mass spectroscopic measurements demonstrate that the oxide bridges in the cluster are exchangeable and can be rapidly replaced by the isotopic oxygen of H2 18O in acetonitrile solution, which supports that the oxide bridge(s) may serve as the active site for the formation of O-O bond during the water-splitting reaction. These results would contribute to our understanding of the structure-reactivity relationship of both natural and artificial clusters and shed new light on the development of efficient water-splitting catalysts in artificial photosynthesis.

Endowing Pt(IV) with Perfluorocarbon Chains and Human Serum Albumin Encapsulation for Highly Effective Antitumor Chemoimmunotherapy.

Tumor metastases and reoccurrence are considered the leading causes of cancer-associated deaths. As an emerging therapeutic method, increasing research efforts have been devoted to immunogenic cell death (ICD)-inducing compounds to solve the challenge. The clinically approved chemotherapeutic Pt complexes are not or are only poorly able to trigger ICD. Herein, the axial functionalization of the Pt(II) complex cisplatin with perfluorocarbon chains into ICD-inducing Pt(IV) prodrugs is reported. Strikingly, while the Pt(II) complex as well as the perfluorocarbon ligands did not induce ICD, the Pt(IV) prodrug demonstrated unexpectantly the induction of ICD through accumulation in the endoplasmic reticulum and generation of reactive oxygen species in this organelle. To enhance the pharmacological properties, the compound was encapsulated with human serum albumin into nanoparticles. While selectively accumulating in the tumorous tissue, the nanoparticles demonstrated a strong tumor growth inhibitory effect against osteosarcoma inside a mouse model. In vivo tumor vaccine analysis also demonstrated the ability of Pt(IV) to be an ideal ICD inducer. Overall, this study reports on axially perfluorocarbon chain-modified Pt(IV) complexes for ICD induction and chemoimmunotherapy in osteosarcoma.

A database overview of metal-coordination distances in metalloproteins.

Metalloproteins are ubiquitous in all living organisms and take part in a very wide range of biological processes. For this reason, their experimental characterization is crucial to obtain improved knowledge of their structure and biological functions. The three-dimensional structure represents highly relevant information since it provides insight into the interaction between the metal ion(s) and the protein fold. Such interactions determine the chemical reactivity of the bound metal. The available PDB structures can contain errors due to experimental factors such as poor resolution and radiation damage. A lack of use of distance restraints during the refinement and validation process also impacts the structure quality. Here, the aim was to obtain a thorough overview of the distribution of the distances between metal ions and their donor atoms through the statistical analysis of a data set based on more than 115 000 metal-binding sites in proteins. This analysis not only produced reference data that can be used by experimentalists to support the structure-determination process, for example as refinement restraints, but also resulted in an improved insight into how protein coordination occurs for different metals and the nature of their binding interactions. In particular, the features of carboxylate coordination were inspected, which is the only type of interaction that is commonly present for nearly all metals.

Dinuclear Rhenium(I) Tricarbonyl Complexes as Anticancer Drug Candidates.

Cancer is one of the deadliest diseases worldwide. Chemotherapy remains one of the most dominant forms for anticancer treatment. Despite their clinical success, the used chemotherapeutic agents are associated with severe side effect and pharmacological limitations. To overcome these drawbacks there is a need for the development of new types of chemotherapeutic agents. Herein, the chemical synthesis and biological evaluation of dinuclear rhenium(I) complexes as potential chemotherapeutic drug candidates are proposed. The metal complexes were found to be internalized by an energy dependent endocytosis pathway, primary accumulating in the mitochondria. The rhenium(I) complexes demonstrated to induce cell death against a variety of cancer cells in the micromolar range through apoptosis. The lead compound showed to eradicate a pancreatic carcinoma multicellular tumor spheroid at micromolar concentrations.

Quest for a stable Cu-ligand complex with a high catalytic activity to produce reactive oxygen species.

Metal ion-catalyzed overproduction of reactive oxygen species (ROS) is believed to contribute significantly to oxidative stress and be involved in several biological processes, from immune defense to development of diseases. Among the essential metal ions, copper is one of the most efficient catalysts in ROS production in the presence of O2 and a physiological reducing agent such as ascorbate. To control this chemistry, Cu ions are tightly coordinated to biomolecules. Free or loosely bound Cu ions are generally avoided to prevent their toxicity. In the present report, we aim to find stable Cu-ligand complexes (Cu-L) that can efficiently catalyze the production of ROS in the presence of ascorbate under aerobic conditions. Thermodynamic stability would be needed to avoid dissociation in the biological environment, and high ROS catalysis is of interest for applications as antimicrobial or anticancer agents. A series of Cu complexes with the well-known tripodal and tetradentate ligands containing a central amine linked to three pyridyl-alkyl arms of different lengths were investigated. Two of them with mixed arm length showed a higher catalytic activity in the oxidation of ascorbate and subsequent ROS production than Cu salts in buffer, which is an unprecedented result. Despite these high catalytic activities, no increased antimicrobial activity toward Escherichia coli or cytotoxicity against eukaryotic AGS cells in culture related to Cu-L-based ROS production could be observed. The potential reasons for discrepancy between in vitro and in cell data are discussed.

Toward a Mechanism-Driven Integrated Framework to Link Human Exposure to Multiple Toxic Metal(loid) Species with Environmental Diseases.

The ongoing anthropogenic pollution of the biosphere with As, Cd, Hg and Pb will inevitably result in an increased influx of their corresponding toxic metal(loid) species into the bloodstream of human populations, including children and pregnant women. To delineate whether the measurable concentrations of these inorganic pollutants in the bloodstream are tolerable or implicated in the onset of environmental diseases urgently requires new insight into their dynamic bioinorganic chemistry in the bloodstream-organ system. Owing to the human exposure to multiple toxic metal(loid) species, the mechanism of chronic toxicity of each of these needs to be integrated into a framework to better define the underlying exposure-disease relationship. Accordingly, this review highlights some recent advances into the bioinorganic chemistry of the Cd2+, Hg2+ and CH3Hg+ in blood plasma, red blood cells and target organs and provides a first glimpse of their emerging mechanisms of chronic toxicity. Although many important knowledge gaps remain, it is essential to design experiments with the intent of refining these mechanisms to eventually establish a framework that may allow us to causally link the cumulative exposure of human populations to multiple toxic metal(loid) species with environmental diseases of unknown etiology that do not appear to have a genetic origin. Thus, researchers from a variety of scientific disciplines need to contribute to this interdisciplinary effort to rationally address this public health threat which may require the implementation of stronger regulatory requirements to improve planetary and human health, which are fundamentally intertwined.

Thermoresponsive carboplatin-releasing prodrugs.

Platinum-based anticancer drugs, while potent, are associated with numerous and severe side effects. Hyperthermia therapy is an effective adjuvant in anticancer treatment, however, clinically used platinum drugs have not been optimised for combination with hyperthermia. The derivatisation of existing anticancer drugs with appropriately chosen thermoresponsive moieties results in drugs being activated only at the heated site. Perfluorinated chains of varying lengths were installed on carboplatin, a clinically approved drug, leading to the successful synthesis of a series of mono- and di- substituted platinum(IV) carboplatin prodrugs. Some of these complexes display relevant thermosensitivity on ovarian cancer cell lines, i.e., being inactive at 37 °C while having comparable activity to carboplatin under mild hyperthermia (42 °C). Nuclear magnetic resonance spectroscopy and mass spectrometry indicated that carboplatin is likely the active platinum(II) anticancer agent upon reduction and cyclic voltammetry revealed that the length of the fluorinated alkyl chain has a strong influence on the rate of carboplatin formation, regulating the subsequent cytotoxicity.

Glutathione Protects other Cellular Thiols against Oxidation by CuII-Dp44mT.

Cu-thiosemicarbazones have been intensively investigated for their application in cancer therapy or as antimicrobials. Copper(II)-di-2-pyridylketone-4,4-dimethyl-thiosemicarbazone (CuII-Dp44mT) showed anticancer activity in the submicromolar concentration range in cell culture. The interaction of CuII-Dp44mT with thiols leading to their depletion or inhibition was proposed to be involved in this activity. Indeed, CuII-Dp44mT can catalyze the oxidation of thiols although with slow kinetics. The present work aims to obtain insights into the catalytic activity and selectivity of CuII-Dp44mT toward the oxidation of different biologically relevant thiols. Reduced glutathione (GSH), L-cysteine (Cys), N-acetylcysteine (NAC), D-penicillamine (D-Pen), and the two model proteins glutaredoxin (Grx) and thioredoxin (Trx) were investigated. CuII-Dp44mT catalyzed the oxidation of these thiols with different kinetics, with rates in the following order D-Pen>Cys≫NAC>GSH and Trx>Grx. CuII-Dp44mT was more efficient than CuII chloride for the oxidation of NAC and GSH, but not D-Pen and Cys. In mixtures of biologically relevant concentrations of GSH and either Cys, Trx, or Grx, the oxidation kinetics and spectral properties were similar to that of GSH alone, indicating that the interaction of these thiols with CuII-Dp44mT is dominated by GSH. Hence GSH could protect other thiols against potential deleterious oxidation by CuII-Dp44mT.

Making and Breaking Helical Open-Chain Oligopyrroles.

Closed-chain oligopyrroles such as porphyrins or corroles have been well-established in literature and experience a steadily strong interest by several fields of science. However, their open-chain derivatives are comparatively underrepresented, despite their intriguing properties and promising applications. Here, we aim to review typical synthetic routes, as well as point towards several emergent properties, marking them as interesting candidates for various fields of study. The review focuses on two traditional methods (each starting from highly symmetric metalloporphyrins) and then expands its scope towards more recent variations before moving on to more exotic and recent highlights that have yet to be included into the canon. Key chemical reactivities (ring closure, substitution and fragmentation) are then followed by notable physicochemical properties, placing special emphasis on potential uses in molecular electronics and sensors.

Stimulus-Responsive Copper Complex Nanoparticles Induce Cuproptosis for Augmented Cancer Immunotherapy.

Cuproptosis, an emerging form of programmed cell death, has received tremendous attention in cancer therapy. However, the efficacy of cuproptosis remains limited by the poor delivery efficiency of copper ion carriers. Herein, copper complex nanoparticles (denoted as Cu(I) NP) are developed that can efficiently deliver copper complex into cancer cells to induce cuproptosis. Cu(I) NP demonstrate stimulus-responsive release of copper complexes, which results in mitochondrial dysfunction and promotes the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), leading to cuproptosis. Notably, Cu(I) NP not only induce cuproptosis, but also elicit robust immune responses to suppress tumor growth. Overall, this study provides a promising strategy for cuproptosis-based cancer therapy.

Improving In Vivo Tumor Accumulation and Efficacy of Platinum Antitumor Agents by Electronic Tuning of the Kinetic Lability.

The impact of kinetic lability or reactivity on in vitro cytotoxicity, stability in plasma, in vivo tumor and tissue accumulation, and antitumor efficacy of functional platinum(II) (Pt) anticancer agents containing a O˄O ß-diketonate leaving ligand remain largely unexplored. To investigate this, we synthesized Pt complexes [(NH3 )2 Pt(L1-H)]NO3 and [(DACH)Pt(L1-H)]NO3 (L1=4,4,4-trifluoro-1-ferrocenylbutane-1,3-dione, DACH=1R,2R-cyclohexane-1,2-diamine) containing an electron deficient [L1-H]- O˄O leaving ligand and [(NH3 )2 Pt(L2-H)]NO3 and [(DACH)Pt(L2-H)]NO3 (L2=1-ferrocenylbutane-1,3-dione) containing an electron-rich [L2-H]- O˄O leaving ligand. While all four complexes have comparable lipophilicity, the presence of the electron-withdrawing CF3 group was found to dramatically enhance the reactivity of these complexes toward nucleophilic biomolecules. In vitro cellular assays revealed that the more reactive complexes have higher cellular uptake and higher anticancer potency as compared to their less reactive analogs. But the scenario is opposite in vivo, where the less reactive complex showed improved tissue and tumor accumulation and better anticancer efficacy in mice bearing ovarian xenograft when compared to its more reactive analog. Finally, in addition to demonstrating the profound but contrasting impact of kinetic lability on in vitro and in vivo antitumor potencies, we also described the impact of kinetic lability on the mechanism of action of this class of promising antitumor agents.

Development of Pan-Anti-SARS-CoV-2 Agents through Allosteric Inhibition of nsp14/nsp10 Complex.

SARS-CoV-2 nsp14 functions both as an exoribonuclease (ExoN) together with its critical cofactor nsp10 and as an S-adenosyl methionine-dependent (guanine-N7) methyltransferase (MTase), which makes it an attractive target for the development of pan-anti-SARS-CoV-2 drugs. Herein, we screened a panel of compounds (and drugs) and found that certain compounds, especially Bi(III)-based compounds, could allosterically inhibit both MTase and ExoN activities of nsp14 potently. We further demonstrated that Bi(III) binds to both nsp14 and nsp10, resulting in the release of Zn(II) ions from the enzymes as well as alternation of protein quaternary structures. The in vitro activities of the compounds were also validated in SARS-CoV-2-infected mammalian cells. Importantly, we showed that nsp14 serves as an authentic target of Bi(III)-based antivirals in SARS-CoV-2-infected mammalian cells by quantification of both the protein and inhibitor. This study highlights the importance of nsp14/nsp10 as a potential target for the development of pan-antivirals against SARS-CoV-2 infection.

Alendronate PtIV Prodrug Amphiphile for Enhanced Chemotherapy Targeting and Bone Destruction Inhibition in Osteosarcoma.

Chemotherapy remains the primary treatment method for osteosarcoma after surgery. However, the lack of selectivity of chemotherapy for osteosarcoma leads to unpredictable therapeutic effects, undesirable side effects, and drug resistance. A platinum(IV) (PtIV ) prodrug amphiphile (ALN-PtIV -Lipo) covalently bound to alendronate (ALN) and a lipid tail is designed to overcome these limitations. ALN-PtIV -Lipo can self-assemble into PtIV lipid nanoparticles (APtIV ) for osteosarcoma targeting chemotherapy and bone destruction inhibition. It is demonstrated that APtIV achieved an eightfold increase in the eradication of osteosarcoma cells compared to cisplatin and threefold selective inhibition of osteosarcoma cells over breast cancer cells via APtIV in vitro. After intravenous injection, APtIV effectively accumulates at the osteosarcoma site in vivo, resulting in significantly suppressed primary osteosarcoma growth, and alleviation of bone destruction. Therefore, APtIV delivers a promising solution for enhanced chemotherapy targeting and bone destruction inhibition in osteosarcoma.

Nitrite and Nitric Oxide Interconversion at Mononuclear Copper(II): Insight into the Role of the Red Copper Site in Denitrification.

Nitrite (NO2 - ) and nitric oxide (NO) interconversion is crucial for maintaining optimum NO flux in mammalian physiology. Herein we demonstrate that [L2 CuII (nitrite)]+ moieties (in 2 a and 2 b; where, L = Me2 PzPy and Me2 PzQu) with distorted octahedral geometry undergo facile reduction to provide tetrahedral [L2 CuI ]+ (in 3 a and 3 b) and NO in the presence of biologically relevant reductants, such as 4-methoxy-2,6-di-tert-butylphenol (4-MeO-2,6-DTBP, a tyrosine model) and N-benzyl-1,4-dihydronicotinamide (BNAH, a NAD(P)H model). Interestingly, the reaction of excess NO gas with [L2 CuII (MeCN)2 ]2+ (in 1 a) provides a putative {CuNO}10 species, which is effective in mediating the nitrosation of various nucleophiles, such as thiol and amine. Generation of the transient {CuNO}10 species in wet acetonitrile leads to NO2 - as assessed by Griess assay and 14 N/15 N-FTIR analyses. A detailed study reveals that the bidirectional NOx -reactivity, namely, nitrite reductase (NIR) and NO oxidase (NOO), at a common CuII site, is governed by the geometric-preference-driven facile CuII /CuI redox process. Of broader interest, this study not only highlights potential strategies for the design of copper-based catalysts for nitrite reduction, but also strengthens the previous postulates regarding the involvement of red copper proteins in denitrification.

Translational toxicology of metal(loid) species: linking their bioinorganic chemistry in the bloodstream to organ damage onset.

The quantification of arsenic, mercury, cadmium and lead in the human bloodstream is routinely used today to assess exposure to these toxic metal(loid)s, but the interpretation of the obtained data in terms of their cumulative health relevance remains problematic. Seemingly unrelated to this, epidemiological studies strongly suggest that the simultaneous chronic exposure to these environmental pollutants is associated with the etiology of autism, type 2 diabetes, irritable bowel disease and other diseases. This from a public health point of view undesirable situation urgently requires research initiatives to establish functional connections between human exposure to multiple toxic metal(loid) species and adverse health effects. One way to establish causal exposure-response relationships is a molecular toxicology approach, which requires one to unravel the biomolecular mechanisms that unfold after individual toxic metal(loid)s enter the bloodstream/organ nexus as these interactions ultimately determine which metabolites impinge on target organs and thus provide mechanistic links to diseases of unknown etiology. In an attempt to underscore the importance of the toxicological chemistry of metal(loid)s in the bloodstream, this review summarizes recent progress into relevant bioinorganic processes that are implicated in the etiology of adverse organ-based health effects and possibly diseases. A better understanding of these bioinorganic processes will not only help to improve the regulatory framework to better protect humans from the adverse effects of toxic metal(loid) species, but also represents an important starting point for the development of treatments to ameliorate pollution-induced adverse health effects on human populations, including pregnant women, the fetus and children.

A designed Copper Histidine-brace enzyme for oxidative depolymerization of polysaccharides as a model of lytic polysaccharide monooxygenase.

The "Histidine-brace" (His-brace) copper-binding site, composed of Cu(His)2 with a backbone amine, is found in metalloproteins with diverse functions. A primary example is lytic polysaccharide monooxygenase (LPMO), a class of enzymes that catalyze the oxidative depolymerization of polysaccharides, providing not only an energy source for native microorganisms but also a route to more effective industrial biomass conversion. Despite its importance, how the Cu His-brace site performs this unique and challenging oxidative depolymerization reaction remains to be understood. To answer this question, we have designed a biosynthetic model of LPMO by incorporating the Cu His-brace motif into azurin, an electron transfer protein. Spectroscopic studies, including ultraviolet-visible (UV-Vis) absorption and electron paramagnetic resonance, confirm copper binding at the designed His-brace site. Moreover, the designed protein is catalytically active towards both cellulose and starch, the native substrates of LPMO, generating degraded oligosaccharides with multiturnovers by C1 oxidation. It also performs oxidative cleavage of the model substrate 4-nitrophenyl-D-glucopyranoside, achieving a turnover number ~9% of that of a native LPMO assayed under identical conditions. This work presents a rationally designed artificial metalloenzyme that acts as a structural and functional mimic of LPMO, which provides a promising system for understanding the role of the Cu His-brace site in LPMO activity and potential application in polysaccharide degradation.

Synergistic Activation of Nitrite and Thiocarbonyl Compounds Affords NO and Sulfane Sulfur via (Per)thionitrite (SNO- /SSNO- ).

(Per)thionitrite (SNO- /SSNO- ) intermediates play vital roles in modulating nitric oxide (NO) and hydrogen sulfide (H2 S) dependent bio-signalling processes. Whilst the previous preparations of such intermediates involved reactive H2 S/HS- or sulfane sulfur (S0 ) species, the present report reveals that relatively stable thiocarbonyl compounds (such as carbon disulfide (CS2 ), thiocarbamate, thioacetic acid, and thioacetate) react with nitrite anion to yield SNO- /SSNO- . For instance, the reaction of CS2 and nitrite anion (NO2 - ) under ambient condition affords CO2 and SNO- /SSNO- . A detailed investigation involving UV/Vis, FTIR, HRMS, and multinuclear NMR studies confirm the formation of SNO- /SSNO- , which are proposed to form through an initial nucleophilic attack by nitrite anion followed by a transnitrosation step. Notably, reactions of CS2 and nitrite in the presence of thiol RSH show the formation of organic polysulfides R-Sn -R, thereby illustrating that the thiocarbonyls are capable of influencing the pool of bioavailable sulfane sulfurs. Furthermore, the availability of both NO2 - and thiocarbonyl motifs in the biological context hints at their synergistic metal-free activations leading to the generation of NO gas and various reactive sulfur species via SNO- /SSNO- .