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BMJ (Clinical Research Ed.) Dec 2014
Topics: Bhopal Accidental Release; Compensation and Redress; Disasters; Drug Industry; Gas Poisoning; Humans; India; Isocyanates; Pesticides; Survivors
PubMed: 25499143
DOI: 10.1136/bmj.g7602 -
Combinatorial Chemistry & High... 2014An efficient parallel synthesis was designed to provide libraries of estradiol mimics that can potentially interact with different biological targets associated with...
An efficient parallel synthesis was designed to provide libraries of estradiol mimics that can potentially interact with different biological targets associated with estradiol-related diseases. Two libraries of 75 members each were synthesized around a non-steroidal core by adding three levels of molecular diversity. Hydroxybenzaldehydes (1st level of diversity), protected as a methoxymethyl ether, first reacted with primary amines (2nd level of diversity) under reductive amination conditions. The resulting secondary amines next reacted with 4-bromo-1,2-epoxybutane to provide epoxide derivatives as precursors of the 3rd level of diversity. Various nucleophiles were then used to open each epoxide. Methyl isocyanate scavenger was finally used to trap out the excess amine and the protecting group was removed by hydrolysis to provide the final compounds.
Topics: Biomimetics; Estradiol; Molecular Structure; Small Molecule Libraries; Solutions
PubMed: 25230027
DOI: 10.2174/1386207317666140915125620 -
Journal of Agricultural and Food... Sep 2014The soil fumigant metam-sodium (CH3NHCS2Na) produces the bioactive respiratory irritant methyl isothiocyanate (MITC). Recent laboratory gas-phase oxidative studies...
The soil fumigant metam-sodium (CH3NHCS2Na) produces the bioactive respiratory irritant methyl isothiocyanate (MITC). Recent laboratory gas-phase oxidative studies indicate that MITC rapidly transforms to the more toxic methyl isocyanate (MIC) in the lower atmosphere. Inhalation exposure risks from MITC plus MIC may therefore be an occupational worker and/or bystander health concern. To address this concern, MIC was monitored, along with MITC, in outdoor residential air in Washington state during the peak fall metam fumigation season. XAD-7 cartridges, coated with 1-(2-pyridyl)piperazine, were developed to retain MIC as its stable substituted urea derivative. Of the 68 residential air measurements of MIC, 15 (22%) were observed to be above the California Environmental Protection Agency's chronic inhalation reference level of 1 μg/m(3), with an observed maximum MIC air concentration of 4.4 μg/m(3). This study indicates MIC air concentrations can be anticipated along with MITC in residential air where seasonal metam soil fumigant applications occur.
Topics: Acrylic Resins; Agrochemicals; Air Pollutants; California; Environmental Monitoring; Fumigation; Humans; Inhalation Exposure; Isocyanates; Maximum Allowable Concentration; Pesticides; Polystyrenes; Seasons; Soil; Thiocarbamates; Washington
PubMed: 25144617
DOI: 10.1021/jf501696a -
PloS One 2014The anticancer agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine), upon decomposition in situ, yields methyl isocyanate and...
The anticancer agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine), upon decomposition in situ, yields methyl isocyanate and the chloroethylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE). 90CE has been shown to kill tumor cells via a proposed mechanism that involves interstrand DNA cross-linking. However, the role of methyl isocyanate in the antineoplastic function of laromustine has not been delineated. Herein, we show that 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE), an analog of laromustine that generates only methyl isocyanate, activates ASK1-JNK/p38 signaling in endothelial cells (EC). We have previously shown that ASK1 forms a complex with reduced thioredoxin (Trx1) in resting EC, and that the Cys residues in ASK1 and Trx1 are critical for their interaction. 101MDCE dissociated ASK1 from Trx1, but not from the phosphoserine-binding inhibitor 14-3-3, in whole cells and in cell lysates, consistent with the known ability of methyl isocyanate to carbamoylate free thiol groups of proteins. 101MDCE had no effect on the kinase activity of purified ASK1, JNK, or the catalytic activity of Trx1. However, 101MDCE, but not 90CE, significantly decreased the activity of Trx reductase-1 (TrxR1). We conclude that methyl isocyanate induces dissociation of ASK1 from Trx1 either directly by carbamoylating the critical Cys groups in the ASK1-Trx1 complex or indirectly by inhibiting TrxR1. Furthermore, 101MDCE (but not 90CE) induced EC death through a non-apoptotic (necroptotic) pathway leading to inhibition of angiogenesis in vitro. Our study has identified methyl isocyanates may contribute to the anticancer activity in part by interfering with tumor angiogenesis.
Topics: Animals; Antineoplastic Agents; Biocatalysis; Carbamates; Cattle; Cell Death; Cells, Cultured; Endothelial Cells; Humans; Hydrazines; Immunoblotting; Isocyanates; MAP Kinase Kinase Kinase 5; Mitogen-Activated Protein Kinase 8; Neovascularization, Physiologic; Signal Transduction; Sulfonamides; Thioredoxin Reductase 1; Thioredoxins
PubMed: 25068797
DOI: 10.1371/journal.pone.0103224 -
The Journal of Physical Chemistry. A May 2015Atmospheric amides have primary and secondary sources and are present in ambient air at low pptv levels. To better assess the fate of amides in the atmosphere, the room...
Atmospheric amides have primary and secondary sources and are present in ambient air at low pptv levels. To better assess the fate of amides in the atmosphere, the room temperature (298 ± 3 K) rate coefficients of five different amides with OH radicals were determined in a 1 m(3) smog chamber using online proton-transfer-reaction mass spectrometry (PTR-MS). Formamide, the simplest amide, has a rate coefficient of (4.44 ± 0.46) × 10(-12) cm(3) molec(-1) s(-1) against OH, translating to an atmospheric lifetime of ∼1 day. N-methylformamide, N-methylacetamide and propanamide, alkyl versions of formamide, have rate coefficients of (10.1 ± 0.6) × 10(-12), (5.42 ± 0.19) × 10(-12), and (1.78 ± 0.43) × 10(-12) cm(3) molec(-1) s(-1), respectively. Acetamide was also investigated, but due to its slow oxidation kinetics, we report a range of (0.4-1.1) × 10(-12) cm(3) molec(-1) s(-1) for its rate coefficient with OH radicals. Oxidation products were monitored and quantified and their time traces were fitted using a simple kinetic box model. To further probe the mechanism, ab initio calculations are used to identify the initial radical products of the amide reactions with OH. Our results indicate that N-H abstractions are negligible in all cases, in contrast to what is predicted by structure-activity relationships. Instead, the reactions proceed via C-H abstraction from alkyl groups and from formyl C(O)-H bonds when available. The latter process leads to radicals that can readily react with O2 to form isocyanates, explaining the detection of toxic compounds such as isocyanic acid (HNCO) and methyl isocyanate (CH3NCO). These contaminants of significant interest are primary oxidation products in the photochemical oxidation of formamide and N-methylformamide, respectively.
Topics: Amides; Atmosphere; Gases; Hydroxyl Radical; Kinetics; Linear Models; Mass Spectrometry; Models, Chemical; Oxidation-Reduction; Temperature
PubMed: 25019427
DOI: 10.1021/jp503759f -
International Journal of Toxicology 2014Emerging studies have linked prooxidative carbamate compound exposures with various human pathologies including pancreatic cancer. In these studies, our aim was to...
Emerging studies have linked prooxidative carbamate compound exposures with various human pathologies including pancreatic cancer. In these studies, our aim was to examine mitochondrial oxidative stress-mediated aberrant chromatin responses in human pancreatic ductal epithelial cells. Posttranslational histone modifications, promoter DNA methylation, and micro-RNA (miRNA) expression patterns were evaluated following induction of mitochondrial oxidative stress by N-succinimidyl N-methylcarbamate exposure. In treated cells, perturbation in mitochondrial machinery led to hypermethylation of p16 and smad4 gene promoters and downregulation of respective gene products. Posttranslational histone modifications that include hypoacetylation of acetylated histone (AcH) 3 and AcH4, hypermethylation of monomethylated histone 3 at lysine 9 and trimethylated histone 4 at lysine 20 ubiquitinated histone (uH) 2A/uH2B, and increased phosphorylation of H2AX and H3 were observed in the treated cells. Altered expression of miRNAs denoted possible location of corresponding genes at oxidatively damaged fragile sites. Collectively, our results provide a direct role of mitochondrial oxidative stress-mediated epigenetic imbalance to perturbed genomic integrity in oxygen radical-induced pancreatic injury. Further, identification and characterization of molecular switches that affect these epigenomic signatures and targets thereof will be imperative to understand the complex role of redox-regulatory network in pancreatic milieu.
Topics: Antioxidants; Apoptosis; Cell Line; Cytokines; DNA Damage; Epigenesis, Genetic; Epithelial Cells; Humans; MicroRNAs; Mitochondria; Oxidative Stress; Pancreas; Reactive Oxygen Species; Smad4 Protein
PubMed: 24563415
DOI: 10.1177/1091581814524064 -
Journal of Agricultural and Food... Feb 2014Gaseous methyl isothiocyanate (MITC), the principal breakdown product of the soil fumigant metam sodium (sodium N-methyldithiocarbamate), is an inhalation exposure...
Gaseous methyl isothiocyanate (MITC), the principal breakdown product of the soil fumigant metam sodium (sodium N-methyldithiocarbamate), is an inhalation exposure concern to persons living near treated areas. Inhalation exposure also involves gaseous methyl isocyanate (MIC), a highly reactive and toxic transformation product of MITC. In this work, gas-phase hydroxyl (OH) radical reaction rate constants of MITC and MIC have been determined using a static relative rate technique under controlled laboratory conditions. The rate constants obtained are 15.36 × 10(-12) cm(3) molecule(-1) s(-1) for MITC and 3.62 × 10(-12) cm(3) molecule(-1) s(-1) for MIC. The average half-lives of MITC and MIC in the atmosphere are estimated to be 15.7 and 66.5 h, respectively. The molar conversion of MITC to MIC for OH radical reactions is 67% ± 8%, which indicates that MIC is the primary product of the MITC-OH reaction in the gas phase.
Topics: Fungicides, Industrial; Hydroxyl Radical; Isocyanates; Isothiocyanates; Kinetics; Phase Transition; Soil Pollutants
PubMed: 24483206
DOI: 10.1021/jf404526t -
Lancet (London, England) Dec 2013
Topics: Bhopal Accidental Release; Biomedical Research; Disasters; Humans; India; Isocyanates; Lost to Follow-Up; Morbidity
PubMed: 24325010
DOI: 10.1016/s0140-6736(13)62562-3 -
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing... Oct 2013To analyze the clinical features and diagnostic points of occupational acute dimethylformamide (DMF) poisoning and to explore the mechanism of occupational acute DMF...
OBJECTIVE
To analyze the clinical features and diagnostic points of occupational acute dimethylformamide (DMF) poisoning and to explore the mechanism of occupational acute DMF poisoning.
METHODS
A comprehensive analysis was performed on the clinical data of 16 cases of occupational acute DMF poisoning, including symptoms, signs, and laboratory testing results.
RESULTS
The main clinical features of occupational acute DMF poisoning were digestive system impairments, especially abdominalgia. Hemorrhagic gastroenteritis was not found by gastroscopy. There was no significant correlation between the degree of abdominalgia and alanine aminotransferase level (r(s) = 0.109, P>0.05).
CONCLUSION
Abdominalgia is recommended to be one of the reference indices for the diagnosis and degrading of occupational acute DMF poisoning, The mechanism of DMF poisoning remains unclear but it is considered to be related to methyl isocyanate, the intermediate product of DMF metabolism.
Topics: Abdominal Pain; Alanine Transaminase; Dimethylformamide; Humans; Occupational Exposure; Solvents
PubMed: 24148956
DOI: No ID Found -
Toxicology and Industrial Health Jan 2016This article reports in silico analysis of methyl isocyanate (MIC) on different key immune proteins against Mycobacterium tuberculosis. The analysis shows that MIC is...
This article reports in silico analysis of methyl isocyanate (MIC) on different key immune proteins against Mycobacterium tuberculosis. The analysis shows that MIC is released in the Bhopal gas tragedy in 1984, which is highly toxic and extremely hazardous to human health. In this study, we have selected immune proteins to perform molecular docking with the help of Autodock 4.0. Results show that the CD40 ligand and alpha5beta1 integrin have higher inhibition compared to plasminogen activator urokinase, human glutathione synthetase, mitogen-activated protein kinase (P38 MAPK 14), surfactant protein-B, -D (SP-D), and pulmonary SP-D. MIC interacted with His-125, Try-146 residue of CD40 ligand and Ala-149, and Arg-152 residue of alpha5beta1 integrin and affects the proteins functioning by binding on their active sites. These inhibitory conformations were energetically and statistically favored and supported the evidence from wet laboratory experiments reported in the literature. We can conclude that MIC directly or indirectly affects these proteins, which shows that survivals of the disaster suffer from the diseases like tuberculosis infection and lung cancer.
Topics: CD40 Ligand; Glutathione Synthase; Humans; Immune System; Integrin alpha5beta1; Isocyanates; Lung Neoplasms; Molecular Docking Simulation; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Protein D; Tuberculosis; Urokinase-Type Plasminogen Activator; p38 Mitogen-Activated Protein Kinases
PubMed: 24081639
DOI: 10.1177/0748233713498447