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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 -
Bioconjugate Chemistry Apr 2014The design of novel chemoselective and site-specific ligation methods provides new tools for obtaining complex scaffolds, peptidomimetics, and peptide conjugates. The... (Review)
Review
The design of novel chemoselective and site-specific ligation methods provides new tools for obtaining complex scaffolds, peptidomimetics, and peptide conjugates. The chemistry of the N-phenylthiocarbonyl group has led to several developments in peptide ligation chemistry and peptide bioconjugation during the last 10 years. The aim of this review is to provide an overview of this emerging field.
Topics: Chemistry Techniques, Synthetic; Peptides; Peptidomimetics; Phenylcarbamates; Sulfhydryl Compounds; Thiocarbamates
PubMed: 24641212
DOI: 10.1021/bc500052r -
Life Sciences Sep 2021Angiotensin-converting enzyme 2 (ACE2) is a key negative regulator of the renin-angiotensin system and also a major receptor for severe acute respiratory syndrome...
AIMS
Angiotensin-converting enzyme 2 (ACE2) is a key negative regulator of the renin-angiotensin system and also a major receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we reveal a role for NF-κB in human lung cell expression of ACE2, and we further explore the potential utility of repurposing NF-κB inhibitors to downregulate ACE2.
MAIN METHODS
Expression of ACE2 was assessed by Western blotting and RT-qPCR in multiple human lung cell lines with or without NF-κB inhibitor treatment. Surface ACE2 expression and intracellular reactive oxygen species (ROS) levels were measured with flow cytometry. p50 was knocked down with siRNA. Cytotoxicity was monitored by PARP cleavage and MTS assay.
KEY FINDINGS
Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, suppressed endogenous ACE2 mRNA and protein expression in H322M and Calu-3 cells. The ROS level in H322M cells was increased after PDTC treatment, and pretreatment with N-acetyl-cysteine (NAC) reversed PDTC-induced ACE2 suppression. Meanwhile, treatment with hydrogen peroxide augmented ACE2 suppression in H322M cells with p50 knockdown. Two repurposed NF-κB inhibitors, the anthelmintic drug triclabendazole and the antiprotozoal drug emetine, also reduced ACE2 mRNA and protein levels. Moreover, zinc supplementation augmented the suppressive effects of triclabendazole and emetine on ACE2 expression in H322M and Calu-3 cells.
SIGNIFICANCE
These results suggest that ACE2 expression is modulated by ROS and NF-κB signaling in human lung cells, and the combination of zinc with triclabendazole or emetine shows promise for clinical treatment of ACE2-related disease.
Topics: Angiotensin-Converting Enzyme 2; Antiparasitic Agents; COVID-19; Cell Line; Down-Regulation; Drug Repositioning; Emetine; Humans; Lung; NF-kappa B; Pyrrolidines; Thiocarbamates; Triclabendazole; Zinc; COVID-19 Drug Treatment
PubMed: 34171382
DOI: 10.1016/j.lfs.2021.119752 -
Archives of Environmental &... Jul 2018This article compares detections and concentrations of specific organophosphate (OP), bis-dithiocarbamate, and pyrethroid pesticide urinary metabolites among Latino male...
This article compares detections and concentrations of specific organophosphate (OP), bis-dithiocarbamate, and pyrethroid pesticide urinary metabolites among Latino male farmworkers and nonfarmworkers in North Carolina. Data are from interviews and urine samples collected in 2012 and 2013. Farmworkers and nonfarmworkers frequently had detections for OP and pyrethroid pesticide urinary metabolites. Detection of bis-dithiocarbamate urinary metabolites was less frequent, but substantial among the nonfarmworkers. The concentrations of organophosphate, bis-dithiocarbamate, and pyrethroid pesticide urinary metabolites were high for farmworkers and nonfarmworkers compared to National Health and Nutrition Examination Survey results. Pesticide urinary metabolite detection was not associated with occupation in nonfarmworkers. Research for reducing pesticide exposure among farmworkers remains important; research is also needed to determine pesticide exposure pathways among Latino nonfarmworkers.
Topics: Adult; Aged; Emigrants and Immigrants; Farmers; Fungicides, Industrial; Hispanic or Latino; Humans; Insecticides; Male; Middle Aged; North Carolina; Nutrition Surveys; Organophosphates; Pyrethrins; Thiocarbamates
PubMed: 28622109
DOI: 10.1080/19338244.2017.1342588 -
Yakugaku Zasshi : Journal of the... 2016The ophthalmic application of drugs is the primary route of administration for the therapy of glaucoma; however, in traditional formulations, only small amounts of the... (Review)
Review
The ophthalmic application of drugs is the primary route of administration for the therapy of glaucoma; however, in traditional formulations, only small amounts of the administered drug penetrate the cornea to reach the desired intraocular tissue due to corneal barriers. Recently, nanoparticulate drug delivery is expected as a technology to overcome the difficulties in delivering drugs across biological barriers (improvement of bioavailability). In this study, we attempted to establish a new method for preparing solid drug nanoparticles by using a bead mill and various additives, and succeeded in preparing a high quality dispersion containing drug nanoparticles. For a more concrete example, a mean particle size of disulfiram (DSF) treated with bead mill is 183 nm. The corneal penetration and corneal residence time of DSF from the ophthalmic dispersion containing DSF nanoparticles were significantly higher than those from a 2-hydroxypropyl-β-cyclodextrin solution containing DSF (DSF solution). It is known that the administration of DSF has intraocular pressure (IOP)-reducing effects. The IOP-reducing effects of the ophthalmic dispersion containing DSF nanoparticles were significantly greater than those of the DSF solution in rabbits (the IOP was enhanced by placing the rabbits in a dark room for 5 h). In addition, the ophthalmic dispersion containing DSF nanoparticles is better tolerated by corneal epithelial cells than DSF solution. It is possible that dispersions containing DSF nanoparticles provide new possibilities for effectively treating glaucoma, and that ocular drug delivery systems using drug nanoparticles may expand their usage for therapy in the ophthalmologic field.
Topics: Animals; Biological Availability; Cornea; Disulfiram; Drug Compounding; Drug Delivery Systems; Drug Design; Glaucoma; Humans; Intraocular Pressure; Nanoparticles; Ophthalmic Solutions; Particle Size; Rabbits
PubMed: 27725388
DOI: 10.1248/yakushi.16-00089 -
European Journal of Medicinal Chemistry May 2023Schistosomiasis is an infectious disease caused by blood flukes of the genus Schistosoma and affects approximately 200 million people worldwide. Since Praziquantel (PZQ)...
Schistosomiasis is an infectious disease caused by blood flukes of the genus Schistosoma and affects approximately 200 million people worldwide. Since Praziquantel (PZQ) is the only drug for schistosomiasis, alternatives are needed. By a biochemical approach, we identified a tegumentally expressed aldehyde dehydrogenase (ALDH) of S. mansoni, SmALDH_312. Molecular analyses of adult parasites showed Smaldh_312 transcripts in both genders and different tissues. Physiological and cell-biological experiments exhibited detrimental effects of the drug disulfiram (DSF), a known ALDH inhibitor, on larval and adult schistosomes in vitro. DSF also reduced stem-cell proliferation and caused severe tegument damage in treated worms. In silico-modelling of SmALDH_312 and docking analyses predicted DSF binding, which we finally confirmed by enzyme assays with recombinant SmALDH_312. Furthermore, we identified compounds of the Medicine for Malaria Venture (MMV) pathogen box inhibiting SmALDH_312 activity. Our findings represent a promising starting point for further development towards new drugs for schistosomiasis.
Topics: Animals; Female; Male; Schistosoma mansoni; Schistosomiasis mansoni; Disulfiram; Aldehyde Dehydrogenase; Schistosomiasis
PubMed: 36948075
DOI: 10.1016/j.ejmech.2023.115179 -
Redox Biology Jan 2019It is known that some metals (Cu, Zn, Cd, Au) markedly increase the toxic effect of thiocarbamates. It was shown in the present study that hydroxycobalamin (a form of...
It is known that some metals (Cu, Zn, Cd, Au) markedly increase the toxic effect of thiocarbamates. It was shown in the present study that hydroxycobalamin (a form of vitamin B, HOCbl), which incorporates cobalt, significantly enhances the cytotoxicity of diethyldithiocarbamate (DDC), decreasing its IC value in tumor cells three to five times. The addition of HOCbl to aqueous DDC solutions accelerated the reduction of oxygen. No hydrogen peroxide accumulation was observed in DDC + HOCbl solutions; however, catalase slowed down the oxygen reduction rate. Catalase as well as the antioxidants N-acetylcysteine (NAC) and glutathione (GSH) partially inhibited the cytotoxic effect of DDC + HOCbl, whereas ascorbate, pyruvate, and tiron, a scavenger of superoxide anion, had no cytoprotective effect. The administration of HOCbl into DDC solutions (> 1 mM) resulted in the formation of a crystalline precipitate, which was inhibited in the presence of GSH. The data of UV and NMR spectroscopy and HPLC and Mass Spectrometry (LC/MS) indicated that the main products of the reaction of DDC with HOCbl are disulfiram (DSF) and its oxidized forms, sulfones and sulfoxides. The increase in the cytotoxicity of DDC combined with HOCbl occurred both in the presence of Cu in culture medium and in nominally Cu-free solutions, as well as in growth medium containing the copper chelator bathocuproine disulfonate (BCS). The results indicate that HOCbl accelerates the oxidation of DDC with the formation of DSF and its oxidized forms. Presumably, the main cause of the synergistic increase in the toxic effect of DDC + HOCbl is the formation of sulfones and sulfoxides of DSF.
Topics: Cell Line; Cell Survival; Copper; Ditiocarb; Humans; Hydrogen Peroxide; Hydroxocobalamin; Ions; Oxidation-Reduction; Oxidative Stress; Spectrum Analysis
PubMed: 30290302
DOI: 10.1016/j.redox.2018.09.016 -
American Journal of Physiology. Renal... Feb 2009Nuclear factor-kappaB (NF-kappaB) plays an important role in hypertensive renal injury; however, its roles in perpetuating mitochondrial oxidative stress and renal...
Nuclear factor-kappaB (NF-kappaB) plays an important role in hypertensive renal injury; however, its roles in perpetuating mitochondrial oxidative stress and renal dysfunction remain unclear. In this study, we assessed the effects of chronic NF-kappaB blockade with pyrrolidine dithiocarbamate (PDTC) on renal dysfunction and mitochondrial redox status in spontaneously hypertensive rats (SHR). PDTC (150 mg.kg body wt(-1).day(-1)) or vehicle was administered orally to 8-wk-old SHR and their respective controls for 15 wk. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography at the start of and at every third week throughout the study. After 15 wk of treatment, anesthetized rats underwent acute renal experiments to determine renal blood flow and glomerular filtration rate using PAH and inulin clearance techniques, respectively. Following renal experiments, kidneys were excised from killed rats, and cortical mitochondria were isolated for reactive oxygen species (ROS) measurements using electron paramagnetic resonance. Tissue mRNA and protein levels of NF-kappaB and oxidative stress genes were determined using real-time PCR and immunofluorescence or Western blotting, respectively. PDTC treatment partially attenuated the increase in SBP (196.4 +/- 9.76 vs. 151.4 +/- 2.12; P < 0.05) and normalized renal hemodynamic and excretory parameters and ATP production rates in SHR. PDTC treatment also attenuated the higher levels of cytosolic and mitochondrial ROS generation and tissue mRNA and protein expression levels of NF-kappaB and oxidative stress genes in SHR without any comparable responses in control rats. These findings suggest that NF-kappaB activation by ROS induces the cytosolic and mitochondrial oxidative stress and tissue injury that contribute to renal dysfunction observed in SHR.
Topics: Albuminuria; Animals; Antioxidants; Blood Pressure; Body Weight; Creatinine; Cytosol; Glomerular Filtration Rate; Hypertension; Kidney Cortex; Kidney Diseases; Male; Mitochondria; NF-kappa B; Oxidative Stress; Pyrrolidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Renal Circulation; Thiocarbamates
PubMed: 19073636
DOI: 10.1152/ajprenal.90628.2008 -
Langmuir : the ACS Journal of Surfaces... Feb 2010Dithiocarbamates (dtcs) have been implicated as important gold-binding groups in molecular electronics. Dtcs have two alkane branches connected at a single anchoring...
Dithiocarbamates (dtcs) have been implicated as important gold-binding groups in molecular electronics. Dtcs have two alkane branches connected at a single anchoring point that has a bidentate resonance structure. Forming readily in situ by the combination of secondary amines and CS(2), dtcs adsorb quickly onto gold surfaces. Electroactive self-assembled monolayers (eSAMs) were prepared by the coadsorption of ferrocene dialkyldithiocarbamates (Fc dtcs) with diluent dtcs on gold electrodes. Short and long alkane chains were used (11 and 16 methylene groups, respectively), and a polar ester group was incorporated. Cyclic voltammetry (CV) shows that the electrochemistry is quasi-reversible. At high surface coverage, the peak separations and full widths at half-maximum for Fc dtcs deviate from theoretical values and are analogous to that of ferrocene alkane thiols on gold at high surface coverage. Importantly, these features do not change at low Fc dtc surface coverage as observed for ferrocene alkane thiols. Ferrocene dtcs were used to label monolayer defect sites and to demonstrate the exchange of surface-bound dtcs with solution dtcs. Finally, the rate of electron transfer was analyzed using Tafel plots and ac voltammetric methods. The results for both techniques are consistent with a kinetically disperse population of redox sites. The length of the diluent alkane chain appears to have an effect on the distribution of electron-transfer rates, likely because of the eSAM structure. This work indicates that structurally, Fc dtc eSAMs are fundamentally different from alkane thiol SAMs on gold.
Topics: Amines; Carbon Disulfide; Electrochemistry; Electrodes; Gold; Kinetics; Membranes, Artificial; Oxidation-Reduction; Surface Properties; Thiocarbamates
PubMed: 19877702
DOI: 10.1021/la902839r -
Molecular Oncology Apr 2022Disulfiram (DSF), an established alcohol-aversion drug, is a candidate for repurposing in cancer treatment. DSF's antitumor activity is supported by preclinical studies,...
Disulfiram (DSF), an established alcohol-aversion drug, is a candidate for repurposing in cancer treatment. DSF's antitumor activity is supported by preclinical studies, case reports, and small clinical trials; however, ongoing clinical trials of advanced-stage cancer patients encounter variable results. Here, we show that one reason for the inconsistent clinical effects of DSF may reflect interference by other drugs. Using a high-throughput screening and automated microscopy, we identify cannabidiol, an abundant component of the marijuana plant used by cancer patients to mitigate side effects of chemotherapy, as a likely cause of resistance to DSF. Mechanistically, in cancer cells, cannabidiol triggers the expression of metallothioneins providing protective effects by binding heavy metal-based substances including the bis-diethyldithiocarbamate-copper complex (CuET). CuET is the documented anticancer metabolite of DSF, and we show here that the CuET's anticancer toxicity is effectively neutralized by metallothioneins. Overall, this work highlights an example of undesirable interference between cancer therapy and the concomitant usage of marijuana products. In contrast, we report that insufficiency of metallothioneins sensitizes cancer cells toward CuET, suggesting a potential predictive biomarker for DSF repurposing in oncology.
Topics: Cannabidiol; Cell Line, Tumor; Copper; Disulfiram; Humans; Metallothionein
PubMed: 34632694
DOI: 10.1002/1878-0261.13114