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ACS Combinatorial Science Sep 2019Two protocols for the combinatorial synthesis of 5-(dialkylamino)tetrazoles were developed. The best success rate (67%) was shown by the method that used primary and...
Two protocols for the combinatorial synthesis of 5-(dialkylamino)tetrazoles were developed. The best success rate (67%) was shown by the method that used primary and secondary amines, 2,2,2-trifluoroethylthiocarbamate, and sodium azide as the starting reagents. The key steps included the formation of unsymmetrical thiourea, subsequent alkylation with 1,3-propane sultone and cyclization with azide anion. A 559-member aminotetrazole library was synthesized by this approach; the overall readily accessible (REAL) chemical space covered by the method exceeded 7 million feasible compounds.
Topics: Alkylation; Amines; Azides; Catalysis; Cyclization; Molecular Structure; Sodium Azide; Temperature; Tetrazoles; Thiocarbamates; Thiophenes; Thiourea
PubMed: 31437394
DOI: 10.1021/acscombsci.9b00120 -
Biomolecules Nov 2019The 'superbug' infection caused by metallo-β-lactamases (MβLs) has grown into an emergent health threat. Given the clinical importance of MβLs, a novel scaffold,...
The 'superbug' infection caused by metallo-β-lactamases (MβLs) has grown into an emergent health threat. Given the clinical importance of MβLs, a novel scaffold, dithiocarbamate, was constructed. The obtained molecules, DC1, DC8 and DC10, inhibited MβLs NDM-1, VIM-2, IMP-1, ImiS and L1 from all three subclasses, exhibiting an IC < 26 μM. DC1 was found to be the best inhibitor of ImiS (IC < 0.22 μM). DC1-2, DC4, DC8 and DC10 restored antimicrobial effects of cefazolin and imipenem against -BL21, producing NDM-1, ImiS or L1, and DC1 showed the best inhibition of cells, expressing the three MβLs, resulting in a 2-16-fold reduction in the minimum inhibitory concentrations (MICs) of both antibiotics. Kinetics and isothermal titration calorimetry (ITC) assays showed that DC1 exhibited a reversible, and partially mixed inhibition, of NDM-1, ImiS and L1, with Ki values of 0.29, 0.14 and 5.06 µM, respectively. Docking studies suggest that the hydroxyl and carbonyl groups of DC1 form coordinate bonds with the Zn (II) ions, in the active center of NDM-1, ImiS and L1, thereby inhibiting the activity of the enzymes. Cytotoxicity assays showed that DC1, DC3, DC7 and DC9 have low toxicity in L929 mouse fibroblastic cells, at a dose of up to 250 μM. These studies revealed that the dithiocarbamate is a valuable scaffold for the development of MβLs inhibitors.
Topics: Animals; Calorimetry; Cell Line; Escherichia coli; Mice; Microbial Sensitivity Tests; Molecular Docking Simulation; Structure-Activity Relationship; Thiocarbamates; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 31694268
DOI: 10.3390/biom9110699 -
Ecotoxicology and Environmental Safety Jul 2022Mancozeb (MCZ) is widely used as a protective fungicide. This study aimed to explore the effects of low level MCZ exposure on ovary in mice. Twenty Kunming mice were...
Mancozeb (MCZ) is widely used as a protective fungicide. This study aimed to explore the effects of low level MCZ exposure on ovary in mice. Twenty Kunming mice were randomly divided into control and MCZ groups (10 mice each). The mice in the MCZ group were given 100 mg/kg MCZ daily via gavage. The mice were sacrificed to collect serum and ovaries on day 31. The experimental indicators were then assessed. The weight of MCZ-exposed mice significantly reduced while ovarian index significantly increased compared with the control group. The FSH, LH, E2, P, CAT, SOD and MDA contents in the serum were significantly decreased and the content of estradiol significantly increased after MCZ exposure. Histological observation showed that the ovarian structure of mice exposed to MCZ was damaged, and the apoptosis was increased. Immunohistochemistry and RT-qPCR showed that the expression of Bax, caspase-3 and caspase-9 significantly increased in the MCZ- group. Conversely, Bcl-2 expression significantly decreased. Transcriptome sequencing showed that the expression of NADH dehydrogenase ND3, ND4L, ND6 subunits, Cyt b, and SDHC genes in mitochondria were down-regulated after MCZ exposure, similar to real-time PCR analysis. These results collectively indicate that the MCZ can affect the abnormal function of mitochondrial respiratory chain, lead to oxidative phosphorylation decoupling, produce oxidative stress, and finally cause ovarian injury and apoptosis in mice.
Topics: Animals; Apoptosis; Female; Maneb; Mice; Ovary; Oxidative Stress; Zineb
PubMed: 35617905
DOI: 10.1016/j.ecoenv.2022.113670 -
Journal of Experimental & Clinical... Jan 2024MEK inhibitors (MEKi) were shown to be clinically insufficiently effective in patients suffering from BRAF wild-type (BRAF WT) melanoma, even if the MAPK pathway was...
BACKGROUND
MEK inhibitors (MEKi) were shown to be clinically insufficiently effective in patients suffering from BRAF wild-type (BRAF WT) melanoma, even if the MAPK pathway was constitutively activated due to mutations in NRAS or NF-1. Thus, novel combinations are needed to increase the efficacy and duration of response to MEKi in BRAF WT melanoma. Disulfiram and its metabolite diethyldithiocarbamate are known to have antitumor effects related to cellular stress, and induction of endoplasmic reticulum (ER) stress was found to synergize with MEK inhibitors in NRAS-mutated melanoma cells. Therefore, we investigated the combination of both therapeutics to test their effects on BRAF-WT melanoma cells and compared them with monotherapy using the MEKi trametinib.
METHODS
The effects of combined therapy with disulfiram or its metabolite diethyldithiocarbamate and the MEKi trametinib were evaluated in a series of BRAF-WT melanoma cell lines by measuring cell viability and apoptosis induction. Cytotoxicity was additionally assessed in 3D spheroids, ex vivo melanoma slice cultures, and in vivo xenograft mouse models. The response of melanoma cells to treatment was studied at the RNA and protein levels to decipher the mode of action. Intracellular and intratumoral copper measurements were performed to investigate the role of copper ions in the antitumor cytotoxicity of disulfiram and its combination with the MEKi.
RESULTS
Diethyldithiocarbamate enhanced trametinib-induced cytotoxicity and apoptosis induction in 2D and 3D melanoma culture models. Mechanistically, copper-dependent induction of oxidative stress and ER stress led to Janus kinase (JNK)-mediated apoptosis in melanoma cells. This mechanism was also detectable in patient-derived xenograft melanoma models and resulted in a significantly improved therapeutic effect compared to monotherapy with the MEKi trametinib.
CONCLUSIONS
Disulfiram and its metabolite represent an attractive pharmaceutical approach to induce ER stress in melanoma cells that potentiates the antitumor effect of MEK inhibition and may be an interesting candidate for combination therapy of BRAF WT melanoma.
Topics: Humans; Animals; Mice; Disulfiram; Proto-Oncogene Proteins B-raf; Copper; Melanoma; Ditiocarb; Disease Models, Animal; Mitogen-Activated Protein Kinase Kinases
PubMed: 38263136
DOI: 10.1186/s13046-023-02941-5 -
Journal of Enzyme Inhibition and... Dec 2022Recently, inorganic anions and sulphonamides, two of the main classes of zinc-binding carbonic anhydrase inhibitors (CAIs), were investigated for inhibition of the...
Recently, inorganic anions and sulphonamides, two of the main classes of zinc-binding carbonic anhydrase inhibitors (CAIs), were investigated for inhibition of the α-class carbonic anhydrase (CA, EC 4.2.1.1) from , NgCA. As an extension to our previous studies, we report that dithiocarbamates (DTCs) derived from primary or secondary amines constitute a class of efficient inhibitors of NgCA. Ks ranging between 83.7 and 827 nM were measured for a series of 31 DTCs that incorporated various aliphatic, aromatic, and heterocyclic scaffolds. A subset of DTCs were selected for antimicrobial testing against , and three molecules displayed minimum inhibitory concentration (MIC) values less than or equal to 8 µg/mL. As NgCA was recently validated as an antibacterial drug target, the DTCs may lead to development of novel antigonococcal agents.
Topics: Anti-Bacterial Agents; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Dose-Response Relationship, Drug; Microbial Sensitivity Tests; Molecular Structure; Neisseria gonorrhoeae; Structure-Activity Relationship; Thiocarbamates
PubMed: 34894954
DOI: 10.1080/14756366.2021.1988945 -
Cells Feb 2021Brassinin is a phytochemical derived from Chinese cabbage, a cruciferous vegetable. Brassinin has shown anticancer effects on prostate and colon cancer cells, among...
Brassinin is a phytochemical derived from Chinese cabbage, a cruciferous vegetable. Brassinin has shown anticancer effects on prostate and colon cancer cells, among others. However, its mechanisms and effects on hepatocellular carcinoma (HCC) have not been elucidated yet. Our results confirmed that brassinin exerted antiproliferative effects by reducing proliferating cell nuclear antigen (PCNA) activity, a proliferation indicator and inducing cell cycle arrest in human HCC (Huh7 and Hep3B) cells. Brassinin also increased mitochondrial Ca levels and depolarized the mitochondrial membrane in both Huh7 and Hep3B cells. Moreover, brassinin generated high amounts of reactive oxygen species (ROS) in both cell lines. The ROS scavenger N-acetyl-L-cysteine (NAC) inhibited this brassinin-induced ROS production. Brassinin also regulated the AKT and mitogen-activated protein kinases (MAPK) signaling pathways in Huh7 and Hep3B cells. Furthermore, co-administering brassinin and pharmacological inhibitors for JNK, ERK1/2 and P38 decreased cell proliferation in both HCC cell lines more than the pharmacological inhibitors alone. Collectively, our results demonstrated that brassinin exerts antiproliferative effects via mitochondrial dysfunction and MAPK pathway regulation on HCC cells.
Topics: Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Indoles; Liver Neoplasms; Mitochondria; Thiocarbamates
PubMed: 33562611
DOI: 10.3390/cells10020332 -
Bulletin of the World Health... 1971The discovery of effective insecticidal materials among the carbamic-acid esters is surveyed to provide insight into some of the factors leading to the development of... (Review)
Review
The discovery of effective insecticidal materials among the carbamic-acid esters is surveyed to provide insight into some of the factors leading to the development of new control agents. Problems associated with attempts to correlate insecticidal activity with acetylcholinesterase inhibition are outlined. The intoxication syndrome is described and its toxicological significance discussed. Structure-activity profiles are presented for selected compounds to illustrate the biological effects produced by structural variations. Categories of carbamates in which no significant insecticidal activity has been discovered are also listed.
Topics: Animals; Carbamates; Chemical Phenomena; Chemistry; Cholinesterase Inhibitors; Coleoptera; Esters; Houseflies; Insecta; Insecticides; Lethal Dose 50; Mites; Species Specificity; Structure-Activity Relationship; Thiocarbamates
PubMed: 4938022
DOI: No ID Found -
Journal of Immunotoxicology Dec 2018Both NF-κB pathway and complement activation appear to be involved in kidney damage induced by trichloroethylene (TCE). However, any relationship between these two...
Both NF-κB pathway and complement activation appear to be involved in kidney damage induced by trichloroethylene (TCE). However, any relationship between these two systems has not yet been established. The present study aimed to clarify the role of NF-κB in complement activation and renal injury in TCE-sensitized BALB/c mice. Mice were sensitized by an initial subcutaneous injection and repeated focal applications of TCE to dorsal skin at specified timepoints. NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) was injected (intraperitoneal) before the final two focal TCE challenges. In the experiments, mice had their blood and kidneys collected. Kidney function was evaluated via blood urea nitrogen (BUN) and creatinine (Cr) content; renal histology was examined using transmission electron microscopy (TEM). Kidney levels of phospho-p65 were assessed by Western blot and kidney mRNA levels of interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor (TNF)-α, and p65 by real-time quantitative PCR. Presence of C3 and C5b-9 membrane attack complexes in the kidneys was evaluated via immunohistochemistry. The results showed there was significant swelling, vacuolar degeneration in mitochondria, shrinkage of microvilli, disappearance of brush borders, segmental foot process fusion, and glomerular basement membrane thickening (or disrobing) in kidneys from TCE-sensitized mice. In conjunction with these changes, serum BUN and Cr levels were increased and IL-1β, IL-6, IL-17, and TNFα mRNA levels were elevated. Levels of p65 and phospho-p65 protein were also up-regulated, and there was significant C3 and C5b-9 deposition. PDTC pretreatment attenuated TCE-induced up-regulation of p65 and its phosphorylation, complement deposition, cytokine release, and renal damage. These results provide the first evidence that NF-κB pathway has an important role in TCE-induced renal damage mediated by enhanced complement activation in situ.
Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Complement C3; Complement C5b; Creatinine; Cytokines; Gene Expression Regulation; Kidney; Mice; Mice, Inbred BALB C; NF-kappa B; Pyrrolidines; Signal Transduction; Thiocarbamates; Trichloroethylene
PubMed: 29534626
DOI: 10.1080/1547691X.2017.1420712 -
European Review For Medical and... Nov 2018To explore the roles of NF-kB in the development of lung injury after one-lung ventilation.
OBJECTIVE
To explore the roles of NF-kB in the development of lung injury after one-lung ventilation.
MATERIALS AND METHODS
Eighteen Sprague-Dawley (SD) rats were randomly divided into 3 groups including control group, one-lung ventilation (OL) group and NF-kB inhibitor pyrrolidine dithiocarbamate (PDTC) group, with 6 rats in each group. Rats in OL and PDTC groups were used to establish one-lung ventilation model, and rats in PDTC group were subjected to intravenous injection of NF-kB specific inhibitor PDTC at 30 min before model construction. One-lung ventilation was performed for 3 h, and arterial blood gas analyzer was used for blood gas analysis. The hemodynamics and respiratory mechanics parameters were detected. The respiratory index (RI) and oxygenation index (OI) were calculated. The pathological changes of lung tissue were observed by HE staining. The levels of TNF-α, IL-1β, IL-6, and IL-8 in lung tissue were detected by ELISA. The expression levels of p65, p-p65, p-IκBα and IκBα and the activity of NF-Kβ in lung tissue were detected by Western Blot.
RESULTS
Compared with OL group, HR, RI and W/D were significantly reduced and MAP and OI were significantly increased in PDTC group (p<0.05). Compared with OL group, alveolar fluid exudation, pulmonary interstitial thickening and inflammatory cell infiltration were significantly improved in PDTC group. The levels of TNF-α, IL-1β, IL-6 and IL-8 in PDTC group were significantly lower than in OL group (p<0.05). The ratios of p-p65/p65 and p-IκBα/IκBα and the activity of NF-kB in OL group were significantly reduced than in PDTC group (p<0.05).
CONCLUSIONS
NF-kB can promote lung injury after one-lung ventilation, and the inhibition of NF-kB may be a new way for the treatment of this disease.
Topics: Animals; Blood Gas Analysis; Cytokines; Hemodynamics; Inflammation; Lung; Lung Injury; NF-kappa B; One-Lung Ventilation; Pyrrolidines; Rats; Rats, Sprague-Dawley; Respiratory Mechanics; Thiocarbamates
PubMed: 30468489
DOI: 10.26355/eurrev_201811_16281 -
Chemical Communications (Cambridge,... Feb 2023Thioamides, thioureas, and thiocarbamates are introduced as stable, sulfur-based metal-binding pharmacophores (MBPs) for use in metalloenzyme fragment-based drug...
Thioamides, thioureas, and thiocarbamates are introduced as stable, sulfur-based metal-binding pharmacophores (MBPs) for use in metalloenzyme fragment-based drug discovery (mFBDD). MBP reactivity, bioactivity, and structural studies show that these molecules can act as ligands for Zn(II)-dependent metalloenzymes including human carbonic anhydrase II (hCAII) and matrix metalloproteinase-2 (MMP-2).
Topics: Humans; Thiourea; Thioamides; Matrix Metalloproteinase 2; Thiocarbamates; Sulfhydryl Compounds; Chelating Agents; Metalloproteins
PubMed: 36735025
DOI: 10.1039/d2cc06596g