A molecular orbital study on the chemical reactivity and biological activity of N-methyl-N'-nitro-N-nitrosoguanidine and some related compounds.
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Chemical Phenomena↗
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[Indene and related compounds. V. Ring expansion of 2-nitro-1-indanone oxime with polyphosphoric acid. (Studies on the syntheses of heterocyclic compounds. 173.)].
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Chemical Phenomena↗
The mutagenicity of some novel phenyl-imidazopyridines.
The mutagenicity of some novel 2-phenyl-imidazopyridines was investigated by the Ames test. Those with nitro substituents, and 2 related nitrophenylpurines, were frame shift mutagens without liver activation. Similar compounds without nitro groups had no activity. The mutagenic compounds were more active against TA1538 than against TA98, and were also active against TA100, a base-pair substitution mutant. This unusual pattern of activity is similar to that of 2-nitrosofluorene and related compounds. Calculations of molecular size showed a relationship between the 2 groups of compounds, suggesting similar modes of action. The more potent mutagens were toxic at high concentrations. Many of the non-mutagenic compounds were toxic, depending upon their substituents. In general, the imidazol[4,5-c]pyridines were more biologically active than the imidazo [4,5-b]pyridines.
Animals↗
Synthetic utilization of polynitroaromatic compounds. 3. Preparation of substituted dibenz[b,f][1,4]oxazepine-11(10H)-ones from 2,4,6-trinitrobenzoic acid via nucleophilic displacement of nitro groups.
[Reaction: see text]. 1,3-dinitrodibenz[b,f][1,4]oxazepin-11(10H)-one, prepared by intramolecular displacement of nitro group in N-(2-hydroxyphenyl)-2,4,6-trinitrobenzamide, reacts with O- and S-nucleophiles to yield the products of mono- or bis-substitution of the nitro groups. The nitro group in position 3 is displaced first. This observation is in contrast with earlier results for the nitro-substituted benzoannulated five-membered heterocycles. This difference in reactivity is likely due to the increased steric hindrance for peri-nitro group displacement in the case of the benzoannulated seven-membered heterocycle. N-Alkylation of the nitro-substituted dibenz[b,f][1,4]oxazepin-11(10H)-ones yields analogues of a known antidepressant drug Sintamil. The structure of the products is confirmed by NOE experiments and alternative synthesis.
Dibenzoxazepines↗
New NO-donors with antithrombotic and vasodilating activities, Part 21. Pseudonitrosites and other azodioxides with vicinal electron acceptors.
Twelve vicinally substituted nitro-nitroso compounds (pseudonitrosites) were synthesized, nine of them for the first time. In the solid state the dimeric azodioxides are present. In the class of the pseudonitrosites 2a-h, all compounds exhibited comparatively strong antiplatelet activity in vitro (Born test, collagen). Four of them showed an IC50 below 10 microM, 2a being the most active substance with an IC50 = 2.1 microM. When administered orally to rats (60 mg/kg) small antithrombotic effects were observed. The pseudonitrosite 6d was the most active compound (18% inhibition in arterioles). The in vitro decomposition of 2a at 37 degrees C gave NO and N2O, indicating that the above pharmacological effects were mediated by an NO-dependent mechanism. The replacement of the nitro group in the pseudonitrosite partial structure by other electron acceptors i.e. acetyl, carboxyl, or acetyloxy groups leads to inactive (10a) or less active compounds (10b, e).
Animals↗
Nitrobenzimidazoles as substrates for DT-diaphorase and redox cycling compounds: their enzymatic reactions and cytotoxicity.
We have synthesized a number of nitrobenzimidazoles containing nitro groups in the benzene ring and found that they acted as relatively efficient substrates for rat liver DT-diaphorase (EC 1.6.99.2), their reactivity exceeding reactivities of nitrofurans and nitrobenzenes. Nitrobenzimidazoles were competitive with NADPH inhibitors of DT-diaphorase in menadione reductase reactions, their inhibition constant being unchanged in the presence of dicumarol and being increased in the presence of 2',5'-ADP. These data indicate that the poor reactivity of nitrobenzimidazoles and other nitroaromatics in comparison to quinones could be determined by their binding in the adenosine-phosphate binding region of the NADPH-binding site, whereas quinones bind at the nicotinamide-binding pocket at the vicinity of FAD of DT-diaphorase. The reduction of 4,5,6-trinitrobenzimidazol-2-one by DT-diaphorase most probably involves reduction of 5-nitro group to 5-nitroso or 5-hydroxylamine derivative at the initial step. A certain parallelism existed between reactivities of nitrobenzimidazoles toward DT-diaphorase and their reactivities in single-electron reduction by Anabaena ferredoxin:NADP+ reductase (EC 1.18.1.2) and Saccharomyces cerevisiae flavocytochrome b2 (EC 1.1.2.3), the latter being determined by electronic factors. However, we suppose that the relatively high reactivity of polinitrobenzimidazoles toward DT-diaphorase was due not only to electronic effects, but also to a sterical crowding of nitrogroups by each other. The toxicity of nitrobenzimidazoles to bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK) with a moderate amount of DT-diaphorase (260 U/mg protein) is partly prevented by dicumarol. That points out to partial determination of nitrobenzimidazole cytotoxicity by their reduction by DT-diaphorase. Another important factor of nitrobenzimidazole toxicity to this cell line was oxidative stress, catalyzed by single-electron transferring enzymes.
Animals↗
Gas phase carboxylate anions fron p-nitrobenzyl esters of fatty acids.
Gas phase carboxylate anions have been efficiently generated from the p-nitrobenzyl esters of nine fatty acids ranging in size from C6 to C22. The process involves the dissociative resonance capture of 2.9 e V electrons by the derivatives. The procedure is specific and gives the carboxylate anions as the base peak in all but two of the derivative. The technique gives extremely simple spectra, with little additional fragmentation and no rearrangement ions.
Benzyl Compounds↗
Analysis of nitramine and nitroaromatic explosives in pink water by capillary electrophoresis.
Analysis of nitramine and nitroaromatic explosives is of interest for environmental applications. Analysis of 14 nitramine and nitroaromatic explosives was accomplished by micellar electrokinetic capillary chromatography (MECC). Analysis times under 14 min were possible employing a phosphate-sodium dodecyl sulfate (SDS) electrolyte and direct UV detection of 254 nm. Analysis of various waste samples (called "pink water") from ammunition plants was performed.
Aniline Compounds↗
Environmental and metabolic transformations of primary aromatic amines and related compounds.
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Amines↗
A gel filament as an analytical tool: the testing of an affinity chromatographic, product-immobilizing linear gel for determination of enzymatic activity.
A new technique for quantitative analysis is proposed. An underfined volume of the test solution is exposed to a reagent in the form of a gel filament of capillary dimensions. The linear progress in the gel of the compound in question is followed with the aid of the coloured reaction products deposited along its path. With the use of the enzyme gamma-glutamyl transpeptidase it is shown that the velocity in the system of the component to be analysed, as determined by measurement of its coloured track, is related to its activity in the test solution.
Aniline Compounds↗
Computer-assisted structure-activity relationships of nitrogenous cyclic compounds tested in salmonella assays for mutagenicity.
Study of the relationship between mutagenicity and molecular structure for a data set of nitrogenous cyclic compounds is reported. A computerized SAR system (ADAPT) was utilized to classify a data set of 114 nitrogenous cyclic compounds with 19 molecular descriptors. All of the descriptors represented at least 10% of the compounds in the data sets. The average correct predictability of the data base was calculated to be 89% after evaluating 100 training/prediction subsets. The actual predictive ability of the discriminants generated by the ADAPT system was demonstrated by predicting the mutagenicity of structurally similar compounds not in the data set. Weight vectors generated in the pattern recognition programs were used to predict the bacterial mutagenicity of 10 compounds which were not included in the data set. All of the compounds were predicted correctly which was actually better than the 89% calculated by the system. This displayed the ability of the system of classify compounds as mutagenic or nonmutagenic by using molecular descriptors and to predict the biological activity of untested chemicals with a high degree of confidence. This paper presents the uses of this type of SAR approach in a research laboratory.
Heterocyclic Compounds↗
Aqueous solubility and alkaline hydrolysis of the novel high explosive hexanitrohexaazaisowurtzitane (CL-20).
The recently developed polycyclic nitramine CL-20 is considered as a possible replacement for the monocyclic nitramines RDX and HMX. The present study reports aqueous solubility data for CL-20, as well as the kinetic parameters for its alkaline hydrolysis with sodium hydroxide below and above its solubility limits. Aqueous solubility of CL-20 was measured in the temperature range of 4-69 degrees C and the data were fitted to a generalized solubility model. Alkaline hydrolysis experiments were conducted at 15, 20, 30 and 40 degrees C, with hydroxide concentrations ranging from 0.25 to 300 mM. Like RDX and HMX, alkaline hydrolysis of CL-20 follows second-order kinetics. CL-20 alkaline hydrolysis was found to proceed at a significantly faster rate than RDX. The temperature dependency of the second-order rate constants was evaluated using the Arrhenius model. The activation energy for CL-20 was found to be within close range of the activation energies reported for RDX and HMX.
Bridged-Ring Compounds↗
Acute and chronic alterations in calcium homeostasis in 3-nitropropionic acid-treated human NT2-N neurons.
3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, induced ATP depletion and both necrosis and apoptosis in human NT2-N neurons. Necrosis occurred predominantly within the first two days, and increased in a dose-dependent fashion with the concentration of 3-NP, whereas apoptosis was observed after 24 h or later at a similar rate in 0.1 mM and 5 mM 3-NP. We focused our efforts on intracellular calcium homeostasis during the first 48 h in 1 mM 3-NP, a period during which 10% of the neurons died by necrosis and 3% by apoptosis. All NT2-N neurons showed a stereotyped [Ca(2+)](i) rise, from 48+/-2 to 140+/-12 nM (mean +/-S.E.M.), during the first 2 h in 3-NP. Despite severe ATP depletion, however, [Ca(2+)](i) remained above 100 nM in only 17% and 25% of the NT2-N neurons after 24 and 48 h in 3-NP, respectively, indicating that most neurons were able to recover from acute [Ca(2+)](i) rise, and suggesting that chronic [Ca(2+)](i) dysregulation is a better indicator of subsequent necrosis. Blockade of N-methyl-D-aspartate-glutamate receptor by MK-801 substantially ameliorated 3-NP-induced ATP depletion, subsequent chronic [Ca(2+)](i) elevation, and survival. Moreover, xestospongin C, an inhibitor of endoplasmic reticulum Ca(2+) release, enhanced the capacity of NT2-N neurons to maintain [Ca(2+)](i) homeostasis and resist necrosis while subjected to sustained energy deprivation. As far as we know, this report is the first to employ human neurons to study the pathophysiology of 3-NP neurotoxicity.
Adenosine Triphosphate↗
Determination of dinitramine residues in soil and plant tissue.
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Aniline Compounds↗
Antitumor activity and toxicity of novel nitroheterocyclic phosphoramidates.
A series of novel nitroheterocyclic phosphoramidates has been evaluated for antitumor activity in murine and xenograft tumor models and for toxicity in mice. Significant increases in lifespan and long-term survivors were noted in L1210 leukemia and B16 melanoma models, and both complete and partial tumor regressions were observed in the MX-1 breast cancer xenograft model. All compounds exhibited some degree of toxicity to granulocyte/macrophage progenitors in the bone marrow of mice. Two drugs were selected for further toxicologic, histopathologic, and pharmacokinetic evaluations. Toxicity of potential clinical significance was observed only in the bone marrow at the highest drug dose; otherwise no significant abnormalities in blood chemistries or organ histopathology were noted. The bone marrow lesions consisted of reduced numbers of progenitor cells in the myeloid and erythroid series; platelets were not affected. The compounds were eliminated rapidly by first-order kinetics, with half-lives in the 4-12 min range. The best of these compounds exhibits excellent antitumor activity and minimal toxicity at therapeutically effective doses in mice.
Animals↗
Capillary gas chromatography with four different detectors for dinitroaniline herbicides in human body fluids.
A simple and rapid method for extraction of seven dinitroaniline herbicides from human whole blood and urine using Sep-Pak C18 cartridges is presented. After mixing with distilled water, whole blood and urine samples containing the herbicides were loaded on Sep-Pak C18 cartridges and eluted with chloroform-methanol (9:1). The recovery of the seven compounds that were added to whole blood and urine was more than 91%. The herbicides were detected by capillary gas chromatography (GC) with electron-capture detection (ECD), surface-ionization detection (SID), nitrogen-phosphorus detection (NPD), and flame-ionization detection (FID). GC-ECD generally gave the highest sensitivity for all herbicides, whereas GC-FID gave the lowest sensitivity. Isopropalin could be detected by GC-SID with a sensitivity comparable with that of GC-ECD; high sensitivity could also be obtained for isopropalin, pendimethalin, and nitralin using GC-NPD. The calibration curve for the seven herbicides measured by GC-ECD showed linearity in the range of 0.047-3.0 pmol on-column. The detection limits of the herbicides were 24-45 fmol on-column for whole blood and 19-40 fmol on-column for urine.
Aniline Compounds↗
Hydroxynitrobiphenyls produced by photochemical reaction of biphenyl in aqueous nitrate solution and their mutagenicities.
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Biphenyl Compounds↗
Reductive transformation of hexahydro-1,3,5-trinitro-1,3,5-triazine, octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine, and methylenedinitramine with elemental iron.
Reductive (pre)treatment with elemental iron is a potentially useful method for degrading nitramine explosives in water and soil. In the present study, we examined the kinetics, products, and mechanisms of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) degradation with elemental iron. Both RDX and HMX were transformed with iron to formaldehyde, NH4+, N2O, and soluble products. The yields of formaldehyde were relatively constant (71% +/- 5%), whereas the yields of NH4+ and N2O varied, depending on the nitramine and the mechanism. The reactions most likely were controlled by a surface process rather than by external mass transfer. Methylenedinitramine (MDNA) was an intermediate of both RDX and HMX and was transformed quantitatively to formaldehyde with iron. However, product distributions and kinetic modeling results suggest that MDNA represented a minor reaction path and accounted for only 30% of the RDX reacted and 14% of the formaldehyde produced. Additional experiments showed that RDX reduction with elemental iron could be mediated by graphite and Fe2+ sorbed to magnetite, as demonstrated previously for nitroaromatics and nitrate esters. Methylenedinitramine was degraded primarily through reduction in the presence of elemental iron, because its hydrolysis was slow compared to its reactions with elemental iron and surface-bound Fe2+. Our results show that in a cast iron-water system, RDX may be transformed via multiple mechanisms involving different reaction paths and reaction sites.
Adsorption↗