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Reversal of multidrug resistance by novel nitrophenyl pyrones, SNF4435C and D.

SNF4435C and D, novel immunosuppressants produced by a strain of Streptomyces spectabilis, were examined for their reversing effects in vitro on various multidrug-resistant (MDR) tumor cells overexpressing P-glycoprotein. These two compounds in the range of 3-10 microM completely reversed the resistance of MDR variant cells, mouse leukemia P388 cells [vincristine (VCR)-resistant P388/VCR and adriamycin (ADM)-resistant P388/ADM], human myelogenous leukemia K562 cells (VCR-resistant K562/VCR and ADM-resistant K562/ADM) and human ovarian cancer A2780 cells (ADM-resistant AD(10)), against VCR. Both compounds moderately potentiated the sensitivity of the MDR cells to ADM but the reversal was not complete. SNF4435C and D significantly increased the intracellular accumulation of VCR in AD(10) cells as potently as verapamil, cyclosporin A (CysA) and FK506, whereas the compounds exerted no effect on the accumulation of VCR in the drug-sensitive parent cells. Moreover, SNF4435C improved the chemotherapeutic efficacy of VCR in the treatment of P388/VCR-bearing mice. When 10 mg/kg SNF4435C was administered intraperitoneally to the mice concurrently with 0.2 mg/kg VCR for every 5 days, a treated/control (T/C) value of 143% was obtained. These results suggest that the compounds are useful candidates or tools for MDR modification in cancer chemotherapy.

Animals↗

Electrochemical oxidation of phenolic wastes with boron-doped diamond anodes.

The electrochemical oxidation of several phenolic aqueous wastes has been studied using a bench-scale plant with a single-compartment electrochemical flow cell. Boron-doped diamond materials were used as the anode. Complete mineralization of the waste was obtained in the treatment of phenols not substituted with chlorine or nitrogen. Chlorinated phenolic compounds were transformed into carbon dioxide; volatile organochlorinated compounds and nitro-substituted phenols deal with the formation of polymeric materials. These polymeric materials behave as final products or treatment intermediates depending on the nature of the initial pollutant. The removal of nitro- or the chloro-group from the phenolic molecule seems to be one of the first stages in the treatment. Non-nitrogenated or chlorinated carboxylic acids have been found to be the main intermediates in the electrochemical oxidation of all the phenolic compounds tested. The efficiencies of the process depend strongly on the concentration of organic pollutants and on their nature, and not on the current density, at least in the operation range studied.

Boron↗

TNT transformation products are affected by the growth conditions of Raoultella terrigena.

High concentrations of 2,4,6-trinitrotoluene (TNT) and related nitroaromatic compounds are commonly found in soil and groundwater at former explosive plants. The bacterium, Raoultella terrigena strain HB, isolated from a contaminated site, converts TNT into the corresponding amino products. Radio-HPLC analysis with [(14)C]TNT identified aminodinitrotoluene, diaminonitrotoluene and azoxy-dimers as the main metabolites. Transformation rate and the type of metabolites that predominated in the culture medium and within the cells were significantly influenced by the culture conditions. The NAD(P)H-dependent enzymatic reduction of nitro-substituted compounds by cell-free extracts of R. terrigena was evaluated in vitro.

Biodegradation, Environmental↗

Biochemical study of resistance to imidacloprid in B biotype Bemisia tabaci from Guatemala.

Systemic uptake bioassays using excised cotton leaves confirmed resistance to imidacloprid in a Guatemalan population of the tobacco whitefly Bemisia tabaci Gennadius. Polyacrylamide gel electrophoresis of naphthyl esterases identified the insects as B-types. Upon collection from the field, resistance was determined to be 58-fold relative to a susceptible strain originating in the Imperial Valley of California. Resistance levels increased to 126-fold in this population during its continuous exposure to systemically treated cotton. In biochemical investigations, there was no detectable NADPH-dependent mixed function oxidase metabolism of 14C-imidacloprid at any time during the selection process. In contrast, microsomal preparations from housefly abdomens readily produced significant amounts of the mono-hydroxy and olefin derivatives of the parent compound. Detoxification of imidacloprid by housefly MFOs may account for reports of lower toxicity of the insecticide towards this insect compared with whiteflies, despite similar binding properties between imidacloprid and the nicotinic acetylcholine receptors in both species.

Animals↗

Comparison of bioassay techniques for determining baseline susceptibilities to imidacloprid for green apple aphid (Homoptera: Aphididae).

The susceptibility of a clone of green apple aphid, Aphis pomi (De Geer), to the neonicotinyl insecticide imidacloprid was determined by direct and indirect bioassay techniques. Aphid numbers were assessed on potted apple seedlings treated with various concentrations of imidacloprid, adults were dipped in test solutions as per the Food and Agriculture Organization protocol, or nymphs and adults were reared on treated apple leaf disks. Effective concentrations required to kill half of the test population (EC50) varied depending on the bioassay technique, ranging from as low as 0.064 ppm for first instars reared for 3 d on treated leaf disks to 1.79 ppm for adult apterae dipped in solutions of imidacloprid and held for 24 h on clean leaf disks. When imidacloprid was directly applied to aphids, mortality continued to increase over 3 d, but the difference was not statistically significant between day 2 (1.36 ppm) and day 3 (1.19 ppm). Toxicity of neonicotinyls to aphids is expressed rather slowly and primarily after oral ingestion. The effect of imidacloprid on reproduction of green apple aphid was also assessed for adult apterae reared on treated leaf disks. Contrary to previous reports, our results demonstrated that imidacloprid does not have a direct negative effect on the reproductive physiology of this species. Negative effects can mostly be attributed to the antifeedant activity of this compound and the protracted time to death. The results of this study contribute to a better understanding of the most suitable techniques for assessing aphid mortality after exposure to these new insecticides and provides a baseline susceptibility to imidacloprid for green apple aphid.

Animals↗

Form III of 2,2',4,4',6,6'-hexanitroazobenzene (HNAB-III).

The crystal structure of form III of the title compound, HNAB [systematic name: bis(2,4,6-trinitrophenyl)diazene], C12H4N8O12, has finally been solved as a pseudo-merohedral twin (monoclinic space group P2(1), rather than the orthorhombic space group C222(1) suggested by diffraction symmetry) using a dual space recycling method. The significant differences in the room-temperature densities of the three crystalline forms allow examination of molecular differences due to packing arrangements. An interesting relationship with the stilbene analog, HNS, is discussed. Interatomic separations are compared with other explosives and/or nitro-containing compounds.

Journal Article↗

Novel correlation for predicting impact sensitivity of nitroheterocyclic energetic molecules.

A novel correlation is introduced for predicting impact sensitivity of a variety nitroheterocyclic molecular types, such as nitropyridines, nitroimidazoles, nitropyrazoles, nitrofurazanes, nitrotriazoles and nitropyrimidines. This approach is based on elemental composition and two structural parameters of C(a)H(b)N(c)O(d) nitroheterocyclic energetic compounds. The results for mentioned compounds are compared with complex neural networks computations which use compositional and topological descriptors. Root mean square (rms) of deviation of different nitroheterocyclic molecules including nitropyridines, nitroimidazoles, nitropyrazoles, nitrofurazanes, nitrotriazoles and nitropyrimidines are 58 and 71cm for new correlation and neural networks computations methods, respectively.

Explosive Agents↗

Evaluation of traps and toxicants in an attract-and-kill system for Rhagoletis mendax (Diptera: Tephritidae).

A series of laboratory and field assays were performed to evaluate new methods for an attract-and-kill approach to control blueberry maggot, Rhagoletis mendax Curran. In laboratory assays, fly mortality was similar among insecticide-treated matted paper, plastic, and biodegradable sphere traps. Plastic and biodegradable traps baited with ammonium acetate captured significantly more flies than baited matted paper traps in field assays, whereas fly captures were similar in baited matted paper traps and unbaited plastic sphere traps. Treatments containing imidacloprid resulted in the highest amount of fly knockdown, and spheres coated with this insecticide still had significant knockdown after 6 wk of field exposure. Fly mortality was comparable on sphere traps coated with fipronil and imidacloprid, with both resulting in significantly more fly mortality than the control when flies were exposed to traps that had been weathered for 4 wk in the field. Spheres coated with acetamiprid resulted in fly mortality, but further evaluation is necessary to determine the potential of this compound. Deltamethrin was ineffective in causing fly knockdown at the rate tested. Our results indicate that fipronil and imidacloprid have potential as insecticidal coatings on either plastic or biodegradable spheres in an attract-and-kill system for control of R. mendax.

Acetates↗

FK409, a novel vasodilator isolated from the acid-treated fermentation broth of Streptomyces griseosporeus. I. Taxonomy, fermentation, isolation, and physico-chemical and biological characteristics.

FK409, a novel vasodilator with anti-platelet aggregation activity, has been isolated from the acid-treated fermentation broth of Streptomyces griseosporeus No. 16917, which was cultured on a medium containing NaNO3 for 4 days. FK409 was purified from the culture-filtrate by extraction with ethyl acetate after adjusting the pH to 3.0 with HC1, followed by silica gel chromatography. The molecular formula of this compound was determined to be C8H13N3O4. In vitro, FK409 showed a potent relaxation activity on noradrenaline induced contraction of rat aorta. In addition to the vasodilating activity, this compound also showed potent anti-aggregation activities towards rabbit platelets. In vivo, intravenously administered FK409 resulted in marked blood pressure lowering in rats.

Animals↗

Anaerobic biodegradation of aromatic compounds.

Many aromatic compounds and their monomers are existing in nature. Besides they are introduced into the environment by human activity. The conversion of these aromatic compounds is mainly an aerobic process because of the involvement of molecular oxygen in ring fission and as an electron acceptor. Recent literatures indicated that ring fission of monomers and obligomers mainly occurs in anaerobic environments through anaerobic respiration with nitrate, sulphate, carbon dioxide or carbonate as electron acceptors. These anaerobic processes will help to work out the better situation for bioremediation of contaminated environments. While there are plenty of efforts to reduce the release of these chemicals to the environment, already contaminated sites need to be remediated not only to restore the sites but to prevent the leachates spreading to nearby environment. Basically microorganisms are better candidates for breakdown of these compounds because of their wider catalytic mechanisms and the ability to act even in the absence of oxygen. These microbes can be grouped based on their energy mechanisms. Normally, the aerobic counterparts employ the enzymes like mono-and-dioxygenases. The end product is basically catechol, which further may be metabolised to CO2 by means of quinones reductases cycles. In the absense of reductases compounds, the reduced catechols tend to become oxidised to form many quinone compounds. The quinone products are more recalcitrant and lead to other aesthetic problems like colour in water, unpleasant odour, etc. On the contrary, in the reducing environment this process is prevented and in a cascade of pathways, the cleaved products are converted to acetyl co-A to be integrated into other central metabolite paths. The central metabolite of anaerobic degradation is invariably co-A thio-esters of benzoic acid or hydroxy benzoic acid. The benzene ring undergoes various substitution and addition reactions to form chloro-, nitro-, methyl- compounds. For complete degradation the side chains must be removed first and then the benzene ring is activated by carboxylation or hydroxylation or co-A thioester formation. In the next step the activated ring is converted to a form that can be collected in the central pool of metabolism. The third step is the channeling reaction in which the products of the catalysis are directed into central metabolite pool. The enzymes involved in these mechanisms are mostly benzyl co-A ligase, benzyl alcohol dehydrogenase. Other enzymes involved in this path are yet to be purified though many of the reactions products that have been theoretically postulated have been identified. This is mainly due to the instability of intermediate compounds as well as the association of the enzyme substrate is femoral and experimental conditions need to be sophisticated further for isolation of these enzymes. The first structural genes of benzoate and hydroxy benzoate ligases were isolated from Rhodopseudomonas palustris. This gene cluster of 30 kb size found in Rhodopseudomonas palustris coded for the Bad A protein. Similarly, some of the bph A,B,C and D cluster of genes coding for the degradation of pentachlorobenzenes were located in Pseudomonas pseudoalgaligenesKF 707.

Anaerobiosis↗

1,3,3-Trinitroazetidine (TNAZ), a melt-cast explosive: synthesis, characterization and thermal behaviour.

1,3,3-Trinitroazetidine (TNAZ) has been prepared at a laboratory scale in HEMRL. The structure of the compound has been confirmed by IR, NMR, mass, elemental analysis and by X-ray crystallography. HPLC technique has been employed to confirm the purity of TNAZ (>99%). The compound is further characterized by thermal techniques and is found to undergo limited decomposition at its melting point. Small scale sensitivity tests have also been carried out and the results show that TNAZ is significantly more sensitive to mechanical stimuli than TNT.

Azetidines↗

Hypoxia-selective antitumor agents. 16. Nitroarylmethyl quaternary salts as bioreductive prodrugs of the alkylating agent mechlorethamine.

Nitrobenzyl quaternary salts of nitrogen mustards have been previously reported as hypoxia-selective cytotoxins. In this paper we describe the synthesis and evaluation of a series of heterocyclic analogues, including pyrrole, imidazole, thiophene, and pyrazole examples, chosen to cover a range of one-electron reduction potentials (from -277 to -511 mV) and substitution patterns. All quaternary salt compounds were less toxic in vitro than mechlorethamine, and all were more toxic under hypoxic than aerobic conditions, although the differentials were highly variable within the series. The most promising analogue, imidazole 2, demonstrated DNA cross-linking selectively in hypoxic RIF-1 cells, and was active in vivo in combination with radiation or cisplatin. However, 2 also produced unpredictable toxicity in vivo, suggestive of nonspecific nitrogen mustard release, and this has restricted further development of these compounds as hypoxia-selective cytotoxins.

Animals↗

Determination and characterization of organic explosives using porous graphitic carbon and liquid chromatography-atmospheric pressure chemical ionization mass spectrometry.

A new LC-MS method for the determination and characterization of three groups of commonly used organic explosives (nitroaromatic compounds, cyclic nitroamines and nitrate esters) was developed using a porous graphitic carbon (PGC) (Hypercarb) column. Twenty-one different explosive-related compounds--including 2,4,6-trinitrotoluene, its by-products and its degradation products--were chromatographically separated in a single analysis. This efficient separation facilitates the identification of the manufacturer of the explosive using the identified analytes as a fingerprint. A final, conclusive identification of the analytes can be obtained using LC-MS equipped with an atmospheric pressure chemical ionization (APCI) interface. Solvent effects on chromatographic behaviour were investigated, as were the effects of solvent mixtures and mobile phase additives. The number and the relative positions of the nitro groups within analyte molecules influence their order of elution; these effects were investigated. The data thus generated can be interpreted to support a hypothesis concerning the retention mechanism of nitro-containing compounds when using PGC. Limits of detection ranged from 0.5 to 41.2 ng. The new methodology described herein improves the sensitivity and selectivity of explosive detection. The effectiveness of the method is demonstrated by the analysis of soil samples containing explosives residue from test fields in Sweden and Afghanistan.

Atmospheric Pressure↗

The reactivity of chloramphenicol reduction products with DNA bases.

PURPOSE: The interaction between the constituent bases of deoxyribonucleic acid and the reduction products of the nitro-aromatic compound chloramphenicol and its nitroso derivative have been studied using an electrochemical system. METHODS AND MATERIALS: The changes to the voltammetry of chloramphenicol and nitrosochloramphenicol upon addition of adenine, cytosine, guanine, and thymine at various concentrations have been measured. The biological implications of reductive activation of both chloramphenicol and nitrosochloramphenicol were examined using a phi X174 double transfection technique which measures biologically relevant deoxyribonucleic acid damage. RESULTS: Measurement of the voltammetric response of chloramphenicol shows that the most noticeable change upon base addition is a decrease in the lifetime of the nitro radical anion in the following order of decreasing activity: adenine, thymine, and cytosine. No effect was observed with guanine. The reversible 2-electron nitrosochloramphenicol-hydroxychloramphenicol couple showed no interaction on the voltammetric timescale, although binding of the hydroxylamine to guanine was observed. Interaction of the azo derivative, formed as a consequence of further reduction plus chemical reaction of nitrosochloramphenicol was observed. Biological studies showed that no significant effect on deoxyribonucleic acid by chloramphenicol or nitrosochloramphenicol was observed under oxic conditions. Controlled reduction of nitrosochloramphenicol to the hydroxylamine gave considerably less damage than when nitrosochloramphenicol or chloramphenicol was completely reduced. CONCLUSION: The chloramphenicol nitro radical anion reacts selectively with the bases of deoxyribonucleic acid. Reduction products of nitrosochloramphenicol beyond the 2-electron hydroxylamine are highly reactive to deoxyribonucleic acid.

Chloramphenicol↗

1,4-dihydropyridines: reactivity of nitrosoaryl and nitroaryl derivatives with alkylperoxyl radicals and ABTS radical cation.

In the present paper, a direct quenching of radical species by a number of synthesized nitrosoaryl 1,4-dihydropyridines and their parent nitroaryl 1,4-dihydropyridines was determined in aqueous media at pH 7.4. These two series of compounds were compared with the C-4 unsubstituted 1,4-dihydropyridines derivatives and the corresponding C-4 aryl substituted 1,4-dihydropyridines derivatives. Kinetic rate constants were assessed by UV-Vis spectroscopy. Nitrosoaryl derivatives were more reactive than the parent nitroaryl 1,4-dihydropyridines. Our results strongly support the assumption that the reactivity between the synthesized 1,4-dihydropyridines derivatives with alkylperoxyl radicals involves electron transfer reactions, which is documented by the presence of pyridine as final product of reaction and the complete oxidation of the nitroso group to give rise the nitro group in the case of the nitrosoaryl 1,4-dihydropyridines derivatives.

Benzothiazoles↗

Synthesis of a novel [125I]neonicotinoid photoaffinity probe for the Drosophila nicotinic acetylcholine receptor.

The insect nicotinic acetylcholine receptor (nAChR) is the target for the major insecticide imidacloprid (IMI) and for the first candidate photoaffinity probe described here. Addition to 1-[(6-chloro-3-pyridinyl) methyl]-4,5-dihydro-2-nitromethylene-1H-imidazolidine (the nitromethylene analog of the nitroimine IMI) of formaldehyde and any one of several primary amines is known to give hexahydro-8-nitroimidazo[1,2-c]pyrimidine derivatives. These imidazopyrimidines with a wide range of N-substituents were found to inhibit [3H]IMI binding to the Drosophila or Musca nAChR by 50% (IC50) at 0.7-38 nM. Esterification of the N-(2-hydroxyethyl) derivative with 2-azido-5-(trimethylstannyl)-benzoic acid and then iododestannylation using Na125I and chloramine-T provide the candidate photoaffinity probe 6-[2-(2-azido-5-[125I]iodobenzoyl) ethyl]-1-[(6-chloro-3-pyridinyl)methyl]-1,2,3,5,6,7-hexahydro-8 -nitroimidazo[1,2-c]pyrimidine. This compound (unlabeled) has an IC50 of 8 nM for [3H]-IMI binding in Drosophila head membranes, and the 125I-labeled photoaffinity probe labels only a 66 kDa protein(s) at a specific site inhibited by (-)-nicotine, consistent with the insecticide-binding subunit of the nAChR.

Affinity Labels↗