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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 -
Theranostics 2020To circumvent the huge cost, long R&D time and the difficulty to identify the targets of new drugs, repurposing the ones that have been clinically approved has been...
To circumvent the huge cost, long R&D time and the difficulty to identify the targets of new drugs, repurposing the ones that have been clinically approved has been considered as a viable strategy to treat different diseases. In the current study, we outlined the rationale for repurposing disulfiram (DSF, an old alcohol-aversion drug) to treat primary breast cancer and its metastases. To overcome a few shortcomings of the individual administration of DSF, such as the dependence on copper ions (Cu) and limited capability in selective targeting, we here artificially synthesized the active form of DSF, diethyldithiocarbamate (DTC)-Cu complex (CuET) for cancer therapeutics. To achieve a greater efficacy , smart nanomedicines were devised through a one-step self-assembly of three functional components including a chemically stable and biocompatible phase-change material (PCM), the robust anticancer drug (CuET) and a near-infrared (NIR) dye (DIR), namely CuET/DIR NPs. A number of assays were performed including the photothermal efficacy, light-triggered drug release behavior, nuclear localization, DNA damage and induction of apoptosis of CuET/DIR NPs and molecular mechanisms underlying CuET-induced repression on cancer metastatic behaviors. Meanwhile, the mice bearing 4T1-LG12-drived orthotopic tumors were employed to evaluate biodistribution and anti-tumor effect of CuET/DIR NPs. The intravenous injection model was employed to reflect the changes of the intrinsic metastatic propensity of 4T1-LG12 cells responding to CuET/DIR NPs. The rationally designed nanomedicines have self-traceability for bioimaging, long blood circulation time for enhanced drug accumulation in the tumor site and photo-responsive release of the anticancer drugs. Moreover, our data unearthed that CuET/DIR nanomedicines behave like "Trojan horse" to transport CuET into the cytoplasm, realizing substantial intracellular accumulation. Upon NIR laser irradiation, massive CuET would be triggered to release from the nanomedicines and reach a high local concentration towards the nucleus, where the pro-apoptotic effects were conducted. Importantly, our CuET/DIR nanomedicines revealed a pronounced capability to leash breast cancer metastases through inhibition on EMT. Additionally, these nanomedicines showed great biocompatibility in animals. These combined data unearthed a remarkably enhanced tumor-killing efficacy of our CuET nanomedicines through nuclear targeting. This work may open a new research area of repurposing DSF as innovative therapeutic agents to treat breast cancer and its metastases.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Nucleus; Copper; Disulfiram; Ditiocarb; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Female; Humans; Low-Level Light Therapy; Mice; Nanomedicine; Nanoparticles; Neoplasm Metastasis; Neoplasms; Theranostic Nanomedicine
PubMed: 32483459
DOI: 10.7150/thno.45558 -
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 -
BMC Biochemistry Dec 2018Sepsis is a severe condition characterised by the body's systemic inflammatory response to infection. The specific sepsis-related biomarkers should be used in clinical...
BACKGROUND
Sepsis is a severe condition characterised by the body's systemic inflammatory response to infection. The specific sepsis-related biomarkers should be used in clinical diagnosis, therapeutic response monitoring, rational use of antibiotics, and prognosis (risk stratification), etc. RESULTS: In this study, we investigated the expression level of Decoy Receptor 3 (DcR3) and the mechanism of high expression in sepsis patients. Septic cell model experiments were performed by treating human umbilical vein endothelial cells (HUVECs) and Jurkat cells with lipopolysaccharide (LPS), lipoteichoic acid (LTA) and zymosan, respectively. SP600125, SB203580 and ammonium pyrrolidinedithiocarbamate (PDTC) were used to inhibit JNK1/2, p38MAPK and NF-κB signalling pathways in septic cell model, respectively. These results showed that DcR3 levels were higher in sepsis group than control. DcR3 mRNA and protein levels in HUVECs were increased following treatment with LPS, LTA and zymosan, and also increased in Jurkat cells treated by LPS, but not by LTA or zymosan. When HUVECs were treated with the NF-κB inhibitor PDTC, DcR3 expression was decreased compared with controls. However, SP600125 and SB203580 had no effect on DcR3 mRNA or protein levels.
CONCLUSIONS
The results indicated that DcR3 secretion proceeded through the NF-κB signalling pathway in HUVECs.
Topics: Anthracenes; Human Umbilical Vein Endothelial Cells; Humans; Imidazoles; Jurkat Cells; Lipopolysaccharides; NF-kappa B; Proline; Protein Kinase Inhibitors; Pyridines; Receptors, Tumor Necrosis Factor, Member 6b; Signal Transduction; Teichoic Acids; Thiocarbamates; Up-Regulation; Zymosan
PubMed: 30587127
DOI: 10.1186/s12858-018-0102-z -
Molecules (Basel, Switzerland) Aug 2020Cu(II) and Zn(II) morpholinyldithiocarbamato complexes, formulated as [Cu(MphDTC)] and [Zn(μ-MphDTC)(MphDTC)], where MphDTC is morpholinyldithiocarbamate were...
Cu(II) and Zn(II) morpholinyldithiocarbamato complexes, formulated as [Cu(MphDTC)] and [Zn(μ-MphDTC)(MphDTC)], where MphDTC is morpholinyldithiocarbamate were synthesized and characterized by elemental analysis, spectroscopic techniques and single-crystal X-ray crystallography. The molecular structure of the Cu(II) complex revealed a mononuclear compound in which the Cu(II) ion was bonded to two morpholinyl dithiocarbamate ligands to form a four-coordinate distorted square planar geometry. The molecular structure of the Zn(II) complex was revealed to be dinuclear, and each metal ion was bonded to two morpholinyl dithiocarbamate bidentate anions, one acting as chelating ligand, the other as a bridge between the two Zn(II) ions. The anticancer activity of the morpholinyldithiocarbamate ligand, Cu(II) and Zn(II) complexes were evaluated against renal (TK10), melanoma (UACC62) and breast (MCF7) cancer cells by a Sulforhodamine B (SRB) assay. Morpholinyldithiocarbamate was more active than the standard drug parthenolide against renal and breast cancer cell lines, and [Zn(μ-MphDTC)(MphDTC)] was the most active complex against breast cancer. The copper(II) complex had a comparable activity with the standard against renal and breast cancer cell lines but showed an enhanced potency against melanoma when compared to parthenolide.
Topics: Antineoplastic Agents; Cell Line, Tumor; Chemistry Techniques, Synthetic; Coordination Complexes; Copper; Crystallography, X-Ray; Humans; Models, Molecular; Molecular Conformation; Thiocarbamates; Zinc
PubMed: 32781741
DOI: 10.3390/molecules25163584 -
Frontiers in Bioscience (Landmark... Jan 2009The most recent data on mechanisms of spin trapping of nitric oxide (NO) by iron dithiocarbamate complexes in animal and plant cells and tissues are considered. The... (Review)
Review
The most recent data on mechanisms of spin trapping of nitric oxide (NO) by iron dithiocarbamate complexes in animal and plant cells and tissues are considered. The rationale is as follows: 1 In the absence of NO in cells and tissues, iron binds primarily to compounds others than dithiocarbamate ligands, e.g., tricarbonic acids. 2. Predominant binding of iron to dithiocarbamate ligands takes place only after its binding to NO, since nitrosylated iron manifests much higher affinity for these ligands that for any non-thiol compounds. 3.Within the composition of mononitrosyl dithiocarbamate complexes, iron exists predominantly in the oxidized (Fe3+) form, i.e., these complexes are originally diamagnetic. Their subsequent single-electron reduction to the paramagnetic, EPR -detectable form is mediated by endogenous or exogenous (e.g., dithionite) reducing agents. 4.Superoxide-mediated transition of paramagnetic mononitrosyl dithiocarbamate iron complexes into EPR-silent state can be accompanied by significant reduction of EPR-detectable complexes. This defect can be overcome through the use of the so-called ABC method. 5. In contrast to hydrophobic complexes fast decomposition of water-soluble mononitrosyl iron complexes in animal organisms testifies to low efficiency of these complexes in determination of NO content in animal cells and tissues.
Topics: Animals; Ferrous Compounds; Nitric Oxide; Peroxynitrous Acid; Spin Labels; Superoxides; Thiocarbamates
PubMed: 19273360
DOI: 10.2741/3538 -
Scientific Reports Oct 2022Phenacoccus solenopsis Tinsley (Hemiptera: Pseudococcidae) an invasive mealybug on cotton is primarily controlled by conventional insecticides. An endoparasitoid...
Phenacoccus solenopsis Tinsley (Hemiptera: Pseudococcidae) an invasive mealybug on cotton is primarily controlled by conventional insecticides. An endoparasitoid Aenasius arizonenesis (Girault) (Hymenoptera: Encyrtidae) is a potential biocontrol agent of this pest. We assessed the susceptibility in field populations of P. solenopsis and A. arizonensis to commonly used insecticides: profenofos, imidacloprid and thiodicarb. Reproductive traits of the parasitoid and Environmental Risk Assessment (ERA) parameters viz., Reduction coefficient, Descriptive analysis, Risk Index (RI), Selectivity ratio and Hazard quotient were measured to assess the direct and indirect effects of these insecticides on the parasitoid. Probit analysis revealed heterogeneity in the insecticide resistance development for both the cotton mealybug and its parasitoid. The field populations of P. solenopsis exhibited resistance to profenofos (18.87-59.86 folds) and thiodicarb (20.07 folds) and susceptibility to imidacloprid. Development of resistance to profenofos was observed in field populations of A. arizonensis. Exposure to lethal doses of imidacloprid and profenofos caused a reduction in parasitization (19-23%) and adult emergence (62-69%) of the parasitoid. Profenofos, thiodicarb and imidacloprid were found to be hazardous, non-selective and harmful to the endoparasitoid, A. arizonensis. There is an urgent need for optimizing insecticide applications for sustainable management of this invasive mealybug in cotton.
Topics: Animals; Gossypium; Hemiptera; Hymenoptera; Insecticide Resistance; Insecticides; Neonicotinoids; Nitro Compounds; Organothiophosphates; Thiocarbamates
PubMed: 36202878
DOI: 10.1038/s41598-022-20779-3 -
International Journal of Molecular... Oct 2018A previous study has revealed that oxidized low‑density lipoprotein (oxLDL)/β2‑glycoprotein I (β2GPI)/anti‑β2‑glycoprotein I (anti‑β2GPI), an immune...
A previous study has revealed that oxidized low‑density lipoprotein (oxLDL)/β2‑glycoprotein I (β2GPI)/anti‑β2‑glycoprotein I (anti‑β2GPI), an immune complex, is able to activate the Toll‑like receptor 4 (TLR4)/nuclear factor κβ (NF‑κβ) inflammatory signaling pathway in macrophages, and consequently enhance foam cell formation and the secretion of prothrombin activators. However, the effects of the oxLDL/β2GPI/anti‑β2GPI complex on vascular smooth muscle cells have yet to be investigated. The present study investigated whether the oxLDL/β2GPI/anti‑β2GPI complex was able to reinforce the pro‑atherogenic activities of a rat thoracic aorta smooth muscle cell line (A7r5) and examined the underlying molecular mechanisms. The results revealed that the oxLDL/β2GPI/anti‑β2GPI complex treatment significantly (P<0.05 vs. the media, oxLDL, oxLDL/β2GPI and β2GPI/anti‑β2GPI groups) enhanced the pro‑atherogenic activation of A7r5 cells, including intracellular lipid loading, Acyl‑coenzyme A cholesterol acyltransferase mRNA expression, migration, matrix metalloproteinase‑9 and monocyte chemoattractant protein 1 secretion, all via TLR4. In addition, the expression of TLR4 and the phosphorylation of NF‑κβ p65, p38 and ERK1/2 were also upregulated in oxLDL/β2GPI/anti‑β2GPI complex‑treated A7r5 cells. Pre‑treatment with TAK‑242, a TLR4 inhibitor, was able to partly attenuate the oxLDL/β2GPI/anti‑β2GPI complex‑induced phosphorylation of NF‑κβ p65; however, it had no effect on the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) and p38. Meanwhile, the NF‑κβ p65 inhibitor ammonium pyrrolidinedithiocarbamate and the ERK1/2 inhibitor U0126, but not the p38 inhibitor SB203580, were able to block oxLDL/β2GPI/anti‑β2GPI complex‑induced foam cell formation and migration in A7r5 cells. Hence, it was demonstrated that the oxLDL/β2GPI/anti‑β2GPI complex is able to enhance the lipid uptake, migration and active molecule secretion of A7r5 cells via TLR4, and finally deteriorate atherosclerosis plaques. Additionally, it was demonstrated that oxLDL/β2GPI/anti‑β2GPI complex‑induced foam cell formation and migration may be partly mediated by the TLR4/NF‑κβ signaling pathway and that ERK1/2 may also participate in the process.
Topics: Animals; Blotting, Western; Butadienes; Cell Line; Cell Movement; Cholesterol; Enzyme-Linked Immunosorbent Assay; Lipoproteins, LDL; NF-kappa B; Nitriles; Phosphorylation; Proline; Rats; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Thiocarbamates; Toll-Like Receptor 4; Wound Healing; beta 2-Glycoprotein I
PubMed: 30085340
DOI: 10.3892/ijmm.2018.3805 -
Molecules and Cells Aug 2006The NFAT family of transcription factors plays pivotal roles in the development and function of the immune system. Their activation process is tightly regulated by... (Review)
Review
The NFAT family of transcription factors plays pivotal roles in the development and function of the immune system. Their activation process is tightly regulated by calcium-dependent phosphatase calcineurin and has been a target of the immunosuppressive drugs cyclosporin A and FK-506. Although the clinical use of these drugs has dramatically increased the success of organ transplantation, their therapeutic use is limited by severe side effects. Recent studies for the calcineurin/NFAT signaling pathway have identified a number of cellular proteins that inhibit calcineurin function. Specific peptide sequences that interfere with the interaction between calcineurin and NFAT have also been characterized. Moreover, diverse approaches to identify small organic molecules that modulate NFAT function have been performed. This review focuses on the recent advances in our understanding of the inhibitory modulation of NFAT function, which may open up the additional avenues for immunosuppressive therapy.
Topics: Adaptor Proteins, Signal Transducing; Aptamers, Nucleotide; Calcineurin; Calcineurin Inhibitors; Immunosuppression Therapy; Models, Immunological; NFATC Transcription Factors; Oligopeptides; Phosphoproteins; Phosphorylation; Pyrazoles; Thiocarbamates
PubMed: 16951543
DOI: No ID Found -
Molecules (Basel, Switzerland) Aug 2019Dithiocarbamates represent a class of compounds that were evaluated in different biomedical applications because of their chemical versatility. For this reason, several... (Review)
Review
Dithiocarbamates represent a class of compounds that were evaluated in different biomedical applications because of their chemical versatility. For this reason, several pharmacological activities have already been attributed to these compounds, such as antiparasitic, antiviral, antifungal activities, among others. Therefore, compounds that are based on dithiocarbamates have been evaluated in different in vivo and in vitro models as potential new antimicrobials. Thus, the purpose of this review is to present the possibilities of using dithiocarbamate compounds as potential new antitrypanosomatids-drugs, which could be used for the pharmacological control of Chagas disease, leishmaniasis, and African trypanosomiasis.
Topics: Animals; Antiparasitic Agents; Chagas Disease; Humans; Leishmaniasis; Thiocarbamates; Trypanosoma; Trypanosomiasis, African
PubMed: 31374887
DOI: 10.3390/molecules24152806