Dithiocarbamate Derivatives Research Articles

A ‘Turn-on’ Fluorescence Glycosyl Dithiocarbamate Probe for Selective Fluoride Sensing in Aqueous Medium

A glycosyl dithiocarbamate derivative is developed as a ‘turn on’ fluorescent sensor for fluorides in aqueous medium. The probe is prepared through a simple chemical strategy reported earlier from our group. The virtually nonfluorescent probe showed significant enhancement of fluorescence upon interaction with fluorides in aqueous solution. It was seen to be selective to fluorides too as the interactions with various other anions resulted in very low increase in fluorescence. The simple preparation and unique interaction of the dithiocarbamato derivative with fluorides in aqueous solution promise the development of a novel turn-on probe for the detection of fluorides.

Radiosynthesis and evaluation of novel 99mTc(CO)3-labelled thymidine dithiocarbamate derivatives for tumor imaging with SPECT

A series of novel thymidine dithiocarbamate derivatives (DTC-TdR) were successfully synthesized and then radiolabelled using [99mTc(CO)3]+ core with high yields. The chemical characterizations of 99mTc(CO)3-labelled dithiocarbamate derivatives have been carried out by preparing their corresponding rhenium complexes. The radiotracers were stable in vitro, and the partition coefficient results indicated that they were lipophilic. The cell uptake studies showed the uptakes of these 99mTc(CO)3-labelled thymidine derivatives were mediated by nucleoside transporters. Biodistribution of the complexes in mice bearing tumor showed that they had high tumor uptake and good tumor/muscle ratio. A clear SPECT imaging of the tumor location was obtained in mice bearing S180 tumor with one of radiotracers, suggesting they would be potential tumor imaging agents.

Synthesis of carboxylic dithiocarbamic anhydride and substituted thiourea derivatives in water

The use of water as a solvent has sometimes benefits such as improving reactivities and selectivities, simplifying work-up procedures, and environmentally benign. Many carboxylic dithiocarbamic anhydride products are valuable building blocks in heterocycles and natural products. Here we present a simple one-pot synthesis of carboxylic dithiocarbamic anhydride by condensation of amines, carbon disulfide, acyl halide, or acetic anhydride in water. We obtained a variety of biologically important acyl dithiocarbamate derivatives in 82–93% yields in 10–30 min. This procedure can be used for the synthesis of thioureas from dithiocarbamates. Here, the sequential, one-pot three-component reaction of amines, carbon disulfide, and isothiocyanates provides unsymmetrical substituted thioureas in 81–91% yields.

Design, synthesis and biological evaluation of new coumarin-dithiocarbamate hybrids as multifunctional agents for the treatment of Alzheimer's disease

A series of new coumarin-dithiocarbamate hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's Disease (AD). The biological assays indicated that most of them showed potent inhibition and excellent selectivity towards acetylcholinesterase (AChE), and could inhibit self-induced β-amyloid (Aβ) aggregation. Especially, compound 4n presented the highest ability to inhibit AChE (IC50, 0.027 μM for hAChE) and good inhibition of Aβ aggregation (40.19% at 25 μM). Kinetic and molecular modeling studies revealed that 4n was a mixed-type inhibitor, which could interact simultaneously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. In addition, it also possessed specific metal-chelating ability, good BBB permeability and low toxicity on SH-SY5Y neuroblastoma cells. Moreover, compound 4n did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and could reverse the cognitive dysfunction of scopolamine-induced AD mice. As far as we know, 4n was the first reported dithiocarbamate derivative with multifunctional activity. Its excellent profiles in vitro and effectivity in vivo highlight this structurally distinct compound as a potential lead compound in the research of innovative multifunctional drugs for AD.

SPECTROPHOTOMETRIC DETERMINATION OF PROPRANOLOL HYDROCHLORIDE AND METOPROLOL TARTRATE IN PHARMACEUTICAL DOSAGE FORMS, SPIKED WATER AND BIOLOGICAL FLUIDS

Objective: A new spectrophotometric method for the determination of propranolol hydrochloride (PRO) and metoprolol tartrate (MTP), beta blocker drugs, has been developed for their analysis in pharmaceutical dosage forms for the purpose of quality control and water samples for monitoring impact on environmental water quality of natural sources and in biological fluids for ascertaining their physiological performance.Methods: The method is based on the derivatization of the amino function present in these drugs to the corresponding yellow copper (I) drug dithiocarbamate derivative through reaction with carbon disulphide, pyridine and copper (I) perchlorate in aqueous acetonitrile and measuring absorbance at 406 nm for propranolol and 400 nm for metoprolol. The different experimental parameters affecting the development and stability of the colour were carefully studied and optimized.Results: The Beer’s law is obeyed in the range of 1.0-40.0 μg/ml of each drug solution with a correlation coefficient 0.999. The maximum relative standard deviations (RSDs) in the analysis of pure PRO and MTP were 1.01 and 1.52 % respectively. The recoveries of the drugs from pharmaceutical formulations, spiked water samples and biological fluids were in the range 98.0-100.5 % with RSDs in the range 0.23-1.94% indicating good accuracy and precision of the method.Conclusion: The instantaneous development of colour and its stability, well-established stoichiometry of the reaction and above simplicity and rapidity of procedures are some special attributes of the proposed method.

Metal Complexes of Dithiocarbamate Derivatives and its Biological Activity

Metal Complexes of Dithiocarbamate Derivatives and its Biological Activity

Design, synthesis, monoamine oxidase inhibition and docking studies of new dithiocarbamate derivatives bearing benzylamine moiety

A new series of thirteen 2-[(4-fluorophenyl)(4-nitrobenzyl)amino]-2-oxoethyl-1-substituted-carbodithioate derivatives (4a-4m) were synthesized and tested for their human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitory potential by an in vitro fluorometric method. Most of the compounds have found to be selective towards MAO-B than MAO-A. Compound 4j that carrying 4-nitrophenyl piperazine moiety, was detected as the most active agent amongst all compounds with the IC50 value of 0.097 ± 0.003 µM for MAO-B while that of selegiline was 0.040 ± 0.002 µM. The enzyme kinetic study reported that compound 4j is a reversible and non-competitive inhibitor. Interaction modes between the hMAO-B and compound 4j were determined by docking studies. The study also revealed that compound 4j has the highest binding scores. Besides, compound 4j has not cytotoxicity at its effective concentration against hMAO-B.

Efficient, straightforward, catalyst-free synthesis of medicinally important S-alkyl/benzyl dithiocarbamates under green conditions

Green synthesis of some novel dithiocarbamate derivatives substituted by aliphatic and aromatic groups as potentially interesting, medicinally important organic compounds via efficient one-pot, catalyst-free reaction is described. In this reaction, dithiocarbamate derivatives are obtained from condensation reaction between primary or secondary amines, carbon disulfide, and alkyl or benzyl halides in one pot and ethanol–aqueous medium. Among aliphatic and aromatic amines, the results generally show that reaction of aliphatic amines with alkyl or benzyl halides led to desired products in highest yields. Also, among aliphatic amines, those which reacted with benzyl halides showed better yields than those that reacted with alkyl halides. Use of environmentally benign solvents is one of the advantages of this procedure. Also, obtaining products in good yield via catalyst-free reaction using a facile, inexpensive, and practical approach can be considered other advantages of this procedure. Target products are very important compounds, because their analogs have been applied in pharmaceutical, chemical, and rubber industries.

Antiproliferative activity of di-2-pyridylhydrazone dithiocarbamate acetate partly involved in p53 mediated apoptosis and autophagy.

Cancer cells have higher demand of iron and copper ions for growth, disturbing the metal's homeostasis can inhibit proliferation of cancer cell. Dithiocarbamates possessing excellent metal chelating ability and antitumor activity are considered as candidates in chelation therapy, however, their antitumor molecular mechanisms remain to be elucidated. In the present study, a dithiocarbamate derivative, di-2-pyridylhydrazone dithiocarbamate s-acetic acid (DpdtaA) was prepared to address the issue whether the molecular mechanism behind biological behavior showed by dithiocarbamate was p53 mediated. The proliferation inhibition assay showed that DpdtaA exhibited excellent antiproliferative effect for hepatocellular carcinoma (IC50= 3.0±0.4µM for HepG2, 6.1±0.6µM for Bel-7402 cell). However, in the presence of copper ion, the antiproliferative activity of DpdtaA significantly attenuated (~3-fold for HepG2) due to formation of copper chelate. The ROS assay revealed that the antiproliferative activity of DpdtaA correlated with ROS generation. Western blotting demonstrated that DpdtaA could upregulate p53 via down-regulating the Mdm2, accordingly leading to changes of bcl family proteins, indicating that a p53-dependent intrinsic apoptosis was partly involved. Simulation from molecular docking hinted that DpdtaA could disrupt interaction between p53 and Mdm2, indicating the disruption might also contribute to the upregulation of p53. The alternations in lysosome membrane permeability and acidic vacuoles as well as LC3-II upregulation indicated that autophagy was involved. The copper addition led to significantly attenuate biological activity of DpdtaA, with few dithiocarbamates, but the mechanism in apoptosis induction was not altered except for weaker ability.

Computer-aided prediction and cytotoxicity evaluation of dithiocarbamates of 9,10-anthracenedione as new anticancer agents

Anticancer activity as an associated action for a series of dithiocarbamates of 9,10-anthracenedione was predicted using the PASS computer program and analysed with PharmaExpert software. The predicted cytotoxic activity of the dithiocarbamate derivatives of 9,10-anthracenedione was evaluated in vitro on cancer cells of the human lung (A549), prostate (PC3), colon (HT29) and human breast (MCF7) using the sulforhodamine B (SRB) cell viability assay. Among these compounds, 9,10-dioxo-9,10-dihydroanthracen-1-yl pyrrolidin-1-carbodithioate and 9,10-dioxo-9,10-dihydroanthracen-2-yl pyrrolidin-1-carbodithioate were identified as the most potent anticancer agents with cytotoxic activity against the MCF-7 human breast cell line with GI50 values of 1.40 μM and 1.52 μM, whereas the GI50 value for the reference anticancer drug mitoxantrone was 3.93 μM. Thus, anticancer activity predicted by PASS with a probability Pa > 30% was confirmed by the experiment. Relatively small Pa values estimated by PASS indicated the novelty of the considered derivatives comparing to the compounds from the PASS training set.

Application of chalcone-based dithiocarbamate derivative incorporated sol–gel for the removal of Hg (II) ion from water

This study demonstrated the application of chalcone-based dithiocarbamate derivative as metal capturing ligand for the removal of mercury ion (Hg2+) in water. Chalcones are a group of naturally occurring compounds which can be obtained from fruits, vegetables, plants, and spice. In this study, chalcone was first chemically modified to produce dithiocarbamate derivative (ODPPNE). Chalcone and ODPPNE were then incorporated into sol–gel to produce SG-C and SG-ODPPNE, respectively, as adsorbents. The result from the adsorption study showed that with the presence of dithiocarbamate functional group, SG-ODPPNE exhibited the highest selectivity toward the adsorption of Hg2+ with lesser response to Cr3+, Ni2+, Cu2+, Zn2+, Cd2+, and Pb2+. The adsorption of Hg2+ by SG-ODPPNE was found to be adsorbent size, adsorbent dosage, contact time, the initial concentration of sorbate and pH dependent. The obtained experimental data were also analyzed using Freundlich and Langmuir adsorption models. The results showed that the adsorption data were well-fitted to Langmuir isotherm, and the monolayer absorption capacity was found to be 13.5 mg/g. In the absorption kinetic study, the data was analyzed using pseudo-first-order, pseudo-second-order kinetic model, and intraparticle diffusion model. The obtained data were well-fitted to pseudo-second order model. According to intraparticle diffusion model, the adsorption process of Hg2+ by SG-ODPPNE involves film diffusion, intraparticle diffusion, and equilibrium stages.

Multi-functional groups of dithiocarbamate derivative assembly on gold nanoparticles for competitive detection of diafenthiuron

In this work, we have fabricated gold nanoparticles (Au NPs) with multifunctional groups of 4-hydroxy-6-methyl-3-nitro-2-pyridone-dithiocarbamate derivative and used as plasmonic sensor for simple and competitive detection of diafenthiuron in water and food samples. The multifunctional groups (OH, NO2 and CO) of HMNP-DTC-Au NPs showed strong ability to interact with diafenthiuron, yielding to form stable HMNP-DTC-Au NPs-diafenthiuron supramolecular network, which results a red-shift in the SPR peak and a color change from red to blue. The plasmonic sensor exhibits good linearity between the absorbance ratio at A618/A522 and the concentration of diafenthiuron in the range of 0.05–10μM with a correlation coefficient (R2) of 0.997. The designed plasmonic sensor showed high selectivity toward diafenthiuron with a detection limit of 7.1nM, which is lower than the permissible limit of diafenthiuron. The developed plasmonic sensor was successfully applied to detect diafenthiuron in water and food samples with good recoveries, avoiding multiple steps for complicated surface modifications on Au NPs and tedious sample preparations.

Thiadiazole과 Dithiocarbamate 유도체의 내마모 특성

Some thiadiazole and dithiocarbamate derivatives were desinged and synthesized in order to study the potential use as anti-wear additives. Their anti-wear properties in three different base oils (DB-51, soybean, and 100 N) were evaluated using a four-ball wear tester (ASTM D4172). The solubilities of dithiocarbamate derivatives in the base oils were better than those of thiadiazole derivatives. The compounds containing oleoyl group rather than nonanoyl group gave good anti-wear properties. The solubilities and anti-wear properties were explained by the polarity of the compounds.

Glucose dithiocarbamate derivatives as capping ligands of water-soluble CdSeS/ZnS quantum dots

In the framework of presented study selected glucose analogues: 1-thio-β-d-glucose (βDG-SH), D-glucosamine dithiocarbamate (DG-DTC) and N-methyl-d-glucamine dithiocarbamate (NMDG-DTC) were used to modify CdSexS1-x/ZnS quantum dots via ligand exchange. The special emphasis was put on the careful optimization of DTC synthesis in an aqueous media. Properties of primary and secondary dithiocarbamates, such as stability in solutions of various pH and capability to form complexes with the divalent ions, which are crucial for their applications as surface ligands of QDs, were thoroughly compared. Due to the facility of DTCs preparation as well as colloidal stability and good optical properties of obtained hydrophilic QDs, DTC-derivatives turn out to be an alternative to most commonly used thiolated ligands. Examination of biological activity of DTC-modified QDs on A549 cell line revealed that DTC-ligands exhibit negligible intrinsic cytotoxicity. Biomimetic character of anchored ligands (similar to glucose) combined with satisfactory physicochemical properties of obtained QDs, such as high hydrophilicity and uncharged surface, indicate the potential of so modified QDs for cellular imaging and biosensing.

Patterns of simultaneous patch test reactions to thiurams and dithiocarbamates in 164 patients.

Thiurams and dithiocarbamates are structurally related sensitizing rubber accelerators. To study patterns of simultaneous patch test reactions to thiurams and dithiocarbamates at the Finnish Institute of Occupational Health in 1991-2015. We searched the patch test files for patients with allergic reactions to thiuram mix, its four components, and three dithiocarbamates, and analysed patterns of simultaneous reactions to these test substances. We found 155 patients who reacted positively to at least one thiuram or dithiocarbamate in the rubber chemical series. Thirty-four (22%) of these patients reacted positively to some dithiocarbamate derivatives. Twenty-one reacted positively to zinc dimethyldithiocarbamate, 20 to zinc diethyldithiocarbamate, and 1 to zinc dibutyldithiocarbamate. All dithiocarbamate-allergic patients reacted positively to some thiurams, and their thiuram reactions were often strong or extreme positive. Nine thiuram mix reactions turned out to be false-positive reactions, without reactions to the constituents, and 24 patients showed false-negative reactions to thiuram mix during the same time period. Dithiocarbamate contact allergy was always connected to thiuram allergy. Screening dithiocarbamate allergy with carba mix thus appears to be unnecessary, but ways to improve the present thiuram mix should be investigated. Meanwhile, individual thiurams are best for diagnosing contact allergy to these accelerators.

Synthesis and investigation of antioxidant activity of the dithiocarbamate derivatives of 9,10-anthracenedione

A variety of new derivatives of 9,10-anthracenedione with mono- and bisdithiocarbamate moiety in the non-catalytic conditions have been synthesized. The obtained compounds were screened for their antioxidant capacity using the cupric-reducing antioxidant capacity (CUPRAC) method. Three of the compounds showed CUPRAC-Trolox equivalent antioxidant capacity (TEAC) coefficients higher than trolox. Scavenging effects on reactive oxygen species (ROS), hydroxyl radical scavenging (HRS), hydrogen peroxide scavenging (HPS), and superoxide anion radical scavenging (SARS) of all synthesized compounds were determined. It was established that the results of HRS-, HPS-, and SARS-CUPRAC methods for three compounds are in accordance with TEAC-CUPRAC assay data.

Synthesis and evaluation of new benzodioxole-based dithiocarbamate derivatives as potential anticancer agents and hCA-I and hCA-II inhibitors

In the current work, new benzodioxole-based dithiocarbamate derivatives were synthesized via the reaction of N-(1,3-benzodioxol-5-ylmethyl)-2-chloroacetamide with appropriate sodium salts of N,N-disubstituted dithiocarbamic acids. These derivatives were evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and C6 rat glioma cell lines. N-(1,3-Benzodioxol-5-ylmethyl)-2-[4-(4-nitrophenyl)-1-piperazinylthiocarbamoylthio]acetamide (10) can be identified as the most promising anticancer agent against C6 cell line due to its notable inhibitory effect on C6 cells with an IC50 value of 23.33 ± 7.63 μg/mL when compared with cisplatin (IC50 = 19.00 ± 5.29 μg/mL). On the other hand, compound 10 did not show any significant cytotoxic activity against A549 cell line. The compounds were also tested for their in vitro inhibitory effects on hCA-I and hCA-II. Generally, the tested compounds were more effective on CAs than acetazolamide, the reference agent. Among these compounds, N-(1,3-benzodioxol-5-ylmethyl)-2-[(morpholinyl)thiocarbamoylthio]acetamide (3) and N-(1,3-benzodioxol-5-ylmethyl)-2-[(thiomorpholinyl)thiocarbamoylthio]acetamide (4) were found to be the most effective compounds on hCA-I with IC50 values of 0.346 nM and 0.288 nM, and hCA-II with IC50 values of 0.287 nM and 0.338 nM, respectively.

Preparation, spectroscopic characterization and antimicrobial activities of mixed metal (Sb and Bi) bridged derivatives with mixed sulfur donor ligands

This article explores the syntheses of six mixed metal derivatives of antimony(III) and bismuth(III) by the reaction of ethane-1,2-dithiol and metal bis derivatives of dithiocarbamates and/or dithiophosphates ligands in 1:1:1 M stoichiometry. These derivatives have been characterized by physicochemical [elemental analysis (C, H, N, S, Sb and Bi), molecular weight and melting point determinations], spectral [UV–Visible, FTIR, NMR (1H, 13C and 31P)], powder X–ray diffraction studies. These derivatives have nano-ranged crystallite size (8.18–18.04 nm) with monoclinic crystal system. All the synthesized derivatives have two metal centers (Sb and Bi) which elevate the zone of inhibition against four bacterial and two fungal species as compared to single metal species (metal precursors) as well as standard drugs.

Copper Ion Attenuated the Antiproliferative Activity of Di-2-pyridylhydrazone Dithiocarbamate Derivative; However, There Was a Lack of Correlation between ROS Generation and Antiproliferative Activity

The use of chelators for cancer treatment has been an alternative option. Dithiocarbamates have recently attracted considerable attention owning to their diverse biological activities; thus, the preparation of new dithiocarbamate derivatives with improved antitumor activity and selectivity as well as probing the underlying molecular mechanism are required. In this study, di-2-pyridylhydrazone dithiocarbamate S-propionic acid (DpdtpA) and its copper complex were prepared and characterized, and its antiproliferative activity was evaluated. The proliferation inhibition assay showed that DpdtpA exhibited excellent antiproliferative effect in hepatocellular carcinoma (IC50 = 1.3 ± 0.3 μM for HepG2, and 2.5 ± 0.6 μM for Bel-7402). However, in the presence of copper ion, the antiproliferative activity of DpdtpA was dramatically attenuated (20–30 fold) owing to the formation of copper chelate. A preliminarily mechanistic study revealed that reactive oxygen species (ROS) generation mediated the antiproliferative activity of DpdtpA, and accordingly induced apoptosis, DNA cleavage, and autophagy. Surprisingly, the cytotoxicity of DpdtpA copper complex (DpdtpA–Cu) was also involved in ROS generation; however, a paradoxical relation between cellular ROS level and cytotoxicity was observed. Further investigation indicated that DpdtpA could induce cell cycle arrest at the S phase; however, DpdtpA–Cu lacked this effect, which explained the difference in their antiproliferative activity.

Abstract 3722: Potent functional inactivation of the MGMT DNA repair protein by dithiocarbamate compounds increases the efficacy of temozolomide in human glioblastoma cells

Abstract There is an urgent need for the design and discovery of new and potent inhibitors for the DNA repair protein MGMT (O6-Methylguanine-DNA-methyltransferase) in glioma therapy. MGMT is highly expressed in brain tumors, and plays a primary role in conferring resistance to alkylating agents. The psuedosubstrates for MGMT such as the O6-benzylguanine have not been successful in the clinic due to prolonged inhibition of DNA repair in the bone marrow stem cells. Recently, we showed that the anti-alcoholism drug, disulfiram (DSF) inhibits MGMT activity in the same way as ALDH by conjugating with the active-site cysteine 145 (Carcinogenesis 35, 692, 2014). DSF, a symmetrical molecule, is metabolized and split in half to yield dithiocarbamate residues. Since the dithiocarbamates resulting from DSF decomposition are the ultimate reactive species that inactivate the aldehyde dehydrogenase and other signaling targets, we surmised that dithiocarbamate derivatives by themselves will be active as MGMT inhibitors and exert anticancer activities. Therefore, we tested various dithiocarbamates (pyrrolidine dithiocarbamate (PDTC); diethyldithiocarbamate (EDTC); dimethyldithiocarbamate (MDTC) and dibenzyldithiocarbamate (BDTC) on MGMT activity, protein levels, and other redox-sensitive proteins such as the NF-κB and GSTP1. The cytotoxicity of these dithiocarbamates against the MGMT-proficient SF-188 glioblastoma cells was comparable with that of DSF, with the MDTC being most effective and the benzyl derivative BDTC least potent. Western blot analysis in HT29 and SF-188 cells revealed a concentration-dependent degradation of MGMT by the dithiocarbamates, similar to DSF. All dithiocarbamates except the BDTC were superior to DSF in degrading MGMT protein. MDTC was the most potent followed by PDTC and EDTC in depleting the MGMT protein from tumor cells. Further, MDTC was also effective in reducing the cellular levels of NF-κB protein. We also established that MDTC binds to the active site cysteine145 in MGMT leading to its inactivation. Currently, we have developed the pegylated PLGA nanoparticles loaded with MDTC or zinc-chelated MDTC to target the glioblastoma and other cancers. The efficacy of these formulations in intracranial glioma models developed in nude mice is being evaluated. The lack of cytotoxicity and inability to bind with MGMT by BDTC suggests that the bulky group attached to the dithiocarbamate may hinder interaction with target proteins or interfere with their metabolism. Since MDTC has a good potential to cross the blood brain-barrier, possess reactive thiol groups that can interact with not only MGMT but also numerous signaling proteins, our strategy using this repurposed compound holds promise in glioma treatment (supported by grants from CPRIT [RP130266] and Carson-Leslie Foundation to KSS). Citation Format: Hanumantha Rao Madala. Potent functional inactivation of the MGMT DNA repair protein by dithiocarbamate compounds increases the efficacy of temozolomide in human glioblastoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3722.