-
Antioxidants & Redox Signaling May 2011Nitroxyl (HNO) demonstrates a diverse and unique biological profile compared to nitric oxide, a redox-related compound. Although numerous studies support the use of HNO... (Review)
Review
Nitroxyl (HNO) demonstrates a diverse and unique biological profile compared to nitric oxide, a redox-related compound. Although numerous studies support the use of HNO as a therapeutic agent, the inherent chemical reactivity of HNO requires the use of donor molecules. Two general chemical strategies currently exist for HNO generation from nitrogen-containing molecules: (i) the disproportionation of hydroxylamine derivatives containing good leaving groups attached to the nitrogen atom and (ii) the decomposition of nitroso compounds (X-N=O, where X represents a good leaving group). This review summarizes the synthesis and structure, the HNO-releasing mechanisms, kinetics and by-product formation, and alternative reactions of six major groups of HNO donors: Angeli's salt, Piloty's acid and its derivatives, cyanamide, diazenium diolate-derived compounds, acyl nitroso compounds, and acyloxy nitroso compounds. A large body of work exists defining these six groups of HNO donors and the overall chemistry of each donor requires consideration in light of its ability to produce HNO. The increasing interest in HNO biology and the potential of HNO-based therapeutics presents exciting opportunities to further develop HNO donors as both research tools and potential treatments.
Topics: Azo Compounds; Cyanamide; Hydroxamic Acids; Molecular Structure; Nitrites; Nitrogen Oxides; Nitroso Compounds; Sulfonamides
PubMed: 21235345
DOI: 10.1089/ars.2010.3838 -
International Journal of Environmental... Jul 2018Nitrate levels in our water resources have increased in many areas of the world largely due to applications of inorganic fertilizer and animal manure in agricultural... (Review)
Review
Nitrate levels in our water resources have increased in many areas of the world largely due to applications of inorganic fertilizer and animal manure in agricultural areas. The regulatory limit for nitrate in public drinking water supplies was set to protect against infant methemoglobinemia, but other health effects were not considered. Risk of specific cancers and birth defects may be increased when nitrate is ingested under conditions that increase formation of -nitroso compounds. We previously reviewed epidemiologic studies before 2005 of nitrate intake from drinking water and cancer, adverse reproductive outcomes and other health effects. Since that review, more than 30 epidemiologic studies have evaluated drinking water nitrate and these outcomes. The most common endpoints studied were colorectal cancer, bladder, and breast cancer (three studies each), and thyroid disease (four studies). Considering all studies, the strongest evidence for a relationship between drinking water nitrate ingestion and adverse health outcomes (besides methemoglobinemia) is for colorectal cancer, thyroid disease, and neural tube defects. Many studies observed increased risk with ingestion of water nitrate levels that were below regulatory limits. Future studies of these and other health outcomes should include improved exposure assessment and accurate characterization of individual factors that affect endogenous nitrosation.
Topics: Animals; Drinking Water; Environmental Monitoring; Europe; Female; Humans; Methemoglobinemia; Neoplasms; Neural Tube Defects; Nitrates; Nitroso Compounds; Pregnancy; Thyroid Diseases; United States; Water Pollutants, Chemical
PubMed: 30041450
DOI: 10.3390/ijerph15071557 -
Redox Report : Communications in Free... Mar 2017We present evidence that nitrite and nitrosothiols, nitrosoamines and non-heme dinitrosyl iron complexes can reversibly inhibit catalase with equal effectiveness.
OBJECTIVE
We present evidence that nitrite and nitrosothiols, nitrosoamines and non-heme dinitrosyl iron complexes can reversibly inhibit catalase with equal effectiveness.
METHODS
Catalase activity was evaluated by the permanganatometric and calorimetric assays.
RESULTS
This inhibition is not the result of chemical transformations of these compounds to a single inhibitor, as well as it is not the result of NO release from these substances (as NO traps have no effect on the extent of inhibition). It was found that chloride and bromide in concentration above 80 mM and thiocyanate in concentration above 20 μM enhance catalase inhibition by nitrite and the nitroso compounds more than 100 times. The inhibition degree in this case is comparable with that induced by azide.
DISCUSSION
We propose that the direct catalase inhibitor is a positively charged NO-group. This group acquires a positive charge in the active center of enzyme by interaction of nitrite or nitroso compounds with some enzyme groups. Halides and thiocyanate protect the NO group from hydration and thus increase its inhibition effect. It is probable that a comparatively low chloride concentration in many cells is the main factor to protect catalase from inhibition by nitrite and nitroso compounds.
Topics: Calorimetry; Catalase; Enzyme Inhibitors; Hydrogen-Ion Concentration; Iron; Nitrites; Nitrogen Oxides; Nitroso Compounds; S-Nitrosothiols
PubMed: 27075937
DOI: 10.1080/13510002.2016.1168589 -
Molecules (Basel, Switzerland) Nov 2019The syntheses of the title compounds demonstrate a privileged introduction of a nitroso (and a hydroxyl via the Baudisch reaction) group to an aromatic ring. These... (Review)
Review
The syntheses of the title compounds demonstrate a privileged introduction of a nitroso (and a hydroxyl via the Baudisch reaction) group to an aromatic ring. These complexes first appeared in the literature as early as 1939, and a range of applications has subsequently been published. However, optimisations of the preparative sequences were not considered, and as such, the reactions have seldom been utilised in recent years; indeed, there remains confusion in the literature as to how such complexes form. In this review, we aim to demystify the misunderstanding surrounding these remarkable complexes and consider their renewed application in the 21st century.
Topics: Chemistry Techniques, Synthetic; Coordination Complexes; Molecular Structure; Nitroso Compounds
PubMed: 31698829
DOI: 10.3390/molecules24224018 -
Chemical Society Reviews Sep 2005The growing interest in the chemistry of C-nitroso compounds (RN=O; R = alkyl or aryl group) is due in part to the recognition of their participation in various... (Review)
Review
The growing interest in the chemistry of C-nitroso compounds (RN=O; R = alkyl or aryl group) is due in part to the recognition of their participation in various metabolic processes of nitrogen-containing compounds. C-Nitroso compounds have a rich organic chemistry in their own right, displaying interesting intra- and intermolecular dimerization processes and addition reactions with unsaturated compounds. In addition, they have a fascinating coordination chemistry. While most of the attention has been directed towards C-nitroso compounds containing a single -NO moiety, there is an emerging area of research dealing with dinitroso and polynitroso compounds. In this critical review, we present and discuss the synthetic routes and properties of these relatively unexplored dinitroso and polynitroso compounds, and suggest areas of further development involving these compounds. (126 references.).
Topics: Chemistry, Organic; Dimerization; Models, Chemical; Nitrogen; Nitroso Compounds; Polymers; Stereoisomerism
PubMed: 16100619
DOI: 10.1039/b500855g -
Environmental Research Apr 2022Human serum and urine samples were analyzed for a suite of nitrosatable pesticides and potentially carcinogenic pesticide-associated N-nitroso (PANN) compounds....
Analysis of human serum and urine for tentative identification of potentially carcinogenic pesticide-associated N-nitroso compounds using high-resolution mass spectrometry.
Human serum and urine samples were analyzed for a suite of nitrosatable pesticides and potentially carcinogenic pesticide-associated N-nitroso (PANN) compounds. Formation of PANN compounds may occur in vivo after consumption of food or water containing trace amounts of nitrosatable pesticide residues and nitrate. Using a modified version of the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method, nine nitrosatable pesticides and byproducts were extracted from serum and urine from 64 individuals from two different sample populations in Atlantic Canada: (i) Prince Edward Island, a region where nitrate and trace amounts of nitrosatable pesticides have been detected in groundwater; and (ii) Halifax, Nova Scotia, a non-agricultural urban area. Samples were then analyzed using ultra-high pressure liquid chromatography (UHPLC) coupled with high-resolution accurate mass (HRAM) single-stage orbitrap mass spectrometry (MS), which allows for semi-targeted analysis and tentative identification of a virtually limitless number of exposure biomarkers. Two nitrosatable target analytes, ethylenethiourea (ETU) and 3,5,6-trichloro-2-pyridinol (TCPy) were found in serum, while atrazine (ATR) and ETU were detected in urine. Five and six PANN compounds were tentatively identified in serum and urine, respectively. The two PANN compounds that were most frequently tentatively identified in serum were N-nitroso dimethoate (N-DIM) and N-nitroso omethoate (N-OME) with detection frequencies of 78% and 95%, respectively. This is the first biomonitoring study of its kind to investigate PANN compounds in human serum and urine.
Topics: Carcinogens; Chromatography, High Pressure Liquid; Humans; Mass Spectrometry; Nitroso Compounds; Pesticide Residues; Pesticides
PubMed: 34896088
DOI: 10.1016/j.envres.2021.112493 -
Accounts of Chemical Research Aug 2019Indazoles are an important class of nitrogen heterocycles because of their excellent performance in biologically relevant applications, such as in chemical biology and... (Review)
Review
Indazoles are an important class of nitrogen heterocycles because of their excellent performance in biologically relevant applications, such as in chemical biology and medicinal chemistry. In these applications, convenient synthesis using commercially available and diverse building blocks is highly desirable. Within this broad class, 2-indazoles are relatively underexploited when compared to 1-indazole, perhaps because of regioselectivity issues associated with the synthesis of 2-indazoles. This Account describes our unfolding of the synthetic utility of the Davis-Beirut reaction (DBR) for the construction of 2-indazoles and their derivatives; parallel unfoldings of mechanistic models for these interrelated N-N bond forming reactions are also summarized. The Davis-Beirut reaction is a robust method that exploits the diverse chemistries of a key nitroso imine or nitroso benzaldehyde intermediate generated in situ under redox neutral conditions. The resulting N-N bond-forming heterocyclization between nucleophilic and electrophilic nitrogens can be leveraged for the synthesis of multiple classes of indazoles and their derivatives, such as simple or fused indazolones, thiazolo-indazoles, 3-alkoxy-2-indazoles, 2-indazole -oxides, and 2-indazoles with various substitutions on the ring system or the nitrogens. These diverse products can all be synthesized under alkaline conditions and the various strategies for accessing these heterocycles are discussed. Alternatively, we have also developed methods involving mild photochemical conditions for the nitrobenzyl → -nitro → nitroso imine sequence. Solvent consideration is especially important for modulating the chemistry of the reactive intermediates in these reactions; the presence of water is critically important in some cases, but water's beneficial effect has a ceiling because of the alternative reaction pathways it enables. Fused 2-indazoles readily undergo ring opening reactions to give indazolones when treated with nucleophiles or electrophiles. Furthermore, palladium-catalyzed cross coupling, the Sonagashira reaction, EDC amide coupling, 1,3-dipolar cycloadditions with nitrile oxides, copper-catalyzed alkyne-azide cycloadditions (click reaction), as well as copper-free click reactions, can all be used late-stage to modify 2-indazoles and indazolones. The continued development and applications of the Davis-Beirut reaction has provided many insights for taming the reactivity of highly reactive nitro and nitroso groups, which still has a plethora of underexplored chemistries and challenges. For example, there is currently a limited number of nonfused 2-indazole examples containing an aryl substitution at nitrogen. This is caused by relatively slow N-N bond formation between -aryl imine and nitroso reactants, which allows water to add to the key nitroso imine intermediate causing imine bond cleavage to be a competitive reaction pathway rather than proceeding through the desired N-N bond-forming heterocyclization.
Topics: Amines; Cyclization; Indazoles; Models, Chemical; Nitroso Compounds
PubMed: 31328502
DOI: 10.1021/acs.accounts.9b00220 -
Nutrition Reviews Apr 1998Experimental animal studies have shown N-nitroso compounds (NOC) to be potent carcinogens. Epidemiologic evidence of the carcinogenic potential of dietary NOC and... (Review)
Review
Experimental animal studies have shown N-nitroso compounds (NOC) to be potent carcinogens. Epidemiologic evidence of the carcinogenic potential of dietary NOC and precursor nitrates and nitrites in humans remains inconclusive with regard to the risk of stomach, brain, esophageal, and nasopharyngeal cancers. Inadequate available data could obscure a small to moderate effect of NOC.
Topics: Animals; Carcinogens; Case-Control Studies; Diet; Food Contamination; Humans; Neoplasms; Nitrates; Nitrites; Nitroso Compounds; Risk Factors
PubMed: 9584494
DOI: 10.1111/j.1753-4887.1998.tb01721.x -
International Journal of Molecular... Oct 2018To better understand the mechanism of in vivo toxicity of -nitroso compounds (NNCs), the toxicity data of 80 NNCs related to their rat acute oral toxicity data (50%...
To better understand the mechanism of in vivo toxicity of -nitroso compounds (NNCs), the toxicity data of 80 NNCs related to their rat acute oral toxicity data (50% lethal dose concentration, LD) were used to establish quantitative structure-activity relationship (QSAR) and classification models. Quantum chemistry methods calculated descriptors and Dragon descriptors were combined to describe the molecular information of all compounds. Genetic algorithm (GA) and multiple linear regression (MLR) analyses were combined to develop QSAR models. Fingerprints and machine learning methods were used to establish classification models. The quality and predictive performance of all established models were evaluated by internal and external validation techniques. The best GA-MLR-based QSAR model containing eight molecular descriptors was obtained with Q² = 0.7533, R² = 0.8071, Q² = 0.7041 and R² = 0.7195. The results derived from QSAR studies showed that the acute oral toxicity of NNCs mainly depends on three factors, namely, the polarizability, the ionization potential (IP) and the presence/absence and frequency of C⁻O bond. For classification studies, the best model was obtained using the MACCS keys fingerprint combined with artificial neural network (ANN) algorithm. The classification models suggested that several representative substructures, including nitrile, hetero N nonbasic, alkylchloride and amine-containing fragments are main contributors for the high toxicity of NNCs. Overall, the developed QSAR and classification models of the rat acute oral toxicity of NNCs showed satisfying predictive abilities. The results provide an insight into the understanding of the toxicity mechanism of NNCs in vivo, which might be used for a preliminary assessment of NNCs toxicity to mammals.
Topics: Administration, Oral; Algorithms; Animals; Molecular Structure; Nitroso Compounds; Quantitative Structure-Activity Relationship; Rats; Reproducibility of Results; Toxicity Tests, Acute
PubMed: 30282923
DOI: 10.3390/ijms19103015 -
Journal of Inorganic Biochemistry Jan 2013Nitroxyl (HNO) has gained interest as a potential treatment of congestive heart failure through the ability of the HNO donor, Angeli's salt (AS), to evoke positive...
Nitroxyl (HNO) has gained interest as a potential treatment of congestive heart failure through the ability of the HNO donor, Angeli's salt (AS), to evoke positive inotropic effects in canine cardiac muscle. The release of nitrite during decomposition limits the use of AS requiring other HNO sources. Acyloxy nitroso compounds liberate HNO and small amounts of nitrite upon hydrolysis and the synthesis of the water-soluble 4-nitrosotetrahydro-2H-pyran-4-yl acetate and pivalate allows for pig liver esterase (PLE)-catalysis increasing the rate of decomposition and HNO release. The pivalate derivative does not release HNO, but the addition of PLE catalyzes hydrolysis (t(1/2)=39 min) and HNO formation (65% after 30 min). In the presence of PLE, this compound converts metmyoglobin (MetMb) to iron nitrosyl Mb and oxyMb to metMb indicating that these compounds only react with heme proteins as HNO donors. The pivalate in the presence and the absence of PLE inhibits aldehyde dehydrogenase (ALDH) with IC(50) values of 3.5 and 3.3 μM, respectively, in a time-dependent manner. Reversibility assays reveal reversible inhibition of ALDH in the absence of PLE and partially irreversible inhibition with PLE. Liquid chromatography-mass spectrometry (LC-MS) reveals formation of a disulfide upon incubation of an ALDH peptide without PLE and a mixture of disulfide and sulfinamide in the presence of PLE. A dehydroalanine residue forms upon incubation of this peptide with excess AS. These results identify acyloxy nitroso compounds as unique HNO donors capable of thiol modification through direct electrophilic reaction or HNO release.
Topics: Aldehyde Dehydrogenase; Chromatography, Gas; Dithiothreitol; Enzyme Inhibitors; Fungal Proteins; Heme; Hydrolysis; Kinetics; Metmyoglobin; Myoglobin; Nitrogen Dioxide; Nitrogen Oxides; Nitroso Compounds; Nitrous Oxide; Oxidation-Reduction; Solubility; Solvents; Sulfhydryl Compounds; Water
PubMed: 23083700
DOI: 10.1016/j.jinorgbio.2012.07.023