Development of a novel HPLC-CDCL method utilizing nitrogen-doped carbon dots for sensitive and selective detection of dithiocarbamate pesticides in tea.

In this study, S-methyl derivatives of dithiocarbamates (DTCs) were shown to significantly enhance chemiluminescence (CL) between Ce(IV) and efficient and environmentally friendly nitrogen-doped carbon dots (NCDs). Based on the elucidation of the CL mechanisms, an innovative approach involving high-performance liquid chromatography coupled with N-CDs and CL detection (HPLC-CDCL) was proposed. The developed method was successfully applied to the highly sensitive detection of three DTC fungicides (dimethyl dithiocarbamate, ethylene bisdithiocarbamate, and propylene bisdithiocarbamate) in tea. The recovery of the established method ranged 70.51-116.45%, with relative standard deviations (RSD) of <9.40%. The limit of detection (S/N = 3) was as low as 0.19 µg/L (as CS2), which is superior to the previous methods and comparable to UPLC-tandem mass spectrometry (MS/MS). Moreover, the proposed approach does not require solid-phase extraction and offers excellent selectivity. This study proposes a novel method for the detection of DTCs in the food safety and environmental fields.

Dynamics of the content of reactive oxygen species and the state of the glutathione system in the oral cavity during subchronic intoxication wuth the fungicide thiram and its antioxidant correction.

Thiram is a dithiocarbamate derivative, which is used as a fungicide for seed dressing and spraying during the vegetation period of plants, and also as an active vulcanization accelerator in the production of rubber-based rubber products. In this study the content of reactive oxygen species (ROS) and the state of the glutathione system have been investigated in the oral fluid and gum tissues of adult male Wistar rats treated with thiram for 28 days during its administration with food at a dose of 1/50 LD50. Thiram induced formation of ROS in the oral cavity; this was accompanied by an imbalance in the ratio of reduced and oxidized forms of glutathione due to a decrease in glutathione and an increase in its oxidized form as compared to the control. Thiram administration caused an increase in the activity of glutathione-dependent enzymes (glutathione peroxidase, glutathione transferase, and glutathione reductase). However, the time-course of enzyme activation in the gum tissues and oral fluid varied in dependence on the time of exposure to thiram. In the oral fluid of thiram-treated rats changes in the antioxidant glutathione system appeared earlier. The standard diet did not allow the glutathione pool to be fully restored to physiological levels after cessation of thiram intake. The use of exogenous antioxidants resviratrol and an Echinacea purpurea extract led to the restoration of redox homeostasis in the oral cavity.

A novel analytical approach for the determination of ethylene-thiourea and propylene-thiourea in vegetal foodstuffs by high-performance liquid chromatography hyphenated to inductively coupled plasma-tandem mass spectrometry.

This study reports a novel analytical approach for the simultaneous determination of ethylene-thiourea (ETU) and propylene-thiourea (PTU) in fruits and vegetables by (reverse phase) high-performance liquid chromatography (HPLC) coupled to inductively coupled plasma-tandem mass spectrometry (ICP-QQQMS or ICP-MS/MS). A baseline separation of ETU and PTU was achieved in less than 5 min. A robust method validation by using the accuracy profile approach was performed by carrying out four measurement series in duplicate at six different levels over a timespan of 4 weeks (different days). The recovery factors ranged from 87 to 101% for ETU and from 98 to 99% for PTU (depending on the spiking level). The coefficient of variation in terms of repeatability (CVr) ranged from 1 to 4.7% for ETU and from 1.8 to 3.9% for PTU (depending also on the analyte level) while the coefficient of variation in terms of intermediate reproducibility (CVR) ranged from 3.4 to 10% for ETU and from 1.8 to 10.8% for PTU. The limit of quantification was 0.022 mg kg-1 (wet weight) for ETU and 0.010 mg kg-1 (ww) for PTU. This novel approach was proved to be highly robust and suitable for the determination of ETU and PTU in foodstuffs of vegetal origin.

Effects of Copper or Zinc Organometallics on Cytotoxicity, DNA Damage and Epigenetic Changes in the HC-04 Human Liver Cell Line.

Copper and zinc organometallics have multiple applications and many are considered "data-poor" because the available toxicological information is insufficient for comprehensive health risk assessments. To gain insight into the chemical prioritization and potential structure activity relationship, the current work compares the in vitro toxicity of nine "data-poor" chemicals to five structurally related chemicals and to positive DNA damage inducers (4-nitroquinoline-oxide, aflatoxin-B1). The HC-04 non-cancer human liver cell line was used to investigate the concentration-response effects (24 h and 72 h exposure) on cell proliferation, DNA damage (γH2AX and DNA unwinding assays), and epigenetic effects (global genome changes in DNA methylation and histone modifications using flow cytometry). The 24 h exposure screening data (DNA abundance and damage) suggest a toxicity hierarchy, starting with copper dimethyldithiocarbamate (CDMDC, CAS#137-29-1) > zinc diethyldithiocarbamate (ZDEDC, CAS#14324-55-1) > benzenediazonium, 4-chloro-2-nitro-, and tetrachlorozincate(2-) (2:1) (BDCN4CZ, CAS#14263-89-9); the other chemicals were less toxic and had alternate ranking positions depending on assays. The potency of CDMDC for inducing DNA damage was close to that of the human hepatocarcinogen aflatoxin-B1. Further investigation using sodium-DMDC (SDMDC, CAS#128-04-1), CDMDC and copper demonstrated the role of the interactions between copper and the DMDC organic moiety in generating a high level of CDMDC toxicity. In contrast, additive interactions were not observed with respect to the DNA methylation flow cytometry data in 72 h exposure experiments. They revealed chemical-specific effects, with hypo and hypermethylation induced by copper chloride (CuCl2, CAS#10125-13-0) and zinc-DMDC (ZDMDC, CAS#137-30-4), respectively, but did not show any significant effect of CDMDC or SDMDC. Histone-3 hypoacetylation was a sensitive flow cytometry marker of 24 h exposure to CDMDC. This study can provide insights regarding the prioritization of chemicals for future study, with the aim being to mitigate chemical hazards.

Identification of novel dithiocarbamate-copper complexes targeting p97/NPL4 pathway in cancer cells.

Dithiocarbamates (DTCs) are simple organic compounds with many applications in industry and medicine. They are potent metal chelators forming complexes with various metal ions, including copper. Recently, bis(diethyldithiocarbamate)-copper complex (CuET) has been identified as a metabolic product of the anti-alcoholic drug Antabuse (disulfiram, DSF), standing behind DSF's reported anticancer activity. Mechanistically, CuET in cells causes aggregation of NPL4 protein, an essential cofactor of the p97 segregase, an integral part of the ubiquitin-proteasome system. The malfunction of p97/NPL4 caused by CuET leads to proteotoxic stress accompanied by heat shock and unfolded protein responses and cancer cell death. However, it is not known whether the NPL4 inhibition is unique for CuET or whether it is shared with other dithiocarbamate-copper complexes. Thus, we tested 20 DTCs-copper complexes in this work for their ability to target and aggregate NPL4 protein. Surprisingly, we have found that certain potency against NPL4 is relatively common for structurally different DTCs-copper complexes, as thirteen compounds scored in the cellular NPL4 aggregation assay. These compounds also shared typical cellular phenotypes reported previously for CuET, including the NPL4/p97 proteins immobilization, accumulation of polyubiquitinated proteins, the unfolded protein, and the heat shock responses. Moreover, the active complexes were also toxic to cancer cells (the most potent in the nanomolar range), and we have found a strong positive correlation between NPL4 aggregation and cytotoxicity, confirming NPL4 as a relevant target. These results show the widespread potency of DTCs-copper complexes to target NPL4 with subsequent induction of lethal proteotoxic stress in cancer cells with implications for drug development.

Exposure to Mancozeb results in increased MAPK phosphorylation and locomotor deficits in zebrafish larvae.

Mancozeb is a widely used fungicide whose toxicity has been reported in non-target organisms, being considered to have high or very high acute toxicity to aquatic organisms. However, the toxicity of this compound is not well characterized in the developmental stages of fish. In this study, Danio rerio with 4-, 5-, and 6-days post fertilization (dpf) was exposed to MZ at non-lethal concentrations for 24, 48, or 72 h and subsequently, behavioral alterations, oxidative stress parameters and ERK, p38MAPK, and Akt phosphorylation were analyzed. MZ exposure during the larval period decreased motor performance evaluated by traveled distance, immobile time, and time spent in the peripheral area. In parallel, MZ induced ROS levels and increased the number of cells in apoptosis, causing severe DNA damage, inducing Acetylcholinesterase and Superoxide dismutase activities, and inhibiting Glutathione peroxidase and thioredoxin reductase. Additionally, phosphorylation levels of the proteins p38MAPK, ERK2, and Akt were stimulated. These findings are relevant considering the ecological implications of MZ exposure to fishes in different developmental stages and the role of the MAPK pathway in events like development and cell death.

Current electroanalytical approaches in the carbamates and dithiocarbamates determination.

Pesticides are a suitable tool for controlling plagues and disease vectors. However, their inappropriate use allows for contamination of the environment, soil, water, and foods. Carbamates and dithiocarbamates pesticides present accumulative effects in the human body resulting in hormonal, neurological and reproductive disorders, and some are still suspected or proven to give carcinogenic or mutagenic effects. This review provides a current electroanalytical approach in the carbamates and dithiocarbamates determination, showing the use of voltammetric techniques such as amperometry, cyclic and linear scan, differential pulse, and square wave voltammetry, indicating their advantages, disadvantages, and perspectives in electroanalytical detection of carbamates and dithiocarbamates in natural water and foods. Also are reported the different materials used in the preparation of working electrodes since their choice has an important impact on the success of the analytical applications, resulting in suitable sensitivity, selectivity, stability, and robustness.

Mancozeb-induced hepatotoxicity: protective role of curcumin in rat animal model.

Background: Mancozeb-a widely used fungicide in the agricultural sector-is believed to cause toxicity by increasing oxidative stress. This work investigated the efficacy of curcumin in protecting mancozeb-induced hepatotoxicity. Materials and Methods: Mature Wistar rats were assigned into 4 equal groups: control, mancozeb (30 mg/kg/day, ip), curcumin (100 mg/kg/day, po), and mancozeb+curcumin. The experiment lasted for 10 days. Results: Our results reported that mancozeb elevated aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, gamma glutamyltranspeptidase enzyme activities, and total bilirubin level in plasma; and decreased total protein and albumin levels, compared with the control group (P < 0.05-0.001). Hepatic tissue levels of malondialdehyde, and advanced oxidation protein products were significantly increased; whereas activities of superoxide dismutase, catalase, glutathione peroxidase, as well as levels of reduced glutathione, vitamin C, and total protein were reduced (P < 0.05-0.001). Histopathological examination showed marked histological changes. Co-treatment with curcumin improved the antioxidant activity; reversed oxidative stress and biochemical changes; and restored most of the liver histo-morphological alterations; thus, attenuating the hepatic toxicities induced by mancozeb. Conclusion: These results indicated that curcumin could protect against detrimental hepatic effects induced by mancozeb.

Development and Evaluation of the Magnetic Properties of a New Manganese (II) Complex: A Potential MRI Contrast Agent.

Magnetic resonance imaging (MRI) is a non-invasive powerful modern clinical technique that is extensively used for the high-resolution imaging of soft tissues. To obtain high-definition pictures of tissues or of the whole organism this technique is enhanced by the use of contrast agents. Gadolinium-based contrast agents have an excellent safety profile. However, over the last two decades, some specific concerns have surfaced. Mn(II) has different favorable physicochemical characteristics and a good toxicity profile, which makes it a good alternative to the Gd(III)-based MRI contrast agents currently used in clinics. Mn(II)-disubstituted symmetrical complexes containing dithiocarbamates ligands were prepared under a nitrogen atmosphere. The magnetic measurements on Mn complexes were carried out with MRI phantom measurements at 1.5 T with a clinical magnetic resonance. Relaxivity values, contrast, and stability were evaluated by appropriate sequences. Studies conducted to evaluate the properties of paramagnetic imaging in water using a clinical magnetic resonance showed that the contrast, produced by the complex [Mn(II)(L')2] × 2H2O (L' = 1.4-dioxa-8-azaspiro[4.5]decane-8-carbodithioate), is comparable to that produced by gadolinium complexes currently used in medicine as a paramagnetic contrast agent.

Synthesis of BaZrS3 and BaHfS3 Chalcogenide Perovskite Films Using Single-Phase Molecular Precursors at Moderate Temperatures.

Chalcogenide perovskites have garnered interest for applications in semiconductor devices due to their excellent predicted optoelectronic properties and stability. However, high synthesis temperatures have historically made these materials incompatible with the creation of photovoltaic devices. Here, we demonstrate the solution processed synthesis of luminescent BaZrS3 and BaHfS3 chalcogenide perovskite films using single-phase molecular precursors at sulfurization temperatures of 575 °C and sulfurization times as short as one hour. These molecular precursor inks were synthesized using known carbon disulfide insertion chemistry to create Group 4 metal dithiocarbamates, and this chemistry was extended to create species, such as barium dithiocarboxylates, that have never been reported before. These findings, with added future research, have the potential to yield fully solution processed thin films of chalcogenide perovskites for various optoelectronic applications.

Trends in dithiocarbamates food research: A bibliometric vision.

Dithiocarbamate Fungicides (DTFs) are widely analyzed and studied mainly due to the fact that they play an important role in the cultivation of fruits and vegetables. This manuscript aims to display the results of a bibliometric analysis based on the Web of Science© database, performed in the DTF and food research area. A total of 374 publications were examined. The most scientific production was concentrated between 2012 and 2021, showing a decrease of 32% over the last two years. The Journal of Agricultural and Food Chemistry, India, and Sardar Vallabhbhai National Institute of Technology were the most productive journal, country, and institution, respectively. Reference Publication Year Spectroscopy index showed a decrease of 95% in the last last years studied. Finally, current and future trends should focus on keywords such as individual DTF (Mancozeb, Thiram and Maneb), metabolites (Ethylenethiourea, Propilenthiourea) and a change in the analysis methodology: HPLC versus traditional GC.

An Improved Synthetic Method for Sensitive Iodine Containing Tricyclic Flavonoids.

The synthesis of new iodine containing synthetic tricyclic flavonoids is reported. Due to the sensitivity of the precursors to the heat and acidic conditions required for the ring closure of the 1,3-dithiolium core, a new cyclization method has been developed. It consists in the treatment of the corresponding iodine-substituted 3-dithiocarbamic flavonoids with a 1:1 (v/v) mixture of glacial acetic acid-concentrated sulfuric acid at 40 °C. The synthesis of the iodine-substituted 3-dithiocarbamic flavonoids has also been tuned in terms of reaction conditions.

Laser-induced electron transfer desorption/ionization on MoO3 and WO3 surfaces for the determination of dithiocarbamates.

Surface layers of molybdenum oxide MoO3 and tungsten oxide WO3 produced by thermal oxidation of molybdenum and tungsten plates in the air were studied for the first time as a platform for laser-induced electron transfer desorption/ionization. High analytical performance of such layers for the determination of metal complexes with dithiocarbamates, such as tetramethylthiuram disulfide, tetraethylthiuram disulfide, and diethyldithiocarbamate, has been demonstrated. All studied complexes are detected as radical cations, with no fragment ions. The ion yields from MoO3 and WO3 surfaces were found to be more than two orders of magnitude higher than those from nanocrystalline silicon surfaces. A novel method has been developed for the determination of trace amounts of dithiocarbamates based on the complexation of analytes with gold ions, followed by laser-induced electron transfer desorption/ionization. The limits of detection of dithiocarbamates were estimated to be about 1 ng/mL. The proposed method was successfully applied to the rapid screening of tetramethylthiuram disulfide residues in juice.

Disulfiram and dithiocarbamate analogues demonstrate promising antischistosomal effects.

Schistosomiasis is a neglected tropical disease with more than 200 million new infections per year. It is caused by parasites of the genus Schistosoma and can lead to death if left untreated. Currently, only two drugs are available to combat schistosomiasis: praziquantel and, to a limited extent, oxamniquine. However, the intensive use of these two drugs leads to an increased probability of the emergence of resistance. Thus, the search for new active substances and their targeted development are mandatory. In this study the substance class of "dithiocarbamates" and their potential as antischistosomal agents is highlighted. These compounds are derived from the basic structure of the human aldehyde dehydrogenase inhibitor disulfiram (tetraethylthiuram disulfide, DSF) and its metabolites. Our compounds revealed promising activity (in vitro) against adults of Schistosoma mansoni, such as the reduction of egg production, pairing stability, vitality, and motility. Moreover, tegument damage as well as gut dilatations or even the death of the parasite were observed. We performed detailed structure-activity relationship studies on both sides of the dithiocarbamate core leading to a library of approximately 300 derivatives (116 derivatives shown here). Starting with 100 µm we improved antischistosomal activity down to 25 µm by substitution of the single bonded sulfur atom for example with different benzyl moieties and integration of the two residues on the nitrogen atom into a cyclic structure like piperazine. Its derivatization at the 4-nitrogen with a sulfonyl group or an acyl group led to the most active derivatives of this study which were active at 10 µm. In light of this SAR study, we identified 17 derivatives that significantly reduced motility and induced several other phenotypes at 25 µm, and importantly five of them have antischistosomal activity also at 10 µm. These derivatives were found to be non-cytotoxic in two human cell lines at 100 µm. Therefore, dithiocarbamates seem to be interesting new candidates for further antischistosomal drug development.

Sample Preparation Methods for Metal Containing Pesticides in Food and Environmental Samples.

Metal-containing pesticides are used in many areas for purposes such as harvest efficiency and keeping pests away from the vegetable environment. Metal-containing pesticides are in the form of dithiocarbamate complexes and are named differently according to the type of metal they contain and are used for different purposes. Since the presence of these pesticides even at residue level threatens human and environmental health, their determination at trace level is important. In this review, studies on the determination of metal-containing dithiocarbamate pesticides in different matrices are discussed. This review on the analysis of dithiocarbamate pesticides with different techniques will shed light on the studies to be carried out for the determination of these pesticides one by one in different matrices.

Ultrasound-Assisted Synthesis and In Silico Modeling of Methanesulfonyl-Piperazine-Based Dithiocarbamates as Potential Anticancer, Thrombolytic, and Hemolytic Structural Motifs.

Piperazine-based dithiocarbamates serve as important scaffolds for numerous pharmacologically active drugs. The current study investigates the design and synthesis of a series of dithiocarbamates with a piperazine unit as well as their biological activities. Under ultrasound conditions, the corresponding piperazine-1-carbodithioates 5a-5j were synthesized from monosubstituted piperazine 2 and N-phenylacetamides 4a-4j in the presence of sodium acetate and carbon disulfide in methanol. The structures of the newly synthesized piperazines were confirmed, and their anti-lung carcinoma effects were evaluated. A cytotoxic assay was performed to assess the hemolytic and thrombolytic potential of the synthesized piperazines 5a-5j. The types of substituents on the aryl ring were found to affect the anticancer activity of piperazines 5a-5j. Piperazines containing 2-chlorophenyl (5b; cell viability = 25.11 ± 2.49) and 2,4-dimethylphenyl (5i; cell viability = 25.31 ± 3.62) moieties demonstrated the most potent antiproliferative activity. On the other hand, piperazines containing 3,4-dichlorophenyl (5d; 0.1%) and 3,4-dimethylphenyl (5j; 0.1%) rings demonstrated the least cytotoxicity. The piperazine with the 2,5-dimethoxyphenyl moiety (5h; 60.2%) showed the best thrombolytic effect. To determine the mode of binding, in silico modeling of the most potent piperazine (i.e., 5b) was performed, and the results were in accordance with those of antiproliferation. It exhibits a similar binding affinity to PQ10 and an efficient conformational alignment with the lipophilic site of PDE10A conserved for PQ10A.

In vitro and in vivo antitumor studies of potential anticancer agents of platinum(II) complexes of dicyclopentadiene and dithiocarbamates§.

Three platinum(II) complexes of dicyclopentadiene (DCP) and dithiocarbamates (DTCs), namely, [Pt(η4-DCP)(Me2DTC)]PF6 (1), [Pt(η4-DCP)(Et2DTC)]PF6 (2), and [Pt(η4-DCP)(Bz2DTC)]PF6 (3) [Me2DTC = dimethyldithiocarbamate, Et2DTC = diethyldithiocarbamate, and Bz2DTC = dibenzyldithiocarbamate] were prepared and characterized by elemental analysis, IR, 1H, and 13C Nuclear Magnetic Resonance spectroscopy. The spectroscopic data indicated the coordination of both DCP and DTC ligands to platinum(II). The solution chemistry of complex 1 revealed that the complexes are stable in both dimethyl sulfoxide (DMSO) and 1:1 mixture of DMSO:H2O. In vitro cytotoxicity of the complexes relative to cisplatin was tested using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, against CHL-1 (human melanoma cancer cells), MDA-MB-231 (breast cancer cells), A549 (lung cancer cells), and B16 (murine melanoma cancer cells). The antiproliferative effect of all three prepared complexes was found to be significantly higher than cisplatin. Furthermore, flow cytometric analysis of complex 1 showed that the complex induced apoptosis, oxidative stress, mitochondrial potential depolarization and cell cycle arrest in a concentration-dependent pattern in the CHL-1 cells. Confirmation of apoptosis via gene expression analysis demonstrated down-regulation of anti-apoptotic genes and up-regulation of pro-apoptotic genes in the CHL-1 cells. Wound-healing assays also lent support to the strong cytotoxicity of the complexes. In vivo studies showed a significant reduction of tumor volume at the end of the experiment. In addition, the drug did not change the weight of the mice. In conclusion, complex 1 inhibited cell proliferation in vitro and reduced tumor growth in vivo.

Design, Synthesis and Anti-Tumor Activity Evaluation of Novel 3,4-(Methylenedioxy)cinnamic Acid Amide-Dithiocarbamate Derivatives.

The fragments, 3,4-(methylenedioxy)cinnamic acid amide and dithiocarbamates, have received increasing attention because of their multiple pharmacological activities in recent years, especially in anti-tumor. We synthesized 17 novel 3,4-(methylenedioxy)cinnamic acid amide-dithiocarbamate derivatives based on the principle of pharmacophore assembly and discovered that compound 4a7 displayed the most potent antiproliferative activity against HeLa cells with IC50 value of 1.01 µM. Further mechanistic studies revealed that 4a7 triggered apoptosis in HeLa cells via activating mitochondria-mediated intrinsic pathways and effectively inhibited colony formation. Also, 4a7 had the ability to arrest cell cycle in the G2/M phase as well as to inhibit the migration in HeLa cells. More importantly, acute toxicity experiments showed that 4a7 had good safety in vivo. All the results suggested that compound 4a7 might serve as a promising lead compound that merited further attention in future anti-tumor drug discovery.

Dithiocarbamates as Effective Reversible Addition-Fragmentation Chain Transfer Agents for Controlled Radical Polymerization of 1-Vinyl-1,2,4-triazole.

Narrow dispersed poly(1-vinyl-1,2,4-triazole) (PVT) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization of 1-vinyl-1,2,4-triazole (VT). AIBN as the initiator and dithiocarbamates, xanthates, and trithiocarbonates as the chain transfer agents (CTA) were used. Dithiocarbamates proved to be the most efficient in VT polymerization. Gel permeation chromatography was used to determine the molecular weight distribution and polydispersity of the synthesized polymers. The presence of the CTA stabilizing and leaving groups in the PVT was confirmed by 1H and 13C NMR spectroscopy. The linear dependence of the degree of polymerization on time confirms the conduct of radical polymerization in a controlled mode. The VT conversion was over 98% and the PVT number average molecular weight ranged from 11 to 61 kDa. The polydispersity of the synthesized polymers reached 1.16. The occurrence of the controlled radical polymerization was confirmed by monitoring the degree of polymerization over time.

Copper-Promoted Hiyama Cross-Coupling of Arylsilanes With Thiuram Reagents: A Facile Synthesis of Aryl Dithiocarbamates.

We report herein a facile Hiyama cross-coupling reaction of arylsilanes with thiuram reagents (tetraalkylthiuram disulfides or tetraalkylthiuram monosulfide) enabled by copper fluoride. Compared to our previous work, this protocol is an alternative protocol for the generation of S-aryl dithiocarbamates. It features low toxic and readily available substrates, cost-effective promoter, easy performance, and provides good yields.