Photolysis kinetics of cartap and nereistoxin in water and tea beverages under irradiation of simulated sunlight and ultraviolet under laboratory conditions.

Cartap applied widely in agricultural crops and tea plants is readily degraded into nereistoxin, resulting in a longer residual period and higher exposure risk to humans. The photolysis kinetics of cartap and nereistoxin in water and tea beverages was firstly investigated to explore the effect and mechanism of pesticide residue removal. Cartap and nereistoxin could be effectively photolyzed by ultraviolet and their photolysis rate increased with light intensity increasing. The photolysis percentage of cartap and nereistoxin in different solutions under ultraviolet irradiation of 200 W mercury lamp reached 81.8%-100.0% within 6 h. Relative to water solution, the water-soluble components in tea had an inhibition effect on the photodegradation of cartap and nereistoxin. This research provided a reference for the development of effective methods for the removal of cartap and its metabolite in water and tea beverages.

Determination of trace levels of selenium in natural water, agriculture soil and food samples by vortex assisted liquid-liquid microextraction method: Multivariate techniques.

A green vortex assisted based liquid-liquid microextraction (VA-LLME) method was developed for preconcentration of selenium. Ammonium pyrrolidine dithiocarbamate (APDC) was used to form a hydrophobic complex with selenium in natural water, agricultural soil and food samples by GFAAS. Whereas Triton X-114, a nonionic surfactant and 1-butyl-3-methylimidazolium hexafluorophosphate ionic liquid were used for Se extraction as a dispersing medium. The conical flasks contents were shack on a vortex mixer to increase the extraction efficiency. Multivariate techniques were used to evaluate extraction parameters; pH, vortex time, APDC amount, volume of ionic liquid and Triton X-114 and centrifugation rate on the recovery of Se. The central composite design (CCD) was used for further optimization of the essential extraction parameters. The enhancement factor and limit of detection were obtained as 98.7 and 0.07 µg L-1. The certified reference materials was used for accuracy of method and the related standard deviation was found to be 3.51%. The resulted data indicated that concentrations of Se in all types of water samples were below the permissible limit recommended by WHO.

Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.

Disulfiram in conjunction with copper has been shown to be a potent anticancer agent. However, disulfiram's therapeutic potential in prostate cancer is hindered by off-target effects due to its reactive and nucleophilic thiol-containing component, diethyldithiocarbamate (DTC). To minimize undesirable reactivity, we have strategically blocked the thiol moiety in DTC with a cleavable p-aminobenzyl (pAB) group linked to peptide substrates recognized by prostate specific antigen (PSA). Here we report the synthesis and evaluation in cancer cell models of two PSA-activatable prodrugs: HPD (Ac-HSSKLQL-pAB-DTC and RPD (RSSYYSL-pAB-DTC). In vitro exposure to PSA was found to trigger activation of HPD and RPD to release diethyldithiocarbamate, and both prodrugs were found to induce toxicity in prostate cancer cells, with HPD showing the most promising selectivity. With copper supplementation, the IC50 of HPD was 1.4 µM in PSA-expressing LNCaP cells, and 11 µM in PC3 cells that do not express PSA. These studies demonstrate the utility of using peptide recognition handles to direct the activity of dithiocarbamate prodrugs for selective cytotoxicity of cancer cells.

Ratiometric electrochemical molecular switch for sensing hypochlorous acid: Applicable in food analysis and real-time in-situ monitoring.

A ratiometric electrochemical molecular sensing platform for real-time quantification of extracellular hypochlorous acid (HClO) production has been developed based on a latent electrochemical probe aminoferrocene thiocarbamate (AFTC 3). The substrate AFTC consist of a masked redox reporter amino ferrocene (AF 4) linked with a dimethylthiocarbamate trigger via hydroxyl benzyl alcohol. The conceptual idea behind the probe design is based on a specific chemical interaction between HClO and dimethylthiocarbamate, which allows only HClO to unmask the probe to releases AF. The scheme was manipulated to establish a highly selective (in presence of various reactive oxygen species, anions and other biological interfering species) and sensitive (detection limit 75 nM) sensing platform not only in lab samples but also in real samples (food samples, and live cells). Real-time in situ quantification platform was developed to profile HClO productions in macrophages, and it did so with great consistency.

Dissipation pattern and safety evaluation of cartap and its metabolites during tea planting, tea manufacturing and brewing.

There are few studies for risk assessment of cartap and its metabolites, although cartap is easily transformed into metabolites which could induce higher toxicity. This study aimed to investigate the dissipation pattern of cartap and its metabolites during tea planting, manufacturing and brewing for evaluating the safety of cartap pesticide. Cartap metabolites were identified using Q-Exactive Orbitrap mass spectrometry. Half-lives of cartap in fresh tea leaves ranged from 0.49 to 0.59 days. Cartap decreased rapidly with time, and it was degraded into nereistoxin and cartap monothiol during tea production chain. Cartap monothiol residues dissipated rapidly by 98% in three days during tea planting. Nereistoxin had a longer residual period than cartap and it dominated the total residue in made tea after tea manufacturing. Transfer rates of nereistoxin during tea brewing ranged from 78.24% to 121.56%. Therefore, we suggested sum of cartap and nereistoxin residues as maximum residual limits in tea.

Potential Angiotensin Converting Enzyme Inhibitors from Moringa oleifera.

BACKGROUND: Hypertension is the chronic medical condition and it affected billions of people worldwide. Natural medicines are the main alternatives to treatment for a majority of people suffering from hypertension. Niazicin-A, Niazimin-A, and Niaziminin-B compounds from Moringa oleifera ethanolic leave extract were reported to have potent antihypertensive activity. OBJECTIVE: These compounds were targeted with Angiotensin-converting enzyme [ACE] which is one of the main regulatory enzymes of the renin-angiotensin system. METHODS: Protein-ligand docking of these compounds with [ACE] [both domain N and C] was conceded out through Autodock vina and visualization was done by chimera. Pharmacokinetics study of these compounds was predicted by ADME-Toxicity Prediction. RESULTS: Niazicin-A, Niazimin-A, and Niaziminin-B showed high binding affinity with ACE and partially blocked the active sites of the enzyme. Niazicin-A, Niazimin-A and Niaziminin-B showed the estimated free binding energy of -7.6kcal/mol kcal/mol, -8.8kcal/mol and -8.0kcal/mol respectively with C-domain of ACE and -7.9kcal/mol, -8.5kcal/mol and -7.7kcal/mol respectively with N-domain of ACE. The compounds showed better binding energy with angiotensinconverting enzyme in comparison to Captopril -5.5kcal/mol and -5.6kcal/mol and Enalapril [standard] -8.4kcal/mol and -7.5kcal/mol with C and N domain, respectively. CONCLUSION: Computationally, the selected bioactive molecules have shown better binding energy to known standard drugs which have been already known for inhibition of ACE and can further act as a pharmacophore for in vitro and in vivo studies in the development of alternative medicine.

In vitro anti-bacterial and time kill evaluation of binuclear tricyclohexylphosphanesilver(I) dithiocarbamates, {Cy3PAg(S2CNRR')}2.

Four binuclear phosphanesilver(I) dithiocarbamates, {cyclohexyl3PAg(S2CNRR')}2 for R = R' = Et (1), CH2CH2 (2), CH2CH2OH (3) and R = Me, R' = CH2CH2OH (4) have been synthesised and characterised by spectroscopy and crystallography, and feature tri-connective, µ2-bridging dithiocarbamate ligands and distorted tetrahedral geometries based on PS3 donor sets. The compounds were evaluated for anti-bacterial activity against a total of 12 clinically important pathogens. Based on minimum inhibitory concentration (MIC) and cell viability tests (human embryonic kidney cells, HEK 293), 1-4 are specifically active against Gram-positive bacteria while demonstrating low toxicity; 3 and 4 are active against methicillin resistant S. aureus (MRSA). Across the series, 4 was most effective and was more active than the standard anti-biotic chloramphenicol. Time kill assays reveal 1-4 to exhibit both time- and concentration-dependent pharmacokinetics against susceptible bacteria. Compound 4 demonstrates rapid (within 2 h) bactericidal activity at 1 and 2 × MIC to reach a maximum decrease of 5.2 log10 CFU/mL against S. aureus (MRSA).

Inhibition of Mitochondrial Bioenergetics by Esterase-Triggered COS/H2S Donors.

Hydrogen sulfide (H2S) is an important biological mediator, and synthetic H2S donating molecules provide an important class of investigative tools for H2S research. Here, we report esterase-activated H2S donors that function by first releasing carbonyl sulfide (COS), which is rapidly converted to H2S by the ubiquitous enzyme carbonic anhydrase (CA). We report the synthesis, self-immolative decomposition, and H2S release profiles of the developed scaffolds. In addition, the developed esterase-triggered COS/H2S donors exhibit higher levels of cytotoxicity than equivalent levels of Na2S or the common H2S donors GYY4137 and AP39. Using cellular bioenergetics measurements, we establish that the developed donors reduce cellular respiration and ATP synthesis in BEAS 2B human lung epithelial cells, which is consistent with COS/H2S inhibition of cytochrome c oxidase in the mitochondrial respiratory chain although not observed with common H2S donors at the same concentrations. Taken together, these results may suggest that COS functions differently than H2S in certain biological contexts or that the developed donors are more efficient at delivering H2S than other common H2S-releasing motifs.

Trace determination of lead, chromium and cadmium in herbal medicines using ultrasound-assisted emulsification microextraction combined with graphite furnace atomic absorption spectrometry.

INTRODUCTION: The World Health Organization (WHO) recommends that medicinal plants should be checked for the presence of heavy metals. A preconcentration and separation technique for trace amounts of heavy metals from plant matrix is necessary in order to increase the sensitivity and precision of their determination. OBJECTIVE: Lead, chromium and cadmium contaminations in herbal medicines were monitored using ultrasound-assisted emulsification microextraction (USAEME) combined with graphite furnace atomic absorption spectrometry (GF-AAS). METHODS: In this work, the metal ions in the aqueous solution were complexed with ammonium pyrrolidine dithiocarbamate (APDC) and were extracted into 45 µL of toluene that was sonically dispersed in the aqueous phase. The emulsion formed was centrifuged and 20 µL of separated toluene was injected into a GF-AAS for analysis. Several factors including the kind of extraction solvent and its volume, sample pH, ionic strength and concentration of APDC were optimised. RESULTS: The linear dynamic range (LDR) values were in the range of 0.05 to 20 µg/L and the limit of detection values were in the range of 0.002-0.03 µg/L for target heavy metals. Enrichment factors were obtained in the range of 70-500. The precision of the proposed method was ≤ 8% (n = 5). The obtained amounts of Pb, Cr and Cd in selected herbal medicines were in the standard range, according to the WHO reports. CONCLUSION: The USAEME with GF-AAS procedure was shown to be an efficient, rapid, inexpensive and eco-friendly method for the determination of lead, chromium and cadmium in herbal medicines. Application of the USAEME method leads to an increased extraction efficiency with satisfactory precision in a short time using an extraction solvent volume at the microlitre level.

Determination and speciation of trace and ultratrace selenium ions by energy-dispersive X-ray fluorescence spectrometry using graphene as solid adsorbent in dispersive micro-solid phase extraction.

A dispersive micro-solid phase extraction (DMSPE) with graphene as a solid adsorbent and ammonium pyrrolidinedithiocarbamate (APDC) as a chelating agent was proposed for speciation and detemination of inorganic selenium by the energy-dispersive X-ray fluorescence spectrometry (EDXRF). In developed DMSPE, graphene particles are dispersed throughout the analyzed solution, therefore reaction between Se(IV)-APDC complexes and graphene nanoparticles occurs immediately. The concentration of Se(VI) is calculated as the difference between the concentration of selenite after and before prereduction of selenate. A central composite face-centered design with 3 center points was performed in order to optimize conditions and to study the effect of four variables (pH of the sample, concentration of APDC, concentration of Triton-X-100, and sample volume). The best results were obtained when suspension consisting of 200 µg of graphene nanosheets, 1.2 mg of APDC and 0.06 mg of Triton-X-100 was rapidly injected to the 50 mL of the analyzed solution. Under optimized conditions Se ions can be determined with a very good recovery (97.7±5.0% and 99.2±6.6% for Se(IV) and Se(VI), respectively) and precision (RSD=5.1-6.6%). Proposed DMSPE/EDXRF procedure allowed to obtain low detection limits (0.032 ng mL(-1)) and high enrichment factor (1013±15). The proposed methodology was successfully applied for the determination of Se in mineral, tap, lake and sea water samples as well as in biological materials (Lobster Hepatopancreas and Pig Kidney).

Mixed-ligand complexes of yttrium-90 dialkyldithiocarbamates with 1,10-phenanthroline as a possible agent for therapy of hepatocellular carcinoma.

Yttrium-90 is a radioelement which has found wide use in targeted radionuclide therapy because of its attractive physical and chemical properties. Radioembolisation of hepatocellular carcinoma with radiolabelled Lipiodol is a method of choice. We have synthesised a series of alkyldithiocarbamate yttrium complexes, easily extracted into Lipiodol due to their high lipophilicity. Among the prepared series, a new radioconjugate, which is stable over an extended period of time, has been prepared, and could represent a potential treatment procedure for hepatocellular carcinoma.

Gold(III)-dithiocarbamato peptidomimetics in the forefront of the targeted anticancer therapy: preclinical studies against human breast neoplasia.

Since the serendipitous discovery of cisplatin, platinum-based drugs have become well-established antitumor agents, despite the fact that their clinical use is limited by many severe side-effects. In order to both improve the chemotherapeutic index and broaden the therapeutic spectrum of current drugs, our most recent anti-neoplastic agents, Au(III) complexes, were designed as carrier-mediated delivery systems exploiting peptide transporters, which are up-regulated in some cancers. Among all, we focused on two compounds and tested them on human MDA-MB-231 (resistant to cisplatin) breast cancer cell cultures and xenografts, discovering the proteasome as a major target both in vitro and in vivo. 53% inhibition of breast tumor growth in mice was observed after 27 days of treatment at 1.0 mg kg(-1) d(-1), compared to control. Remarkably, if only the most responsive mice are taken into account, 85% growth inhibition, with some animals showing tumor shrinkage, was observed after 13 days. These results led us to file an international patent, recognizing this class of gold(III) peptidomimetics as suitable candidates for entering phase I clinical trials.

Antitrypanosomal isothiocyanate and thiocarbamate glycosides from Moringa peregrina.

O-Methyl (1), O-ethyl (2), and O-butyl (3) 4-[(α-L-rhamnosyloxy) benzyl] thiocarbamate (E), along with 4-(α-L-rhamnosyloxy) benzyl isothiocyanate (4) have been isolated from the aerial parts of Moringa peregrina. The compounds were tested for in vitro activity against Trypanosoma brucei rhodesiense and cytotoxicity in rat skeletal myoblasts (L6 cells). The most potent compound was 4 with an IC50 of 0.10 µM against T.b. rhodesiense and a selectivity index of 73, while the thiocarbamate glycosides 1, 2, and 3 showed only moderate activity. Intraperitoneal administration of 50 mg/kg body weight/day of 4 in the T.b. rhodesiense STIB 900 acute mouse model revealed significant in vivo toxicity. Administration of 10 mg/kg body weight/day resulted in a 95% reduction of parasitemia on day 7 postinfection, but did not cure the animals. Because of its high in vitro activity and its ability to irreversibly inhibit trypanothione reductase, an attractive parasite-specific target enzyme, 4-[(α-L-rhamnosyloxy) benzyl] isothiocyanate (4), can be considered as a lead structure for the development and characterization of novel antitrypanosomal drugs.

Combined determination and confirmation of ethylenethiourea and propylenethiourea residues in fruits at low levels of detection.

In this work, a new method for the determination of ethylenethiourea (ETU) and propylenethiourea (PTU) in fruits and vegetables is presented. Different extraction and purification techniques, including matrix solid phase dispersion (MSPD) and solid-liquid extraction (SLE), followed by a clean-up step by solid phase extraction (SPE), were compared. The determination of ETU and PTU was performed by high performance liquid chromatography with diode array detection (HPLC/DAD) or by gas chromatography with mass spectrometry detection (GC/MS). The effect of several parameters on the extraction, separation and detection was studied. The proposed method based on solid-liquid extraction with acetonitrile, clean-up with Envicarb II/PSA cartridges and subsequent analysis by HPLC/DAD was characterised and applied to the analysis of fruits and vegetables from different countries. Analytes recoveries were between 71% and 94% with relative standard deviations (RSDs) ranging from 8% to 9.5%. Quantification limits obtained for ETU and PTU with the HPLC/DAD method were 7 and 16 µg kg⁻¹ in strawberries (fresh weight), respectively. For apples, they were 11 and 25 µg kg⁻¹, respectively.

Evaluation of a dithiocarbamate derivative as an inhibitor of human glutaredoxin-1.

CONTEXT: Glutaredoxins (GRX) are involved in the regulation of thiol redox state. GRX-1 is a cytosolic enzyme responsible for the catalysis of deglutathionylation of proteins. To date, very few inhibitors of GRX-1 have been reported. OBJECTIVE: The objective of this paper is to report 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethyl-sulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid (2-AAPA) as an inhibitor of human GRX-1. MATERIALS AND METHODS: The mechanism of inhibition of GRX-1 was investigated using dialysis, substrate protection, and mass spectrometry. RESULTS: 2-AAPA inhibits GRX-1 in a time and concentration dependent manner. The activity did not return following dialysis indicating that inhibition is irreversible. Results of substrate protection and mass spectrometry indicate that the inhibition is occurring at the active site. The compound also produced GRX inhibition in human ovarian cancer cells. DISCUSSION: 2-AAPA is an irreversible GRX-1 inhibitor with similar or greater potency compared to previously reported inhibitors. CONCLUSION: The inhibition of GRX-1 by 2-AAPA could be used as a tool to study thiol redox state.

A Box-Behnken design for determining the optimum experimental condition of the fungicide (Vapam) sorption onto soil modified with perlite.

In the present study, response surface methodology (RSM) based on the Box-Behnken design (BBD) was employed to investigate the effects of the different operating conditions on the removal of the fungicide (Vapam) onto soil modified with perlite using sorption process. The process parameters such as pH of the fungicide solution (2, 5 and 8), temperature (15, 25 and 35°C), shaking time (2, 13 and 24 h) and the percentage of perlite in the modified soil (0, 2 and 4 %) were investigated using a four-factor-three-level Box-Behnken design at an initial fungicide concentration of C(0) = 1.6 mg/L as a fixed input parameter. A second-order quadratic model suggested the optimum conditions to be as follows: fungicide solution pH of 3.57, temperature of 15°C, shaking time of 3.5 h and 4% of perlite in the modified soil which resulted in the improvement of Vapam sorption. Under optimum conditions, the fungicide (Vapam) removal was predicted 12.88 µg/g by BBD. The confirmatory experiments were conducted and the results revealed that the fungicide removal was 13.14 µg/g which indicated that the predicted and the observed values of response (Vapam removal) were in close agreement. Therefore, the soil modified with perlite holds good potential for Vapam sorption. This is the first report on fungicide Vapam sorption onto soil modified with perlite using statistical experimental design employing response surface methodology.

A synthetic decursin analog with increased in vivo stability suppresses androgen receptor signaling in vitro and in vivo.

Targeting androgen receptor (AR) signaling with agents distinct from current antagonist drugs remains a rational approach to the prevention and treatment of prostate cancer (PCa). Our previous studies have shown that decursin and isomer decursinol angelate (DA), isolated from the Korean medicinal herb Angelica gigas Nakai, interrupt AR signaling and possess anti-PCa activities in vitro. In the LNCaP PCa cell model, these pyranoccoumarin compounds exhibit properties distinct from currently used antagonists (e.g., Casodex). However, both are rapidly de-esterified to decursinol, a partial AR agonist. We report here that a synthetic decursin analog, decursinol phenylthiocarbamate (DPTC), has greater in vivo stability than the parent compounds. DPTC-decursinol conversion was undetectable in mice. Furthermore, in LNCaP cells, DPTC decreased prostate specific antigen (PSA) expression, down-regulated AR abundance and mRNA and inhibited AR nuclear translocation. The effect of DPTC on AR and PSA mRNA and protein abundance was also observed in VCaP cells expressing wild type AR. DPTC inhibited growth of both PCa cell lines through G(1) cell cycle arrest and apoptosis, as did decursin and DA. Furthermore, i.p. administration of DPTC for 3 weeks suppressed the expression of AR target genes probasin and Nkx3.1 in mouse prostate glands. Overall, our data suggest that DPTC represents a prototype lead compound for development of in vivo stable and active novel decursin analogs for the prevention or therapy of PCa.

Discovery of inhibitors and substrates of brassinin hydrolase: Probing selectivity with dithiocarbamate bioisosteres.

Brassinin hydrolase (BHAb), an inducible enzyme produced by the plant pathogen Alternaria brassicicola under stress conditions, catalyzes the hydrolysis of the methyl dithiocarbamate group of the phytoalexin brassinin, to indolyl-3-methanamine, methane thiol and carbonyl sulfide. Thirty four substrate inspired compounds, bioisosteres of brassinin and a range of related compounds, were evaluated as potential substrates and inhibitors of BHAb for the first time. While six compounds containing thiocarbamate, carbamate and carbonate groups displayed inhibitory activity against BHAb, only two were found to be substrates (thionecarbamate and dithiocarbamate). Methyl naphthalen-1-yl-methyl carbamate, the most potent inhibitor of the six, and methyl N'-(1-methyl-3-indolylmethyl)carbamate inhibited BHAb through a reversible noncompetitive mechanism (K(i)=89±9 and 695±60µM, respectively). Importantly, these carbamate inhibitors were resistant to degradation by A. brassicicola. Carbonates were also inhibitory of BHAb, but a quick degradation by A. brassicicola makes their potential use as crop protectants less likely. Overall, these results indicate that indolyl and naphthalenyl carbamates are excellent lead structures to design new paldoxins that could inhibit the detoxification of brassinin by A. brassicicola.

Determination of inorganic selenium species in water and garlic samples with on-line ionic liquid dispersive microextraction and electrothermal atomic absorption spectrometry.

A non-chromatographic separation and preconcentration method for Se species determination based on the use of an on-line ionic liquid (IL) dispersive microextraction system coupled to electrothermal atomic absorption spectrometry (ETAAS) is proposed. Retention and separation of the IL phase was achieved with a Florisil(®)-packed microcolumn after dispersive liquid-liquid microextraction (DLLME) with tetradecyl(trihexyl)phosphonium chloride IL (CYPHOS(®) IL 101). Selenite [Se(IV)] species was selectively separated by forming Se-ammonium pyrrolidine dithiocarbamate (Se-APDC) complex followed by extraction with CYPHOS(®) IL 101. The methodology was highly selective towards Se(IV), while selenate [Se(VI)] was reduced and then indirectly determined. Several factors influencing the efficiency of the preconcentration technique, such as APDC concentration, sample volume, extractant phase volume, type of eluent, elution flow rate, etc., have been investigated in detail. The limit of detection (LOD) was 15 ng L(-1) and the relative standard deviation (RSD) for 10 replicates at 0.5 µg L(-1) Se concentration was 5.1%, calculated with peak heights. The calibration graph was linear and a correlation coefficient of 0.9993 was achieved. The method was successfully employed for Se speciation studies in garlic extracts and water samples.

Cytotoxic thiocarbamate derivatives of boldine.

Two new boldine derivatives: the 3-thiocarbamateboldine (3) and the 2,9-O,O-diacetyl-3-thiocarbamateboldine (4) have been synthesized and their cytotoxicity evaluated.