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Expert Opinion on Drug Metabolism &... Jan 2015Thiocarbamates are chemicals widely used as pesticides. Occupational exposure is associated with acute intoxication. Populations can be exposed through food and water.... (Review)
Review
INTRODUCTION
Thiocarbamates are chemicals widely used as pesticides. Occupational exposure is associated with acute intoxication. Populations can be exposed through food and water. Moreover, certain thiocarbamates are used clinically. The widespread use of thiocarbamates raises many issues regarding their toxicological and pharmacological impact.
AREAS COVERED
Thiocarbamates and their metabolites can modify biological macromolecules functions, in particular enzymes, through modification of cysteine residues, chelation of metal ions or modulation of the oxidative stress. Loss of enzyme activity can lead to the disruption of metabolic pathways, and explain, at least in part, the effects of these pesticides. Additionally, their reactivity and ability to easily cross biological barrier confer them a great interest for development of clinical applications.
EXPERT OPINION
Many advances in the study of thiocarbamates metabolism and reactivity have led to a better knowledge of biological effects of these compounds. However, more data are needed on the determination of targets and specificity. Only few data concerning the exposure to a cocktail of pesticides/chemicals are available, raising the need to evaluate the toxic side effects of representative pesticides mixtures. Moreover, the dithiocarbamate Disulfiram has shown great potential in therapeutic applications and leads to the development of pharmacological thiocarbamates derivatives, highly specific to their target and easily distributed.
Topics: Animals; Environmental Exposure; Humans; Metabolic Networks and Pathways; Pesticides; Thiocarbamates
PubMed: 25391334
DOI: 10.1517/17425255.2015.975691 -
ACS Chemical Biology Feb 2019Hydrogen sulfide (HS) is an important gasotransmitter and biomolecule, and many synthetic small-molecule HS donors have been developed for HS-related research. One...
Hydrogen sulfide (HS) is an important gasotransmitter and biomolecule, and many synthetic small-molecule HS donors have been developed for HS-related research. One important class of triggerable HS donors is self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly converted to HS by the ubiquitous enzyme carbonic anhydrase (CA). Prior studies of esterase-triggered thiocarbamate donors reported significant inhibition of mitochondrial bioenergetics and toxicity when compared to direct sulfide donors, suggesting that COS may function differently than HS. Here, we report a suite of modular esterase-triggered self-immolative COS donors and include the synthesis, HS release profiles, and cytotoxicity of the developed donors. We demonstrate that the rate of ester hydrolysis correlates directly with the observed cytotoxicity in cell culture, which further supports the hypothesis that COS functions as more than a simple HS shuttle in certain biological systems.
Topics: Esterases; HeLa Cells; Humans; Sulfur Oxides; Thiocarbamates
PubMed: 30640440
DOI: 10.1021/acschembio.8b00981 -
European Journal of Medicinal Chemistry Apr 2021Colchicine shows very high antimitotic activity, therefore, it is used as a lead compound for generation of new anticancer agents. In the hope of developing novel,...
Colchicine shows very high antimitotic activity, therefore, it is used as a lead compound for generation of new anticancer agents. In the hope of developing novel, useful drugs with more favourable pharmacological profiles, a series of doubly modified colchicine derivatives has been designed, synthesized and characterized. These novel carbamate or thiocarbamate derivatives of 10-demethoxy-10-methylaminocolchicine have been tested for their antiproliferative activity against four human cancer cell lines. Additionally, their mode of action has been evaluated as colchicine binding site inhibitors, using molecular docking studies. Most of the tested compounds showed greater cytotoxicity (IC in a low nanomolar range) and were characterized by a higher selectivity index than standard chemotherapeutics such as cisplatin and doxorubicin as well as unmodified colchicine. Their pharmacological use in cancer therapy could possibly be accomplished with lower dosages and result in less acute toxicity problems than in the case of colchicine. In addition, we present a QSAR model for predicting the antiproliferative activity of doubly modified derivatives for two tumour cell lines.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Colchicine; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Protein Binding; Quantitative Structure-Activity Relationship; Thiocarbamates; Tubulin; Tubulin Modulators
PubMed: 33611191
DOI: 10.1016/j.ejmech.2021.113282 -
The Journal of Organic Chemistry Apr 2021Hydrogen sulfide (HS) is an important biomolecule, and self-immolative thiocarbamates have shown great promise as triggerable HS donors with suitable analogous control...
Hydrogen sulfide (HS) is an important biomolecule, and self-immolative thiocarbamates have shown great promise as triggerable HS donors with suitable analogous control compounds; however, thiocarbamates with electron-deficient payloads are less efficient HS donors. We report here the synthesis and study of a series of -methylated esterase-triggered thiocarbamates that block the postulated unproductive deprotonation-based pathway for these compounds. The relative reaction profiles for HS release across a series of electron-rich and electron-poor N-Me aniline payloads are examined experimentally and computationally. We show that thiocarbamate -methylation does block some side reactivity and increases the HS release profiles for electron-poor donors. Additionally, we show that isothiocyanate release is not a competitive pathway, and rather that the reduced efficiency of electron-poor donors is likely due to other side reactions.
Topics: Hydrogen Sulfide; Methylation; Sulfur Oxides; Thiocarbamates
PubMed: 33818104
DOI: 10.1021/acs.joc.0c02778 -
Journal of the American Chemical Society Aug 2019Hydrogen sulfide (HS) is an important signaling molecule that provides protective activities in a variety of physiological and pathological processes. Among the...
Hydrogen sulfide (HS) is an important signaling molecule that provides protective activities in a variety of physiological and pathological processes. Among the different types of HS donor compounds, thioamides have attracted attention due to prior conjugation to nonsteroidal anti-inflammatory drugs (NSAIDs) to access HS-NSAID hybrids with significantly reduced toxicity, but the mechanism of HS release from thioamides remains unclear. Herein, we reported the synthesis and evaluation of a class of thioamide-derived sulfenyl thiocarbamates () that function as a new class of HS donors. These compounds are efficiently activated by cellular thiols to release carbonyl sulfide (COS), which is quickly converted to HS by carbonic anhydrase (CA). In addition, through mechanistic investigations, we establish that COS-independent HS release pathways are also operative. In contrast to the parent thioamide-based donors, the exhibit excellent HS releasing efficiencies of up to 90% and operate through mechanistically well-defined pathways. In addition, we demonstrate that the sulfenyl thiocarbamate group is readily attached to common NSAIDs, such as naproxen, to generate as an efficient HS-NSAID hybrid, which we demonstrate releases HS in cellular environments. Taken together, this new class of HS donor motifs provides an important platform for new donor development.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Carbonic Anhydrases; Cyclization; HeLa Cells; Humans; Hydrogen Sulfide; Naproxen; Sulfhydryl Compounds; Sulfur Oxides; Thiocarbamates
PubMed: 31373809
DOI: 10.1021/jacs.9b06319 -
Contact Dermatitis Aug 1976
Topics: Dermatitis, Contact; Humans; Patch Tests; Thiocarbamates; Thiram
PubMed: 1021353
DOI: 10.1111/j.1600-0536.1976.tb03035.x -
Toxicology Jun 1994
Topics: Agricultural Workers' Diseases; Animals; Environmental Monitoring; First Aid; Fungicides, Industrial; Humans; Occupational Health Services; Physical Examination; Skin Absorption; Thiocarbamates
PubMed: 8052983
DOI: 10.1016/0300-483x(94)90238-0 -
International Journal of Molecular... Jan 2022Dithiocarbamate ligands have the ability to form stable complexes with transition metals, and this chelating ability has been utilized in numerous applications. The... (Review)
Review
Dithiocarbamate ligands have the ability to form stable complexes with transition metals, and this chelating ability has been utilized in numerous applications. The complexes have also been used to synthesize other useful compounds. Here, the up-to-date applications of dithiocarbamate ligands and complexes are extensively discussed. Some of these are their use as enzyme inhibitor and treatment of HIV and other diseases. The application as anticancer, antimicrobial, medical imaging and anti-inflammatory agents is examined. Moreover, the application in the industry as vulcanization accelerator, froth flotation collector, antifouling, coatings, lubricant additives and sensors is discussed. The various ways in which they have been employed in synthesis of other compounds are highlighted. Finally, the agricultural uses and remediation of heavy metals via dithiocarbamate compounds are comprehensively discussed.
Topics: Anti-Bacterial Agents; Enzyme Inhibitors; Humans; Ligands; Metals, Heavy; Thiocarbamates; Transition Elements
PubMed: 35163241
DOI: 10.3390/ijms23031317 -
Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates.Molecules (Basel, Switzerland) Feb 2016Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit...
Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM). Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.
Topics: Acetylcholinesterase; Butyrylcholinesterase; Catalytic Domain; Cholinesterase Inhibitors; Hep G2 Cells; Humans; Inhibitory Concentration 50; Molecular Docking Simulation; Protein Binding; Structure-Activity Relationship; Thiocarbamates
PubMed: 26875979
DOI: 10.3390/molecules21020191 -
Journal of the American Chemical Society Jun 2016Hydrogen sulfide (H2S) is an important biological signaling molecule, and chemical tools for H2S delivery and detection have emerged as important investigative methods....
Hydrogen sulfide (H2S) is an important biological signaling molecule, and chemical tools for H2S delivery and detection have emerged as important investigative methods. Key challenges in these fields include developing donors that are triggered to release H2S in response to stimuli and developing probes that do not irreversibly consume H2S. Here we report a new strategy for H2S donation based on self-immolation of benzyl thiocarbamates to release carbonyl sulfide, which is rapidly converted to H2S by carbonic anhydrase. We leverage this chemistry to develop easily modifiable donors that can be triggered to release H2S. We also demonstrate that this approach can be coupled with common H2S-sensing motifs to generate scaffolds which, upon reaction with H2S, generate a fluorescence response and also release caged H2S, thus addressing challenges of analyte homeostasis in reaction-based probes.
Topics: Animals; Biosensing Techniques; Carbonic Anhydrases; Catalysis; Fluorescent Dyes; Hydrogen Sulfide; Male; Mice; Sulfur Oxides; Thiocarbamates
PubMed: 27218691
DOI: 10.1021/jacs.6b03780