N-nitroso Derivatives Research Articles

N-Nitroso compounds produced in deer mouse (Peromyscus maniculatus) GI tracts following hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) exposure

Given the potent carcinogenic effects of most N-nitroso compounds, the reductive transformation of the common explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) to a group of N-nitroso derivatives, hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX) in the environment have caused concerns among the general public. Questions are arising about whether the same transformations also occur in mammals, and if true, to what extent. This study investigated the N-nitroso derivatives production in the deer mouse GI tract following RDX administration. Findings verified that such transformations do occur in the mammalian GI tract at notable levels: the average MNX concentrations in deer mice stomach were 85 microg/kg and 1318 microg/kg for exposure to 10mg/kg and 100mg/kg diet, respectively. DNX in stomach were 217 microg/kg for the 10mg/kg dose group and 498 microg/kg for the 100mg/kg dose group. Changes in other toxic endpoints including body weight gain, food consumption, organ weight, and behavior were also reported.

Transnitrosation of Thiols from Aliphatic N-Nitrosamines: S-Nitrosation and Indirect Generation of Nitric Oxide

S-Nitrosothiols and heme nitrosyl species are nitric oxide (NO)-derived metabolites that provide an endogenous reservoir of NO and also play roles in protein S-nitrosation, that is, transnitrosation of thiols (or thiolates) in proteins, thereby regulating protein functions and signal transduction pathways. Intriguingly, endogenous N-nitrosamines are present in similar abundance to S-nitrosothiols, and though they are thought to play similar physiological roles to S-nitrosothiols, their transnitrosation reactivities and their contribution to biological events are little understood. Herein we report aliphatic N-nitroso derivatives of 7-azabicyclo[2.2.1]heptanes, which do not act as NO donors themselves, but can transnitrosate thiols. On the basis of the calculated activation energies of transnitrosation and the aorta smooth-muscle relaxation activities of these N-nitrosamines, we present a possible scenario of S-transnitrosation from aliphatic N-nitrosamines, leading to indirect generation of NO.

The delayed genotoxic effect of N-nitroso N-propoxur insecticide in mammalian cells

The N-nitroso derivative of an extensively used insecticide, propoxur, consistently induced dose-responsive chromosome aberrations and sister-chromatid exchanges (SCEs) in Chinese hamster ovary (CHO-W8) cells. Further investigations indicated that post-treatment incubation with a regular 1.5-cell-cycle period did not offer an unbiased estimation of the genotoxicity of N-nitroso carbamate insecticides. The scale of chromosome aberration induction increased with extension of the post-treatment incubation period. Comparable phenomena were not found in CHO-AGT cells proficient for O 6-methylguanine-DNA-methyltransferase. In CHO-W8 cells, pulsed-treatment of the insecticide in the 1st replication cycle showed higher SCE induction than in the 2nd cycle. Similar phenomenon was also found in SCE induced by N-nitroso derivatives from other carbamate insecticides including aldicarb, carbofuran and methomyl. Treated cells did not show significantly perturbed cell cycle progression until 12 h after treatment removal. Based on the above observations, the O 6-methylguanine-DNA adduct is suggested to be the major lesion caused by the delayed genotoxic effect of N-methyl carbamate insecticides as described in this report.

Synthesis of 3-alkyl-5-arylamino-6,11-dihydro-3H-anthra[1,2-d]-[1,2,3]triazole-6,11-dione 2-oxides by nitrosation of 3-alkylamino-5-arylamino-6H-anthra[1,9-cd]isoxazol-6-ones

Nitrosation of 3-alkylamino-5-arylamino-6H-anthra[1,9-cd]isoxazol-6-ones with sodium nitrite in acetic acid leads to the formation of the corresponding unstable N-nitroso derivatives which are converted into 3-alkyl-5-arylamino-6,11-dihydro-3H-anthra[1,2-d][1,2,3]triazole-6,11-dione 2-oxides on heating.

Microwave‐Assisted Synthesis of N‐Arylglycines: Improvement of Sydnone Synthesis.

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Determination of N-nitroso derivatives of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in soils by pressurized liquid extraction and liquid chromatography–electrospray ionization mass spectrometry

To aid in the evaluation of the potential toxicity of N-nitroso derivatives of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), we describe a pressurized liquid extraction (PLE) followed by liquid chromatography-electrospray ionization-mass spectrometry (LC–ESI-MS) method for determination of RDX and its N-nitroso derivatives: hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX) in soils. Sandy loam soil was spiked with RDX and its N-nitroso derivatives (MNX, DNX, and TNX). Acetonitrile was used as the PLE extraction solvent at 100 °C and 1500 psi for 15 min. Florisil was used to cleanup extracts following PLE. Instrumental analysis employed LC–ESI-MS, in which 1 mM acetic acid was added to the mobile phase to facilitate formation of acetate adduct ions [M + CH 3COO] −. The method detection limits (MDLs) for RDX, MNX, DNX, and TNX were 1.46, 1.46, 1.69, and 1.93 ng/g, respectively. High recovery (91.1–108.3%), good precision (RSD: 3.2–12.4%), and reproducibility were achieved. This method proved effective and was applied to monitor the reductive biotransformation of MNX in soils with the presence of earthworms ( Eisenia fetida).

Microwave-assisted Synthesis of N-Arylglycines: Improvement of Sydnone Synthesis

Reactions of anilines with ethyl bromoacetate under microwave irradiation have afforded N-arylglycines that are subsequently converted to their N-nitroso derivatives with a combination of silica chloride or periodic acid, wet SiO 2 and sodium nitrite in CH 2 Cl 2 with satisfactory yields. In the final step, the use of 1,3-dibromo-5,5-dimethylhydantoin (DBH) as a new and effective reagent for dehydration of N-nitroso-N-arylglycines to sydnones was successfully examined.

Peri-Naphthylenediamines: XXXIX. Synthesis and Structure of N,N′,N′-Trimethyl-N-nitrosonaphthalene-1,8-diamine Derivatives

The corresponding N-nitroso derivatives were synthesized by the action of nitrous acid on N,N,N′-trimethylnaphthalene-1,8-diamine, N,N,N′-trimethyl-5-nitronaphthalene-1,8-diamine, and N,N,N′-trimethylacenaphthene-5,6-diamine, and molecular structure of the products was studied.

Nitrosation of hydrochlorothiazide and the modes of binding of the N-nitroso derivative with two macrocycles possessing an 18-membered crown ether cavity

The hydrochlorothiazide, 6-chloro-3,4-dihydro-2 H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide, ( HCTZ ), widely used as a diuretic and anti-hypertensive drug, was transformed into its N-nitroso-derivative, 6-chloro-4-nitroso-3,4-dihydro-2 H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide ( O N– HCTZ ) by sodium nitrite in an acidic medium. The crystalline complexes of O N– HCTZ with 18-crown-6 (18C6) and cis- anti- cis-dicyclohexyl-18C6 (DCH6B) demonstrated different H-bonding modes from those present in the co-crystals of HCTZ with the same crown ethers. The influence of the nitroso-group on the binding mode and crystal packing is discussed.

N-Nitrosofenfluramine induces cytotoxicity via mitochondrial dysfunction and oxidative stress in isolated rat hepatocytes

The cytotoxic effects of fenfluramine, an appetite suppressant, and its N-nitroso derivative, N-nitrosofenfluramine, have been studied in freshly isolated rat hepatocytes and isolated hepatic mitochondria. Exposure of hepatocytes to N-nitrosofenfluramine caused not only concentration (0.25-1.0 mmol L(-1)) and time (0-3 h)-dependent cell death accompanied by the loss of cellular ATP, adenine nucleotide pools, reduced glutathione (GSH), and protein thiols, but also the accumulation of oxidized glutathione and malondialdehyde (MDA), indicating lipid peroxidation. There was a time lag for the onset of the accumulation of MDA after the rapid depletion of ATP. Supplementation of the hepatocyte suspensions with N-acetylcysteine (4 mmol L(-1)), a precursor of intracellular GSH, partially inhibited N-nitrosofenfluramine (1 mmol L(-1))-induced cytotoxicity. In comparative effects based on cell viability and rhodamine 123 retention, an index of mitochondrial membrane potential, fenfluramine was less toxic than N-nitrosofenfluramine. In mitochondria isolated from rat liver, N-nitrosofenfluramine caused an increase in the rate of state-4 oxygen consumption, indicating an uncoupling effect, and a decrease in the rate of state-3 oxygen consumption in a concentration-dependent manner. These results indicate that (a) mitochondria are target organelles for N-nitrosofenfluramine, which elicits cytotoxicity through mitochondrial dysfunction related to membrane potential and/or oxidative phosphorylation at an early stage and subsequently lipid peroxidation at a later stage; and (b) the toxicity of N-nitrosofenfluramine is greater than that of fenfluramine, suggesting participation of the nitroso group in the toxicity.

Quantum-chemical study of the structure and thermochemical properties of nitropiperazines and nitrosopiperazines

We have used MNDO and PM3 approximations and the density functional method (6–31G*) for a quantum chemical study of the structure and some physicochemical properties of N-nitro and N-nitroso derivatives of piperazine, furazano[3,4-b]piperazine, and bisfurazano[3,4-b;3′,4′-e]piperazine. We have analyzed the structural, electronic, and thermochemical characteristics and the enthalpies of formation for the compounds in the gas phase and in the solid phase. We have found a correlation between the strength of the N-N bond and the N-N bond length, the pyramidality of the nitrogen atom of the piperazine ring, and the size of the energy gap between the frontier orbitals. Based on calculations by the density functional method, we have carried out a comparative analysis of the thermochemical stability of the compounds in homolytic reactions.

Maternal medication use and neuroblastoma in offspring.

The association between a mother's use of specific medications during pregnancy and lactation and neuroblastoma in her offspring was evaluated in a case-control study. Newly diagnosed cases of neuroblastoma (n=504) in the United States and Canada were identified between 1992 and 1994 at 139 hospitals affiliated with the Pediatric Oncology Group or the Children's Cancer Group clinical trial programs. One age-matched control was sampled from the community of each case by means of random digit dialing. Exposure information was ascertained retrospectively from mothers in a structured telephone interview. Odds ratios were estimated using conditional logistic regression, with adjustment for maternal sociodemographic factors. The results did not support an association between neuroblastoma and maternal exposure to diuretic agents, antiinfective agents, estrogens, progestins, sedatives, anticonvulsant drugs, or drugs that may form N-nitroso derivatives. Mothers of cases were more likely to report using medications containing opioid agonists while they were pregnant or nursing than were mothers of controls (odds ratio=2.4, 95% confidence interval: 1.3, 4.3). Specifically, more mothers of cases reported using medications containing codeine while pregnant or nursing than did mothers of controls (odds ratio=3.4, 95% confidence interval: 1.4, 8.4). This preliminary finding may be due to bias, confounding, or chance, and additional studies are needed for confirmation.

Interaction of N,N‐Dimethylperfluoroarylamines with Nitric and Nitrous Acids.

Abstract N,N-Dimethylpentafluoroaniline enters easily into reactions with a mixture of nitric and sulphuric acids or nitric acid with conversion of the side chain. In the reactions with mixtures of HNO3 and H2SO4, the formation of N-nitroso-N-methyl and N-nitro-N-methylpentafluoroanilines is observed. The ratio of these products was found to depend on the ratio of the acids: the formation of N-nitro-N-methylpentafluoroaniline increases with the quantity of sulphuric acid; N-nitroso-N-methylpentafluoroaniline is obtained when only nitric acid is employed. N,N-Dimethylperfluoro-p-toluidine, N,N-dimethylperfluoro-2,4-xylidine, N,N-dimethylperfluoro-5-aminoindane undergo similar transformations. N-Nitroso derivatives were converted by a mixture of HNO3 and H2SO4, HNO3 or NO2BF4 into the corresponding N-nitro derivatives. Formation of the corresponding N-nitroso-N-methyl derivatives occurs when N,N-dimethylpentafluoroaniline, N,N-dimethylperfluoro-p-toluidine are treated with HNO2.

Interaction of N, N-dimethylperfluoroarylamines with nitric and nitrous acids

N, N-Dimethylpentafluoroaniline enters easily into reactions with a mixture of nitric and sulphuric acids or nitric acid with conversion of the side chain. In the reactions with mixtures of HNO 3 and H 2SO 4, the formation of N-nitroso- N-methyl and N-nitro- N-methylpentafluoroanilines is observed. The ratio of these products was found to depend on the ratio of the acids: the formation of N-nitro- N-methylpentafluoroaniline increases with the quantity of sulphuric acid; N-nitroso- N-methylpentafluoroaniline is obtained when only nitric acid is employed. N, N-Dimethylperfluoro- p-toluidine, N, N-dimethylperfluoro-2,4-xylidine, N, N-dimethylperfluoro-5-aminoindane undergo similar transformations. N-Nitroso derivatives were converted by a mixture of HNO 3 and H 2SO 4, HNO 3 or NO 2BF 4 into the corresponding N-nitro derivatives. Formation of the corresponding N-nitroso- N-methyl derivatives occurs when N, N-dimethylpentafluoroaniline, N, N-dimethylperfluoro- p-toluidine are treated with HNO 2.

Naphthoindazoles. Synthesis of 4,11-Dimethoxynaphtho[2,3-f]indazole-5,10-dione

The previously unknown 4,11-dimethoxynaphtho[2,3-f]indazole-5,10-dione has been obtained by the thermal cyclization of N-nitroso derivative of 2-acetamido-3-methyl-1,4-dimethoxyanthraquinone.

Polyfluorinated arylnitrosamines

N-Methyl-, N-n-butyl-, N-t-butylperfluoroarylamines undergo nitrosation with nitrous acid to give the corresponding N-nitroso derivatives. Perfluoroaryl groups were selected from the benzene, indane, biphenyl, naphthalene and pyridine series. According to 1H and 19F NMR spectra, N-nitroso-N-methyl derivatives of polyfluoroarenes consist of E and Z isomers with the former prevailing. The more bulky n-butyl group promotes an increase in the formation of Z isomers. Only Z isomers have been obtained from N-t-butyl derivatives of perfluorinated 4-toluidine and 4-aminopyridine. The structure of the Z isomer of N-nitroso-N-methylperfluoro-4-toluidine is confirmed by X-ray data.

Sulfur-to-nitrogen transnitrosation: transfer of nitric oxide from S-nitroso compounds to diethanolamine and the role of intermediate sulfur-to-sulfur transnitrosation

S-Nitrosothiols are formed in vivo and are involved in NO signaling. We investigated the sulfur-to-nitrogen transnitrosation activity of S-nitrosocysteine, S-nitrosoglutathione, S-nitrosohomocysteine, S-nitrosocysteinylglycine and S-nitroso- N-acetylcysteine in their reaction with the secondary amine diethanolamine in vitro. The resulting N-nitrosodiethanolamine, a strong carcinogen, was formed in yields of up to 11% from S-nitrosocysteine and S-nitrosocysteinylglycine, whereas the transnitrosation activity of the other S-nitroso compounds was weak. However, the addition of l-cysteine to a solution of S-nitrosohomocysteine and diethanolamine accelerated the decomposition of S-nitrosohomocysteine and resulted in a significant formation of N-nitrosodiethanolamine accompanied by the intermediate generation of S-nitrosocysteine. Thus, reactive nitrosothiols can be formed from less reactive analogs via sulfur-to-sulfur transnitrosation. We suggest that this affects regulation of NO trafficking in vivo. The reaction provides an alternative mechanism for the generation of carcinogenic N-nitroso derivatives.

Crystal structure and conformational analysis of N-formyl and N-nitroso derivatives of piperidinone

Single crystal X-ray studies for N-formyl-2,6-diortho chlorophenyl-3,5-dimethyl piperidin-4-one (FOCDMPO) and N-nitroso-2,6-di(3′,4′,5′-trimethoxyphenyl)-3,5-dimethyl piperidin-4-one (NTMPO) are reported. Crystals of FOCDMPO and NTMPO belong to the monoclinic space groups P21/n and C2/c, respectively. FOCDMPO: a = 9.147(2), b = 14.586(3), c = 13.665(5) A and β = 101.68(2)° NTMPO: a = 38.52(2), b = 13.727(5), c = 9.564(3) A and β = 98.60(1)°. In both the structures, the piperidine ring adopts a boat conformation with slight distortion. In FOCDMPO, one of the phenyl and methyl groups are in axial positions while the other phenyl and methyl groups are in equatorial orientations. In NTMPO, the situation is reversed. The molecules are stabilized by weak intermolecular C—H ··· O interactions in addition to van der Waals forces.

Genotoxicity of propoxur and its N-nitroso derivative in mammalian cells.

N-Nitroso propoxur (NP) can be synthesized from a widely used N-methylcarbamate insecticide, propoxur, in vitro in the laboratory. Because of the extensive use of aerosol propoxur, the adverse effect on cells of respiratory origin is worth elucidating. In this report, two mammalian cell cultures from respiratory tissues [a hamster lung fibroblast, V79, and a primary rat tracheal epithelial cell (RTE)], were used to investigate the genotoxicity of propoxur and NP. NP was more cytotoxic than propoxur, with LC50s (20 and six times smaller, respectively in V79 and RTE cells. NP significantly induced sister chromatid exchange (> or = 0.01 microg/ml), chromosome aberration (> or = 2.5 microg/ml) and hprt gene mutation (> or = 0.5 microg/ml) in V79 cells, and cell transformation (> or = 0.2 microg/ml) in RTE cells. Results of chromosome aberration and hprt gene mutation indicated that the major pre-mutagenic lesion induced by NP must be the O6-methylguanine adduct, which frequently mispairs with thymine and thus gives rise to a GC-->AT transition. Propoxur was not mutagenic to either type of cells. However, it inhibited gap-junctional intercellular communication in V79 cells, which indicates that propoxur could act through some epigenetic mechanisms, such as tumor promotion or cell proliferation, in the multiple process of chemical carcinogenesis.

Genetic toxicity of N-methylcarbamate insecticides and their N-nitroso derivatives

N-Methylcarbamate esters are an important group of insecticides. They have lower acute toxicity to vertebrates than organophosphates, although their genotoxicity has not been adequately studied. Here we investigate the cytotoxicity and genotoxicity of N-methylcarbamate insecticides and their N-nitroso derivatives in Chinese hamster V79 cells, using the hprt locus as a marker, and also assess inhibition of gap junctional intercellular communication. N-Methylcarbamate insecticides were chemically N-nitrosated to obtain the N-nitroso derivatives. N-Nitrosation greatly increased the cytotoxicity and mutagenicity of N-methylcarbamates at the hprt locus in Chinese hamster V79 cells. The mutagenic potential of N-nitroso-N-methylcarbamates was much higher than those of many other known mutagenic nitroso compounds, as well as some non-nitroso mutagenic alkylating agents. Parental N-methylcarbamates themselves were not mutagenic, however, they inhibited gap junctional intercellular communication half as effectively as the well-studied tumor promoter 12-O-tetradecanoylphorbol-13-acetate. The findings show that N-methylcarbamate insecticides and their N-nitroso derivatives have the potential to act through mediation of epigenetic and genotoxic mechanisms respectively in the multiple stages of chemical carcinogenesis.