The metabolism of radiolabeled monochloronitrobenzene isomers was compared in isolated hepatocytes and hepatic subcellular fractions from male Fischer-344 rats. 2-Chloronitrobenezene was converted by isolated hepatocytes to 2-chloroaniline, 2-chloroaniline-N-glucuronide, and S-(2-nitrophenyl)glutathione in approximately equal quantities (13-19% of the added substrate in 90 min). ... Studies with hepatic microsomes showed that reduction of the chloronitrobenzenes to chloroanilines was inhibited by SKF 525-A, metyrapone, and carbon monoxide, suggesting that cytochrome P-450 played a role in the reaction.
The main metabolic routes for 1-chloro-2-nitrobenzene in the body consist in reduction of the nitro group to an amino group and hydroxylation of the benzene ring. Apart from 2-chloroaniline, the corresponding nitrophenols and aminophenols are formed, which are excreted as conjugates of glucuronic acid and sulfuric acid. 2-chloroaniline also appears in the urine and feces in the unconjugated form. During reduction of the nitro group to the amino group, the hydroxylamine compound is formed as a highly reactive intermediate which has been detected both in vivo in rats, and in vitro.
来源:Hazardous Substances Data Bank (HSDB)
代谢
体外代谢：将标记有放射性碳-14（14C）的邻氯硝基苯与分离的大鼠肝细胞一起孵化。90分钟后，71%的邻氯硝基苯已被代谢；邻氯硝基苯的主要代谢途径是还原为邻氯苯胺（占总放射活性的19.2%）；邻氯硝基苯还与谷胱甘肽结合；另外两种非常极性的代谢物，占总14C的14.2%，尚未被鉴定。为了确定参与分离的大鼠肝细胞代谢邻氯硝基苯的特定酶，从大鼠中分离出肝亚细胞组分；在NADPH存在下，微体与标记有放射性碳-14（14C）的邻氯硝基苯一起孵化，在 aerobic 条件下产生了邻氯苯胺，SKF 525 A 和甲乙酮对代谢为邻氯苯胺没有影响：这些发现表明细胞色素P-450还原酶负责邻氯硝基苯的还原；放射性标记的邻氯硝基苯也在有或没有微体、细胞质和/或谷胱甘肽的情况下孵化：在细胞质和谷胱甘肽存在的情况下，邻氯硝基苯转化为S-(2-硝基苯基)谷胱甘肽，这表明细胞质谷胱甘肽转移酶参与了这种结合（未指定测试物质的浓度）。
Metabolism in vitro: radiolabelled (14C) o-chloronitrobenzene was incubated with isolated rat hepatocytes. After 90 min., 71% of the o-chloronitrobenzene had been metabolized; the primary metabolic pathway for o-chloronitrobenzene was reduction to o-chloroaniline (19.2% of the total radioactivity); o-chloronitrobenzene was also conjugated with glutathione; two other very polar metabolites, comprising 14.2% of the total 14C from o-chloronitrobenzene, have not been identified. in order to identify the specific enzymes involved in the metabolism of o-chloronitrobenzene by isolated rat hepatocytes, hepatic subcellular fractions were isolated from rats; microsomes incubated with radiolabelled (14C) o-chloronitrobenzene in the presence of NADPH produced o-chloroaniline under aerobic conditions and SKF 525 A and metyrapone had no effect on the metabolism to o-chloroaniline: these findings suggest that cytochrome P-450 reductase is responsible for o-chloronitrobenzene reduction; radiolabelled o-chloronitrobenzene was also incubated with or without microsomes, cytosol and/or glutathione: o-chloronitrobenzene was converted to S-(2-nitrophenyl)glutathione in the presence of cytosol and glutathione suggesting that cytosolic glutathione transferase is involved in this conjugation (concentration of the test substance unspecified).
Human Health: After single oral application 1-chloro-2-nitrobenzene is toxic to moderate toxic ... ; the acute inhalative and dermal toxicity is moderate ...: Cyanotic appearance was the predominant symptom for all routes of application. ... 1-Chloro-2-nitrobenzene caused slight irritation effects to the eyes of rabbits, which were reversible within 24 hours. Due to the limited and poor quality information available regarding skin sensitization, it cannot be concluded whether or not the chemical has a sensitizing activity. Target organs of repeated dose toxicity in rats and mice are blood, liver, kidney and spleen with methemogobinemia as the most sensitive parameter. The repeated dose toxicity was examined in rats and in mice for a period of 13 weeks via whole body inhalation. The NOAEL in rats was not achieved, the LOAEL is 1.1 ppm (7 mg/cu m). In mice, increased liver and kidney weights were observed even at 1.1 ppm and respectively 2.3 ppm. The NOAEL for histopathological injury in mice is 4.5 ppm (28.8 mg/cu m). In a subacute feeding study with mice the NOAEL was 50 ppm (males: 16 mg/kg bw/day; females: 24 mg/kg bw/day). 1-Chloro-2-nitrobenzene showed weak mutagenic activity in bacterial test systems but not in mammalian cell test systems in vitro. It was not mutagenic in Drosophila melanogaster . In mammalian cells in vitro, it showed weak clastogenic activity. The substance induced increased rates of Sister Chromatid Exchanges, whereas the biological relevance of this effect is not yet clear. Intraperitoneal injection into mice resulted in DNA damage in the liver and kidney. The inconsistent results of the available genotoxic studies are typical for nitroaromatics. As a whole 1- chloro-2-nitrobenzene is suspected of being genotoxic, at least a weak clastogen. 1-Chloro-2-nitrobenzene induced tumors in different organs of rats and in the liver of mice. Based on the available studies, which have methodological deficiencies, there is a concern for a carcinogenic potential of 1-chloro-2- nitrobenzene. Following inhalative exposure of F344/N rats and B6C3F1 mice for 13 weeks, only in males 1- chloro-2-nitrobenzene affects the reproductive organs. Performance of a specific study on toxicity to reproduction (NTP continuous breeding protocol) reveals that 1-chloro-2-nitrobenzene was without reproductive toxicity in a different mice strain following oral treatment by gavage despite of significant changes in liver and spleen weight and despite of elevated methaemoglobin levels. Thus, the NOAEL fertility in Swiss CD-1 mice after oral application is 160 mg/kg bw/day whereas the dams showed general toxicity effects at this concentration. Because 1-choro-2- nitrobenzene affected the reproductive organs in systemic toxic doses in male rats and in males of one strain of mice after subchronic inhalation there is a concern for a reproductive toxicity potential, even if an impairment of reproduction after oral administration in males of a second strain of mice could not be detected. Developmental toxicity was examined by two studies with Sprague-Dawley rats which have methodology deficiencies. In one study, due to high mortality rate at the highest dose level, only two doses could be evaluated. NOAEL maternal toxicity is 25 mg/kg bw/day, a NOAEL developmental toxicity could not be conclusively derived since there was an increase in the number of litters exhibiting specific skeletal variations. In the second study only one dose was applied: NOAEL developmental toxicity is 100 mg/kg bw/day, a NOAEL maternal toxicity could not be derived. Based on the available studies the overall conclusion is, that there is no indication of developmental toxicity, although there are some limitations within the studies. Environment: ... The acute toxicity has been determined for: fish (Cyprinus carpio) with a 96 hr-LC50 of 25.5 mg/L; daphnia (Daphnia magna) with a 24 hr-EC50of 12 mg/L and a 48 hr-EC50 of 23.9 mg/L, and Daphnia carinata with a 48 hr-EC50 of 21.3 mg/L; algae (Chlorella pyrenoidosa) with a 96 hr-EbC50 of 6.9 mg/L. With another alga species (Secendesmus subspicatus) a 48 hr-ErC50 of 75 mg/L and a 48h-ErC10 of 19 mg/L was found. Chronic toxicity has been tested for Daphnia magna with a 21 d-NOEC of 3 mg/L on reproduction (measured concentration) and for fish (Pimephales promelas) in an Early Life Stage Test with a 33 d-NOEC of 0.264 mg/L concerning the endpoint normal larvae (measured concentration). A PNECaqua of 0.026 mg/L is derived using an assessment factor of 10. In a test with terrestrial plants a 14 d-EC50 in the range of 3.2 - 10 mg/kg soil dry weight was determined for Lactuca sativa regarding the endpoint of growth. APNECsoil of 3.2 ug/kg bw was derived from this value using an assessment factor of 1000.
Evaluation: There is inadequate evidence in humans for the carcinogenicity of chloronitrobenzenes. There is inadequate evidence in experimental animals for the carcinogenicity of chloronitrobenzenes. Overall evaluation: Chloronitrobenzenes are not classifiable as to their carcinogenicity to humans (Group 3). /Chloronitrobenzenes/
The effect of dose on the dermal absorption of 2-chloronitrobenzene and 4-chloronitrobenzene was studied in rats. (14)C labeled 2-chloronitrobenzene or 4-chloronitrobenzene was applied to the shaved backs of male Fischer 344 rats at an application rates equivalent to doses of 0, 0.65, 6.5 or 65 mg/kg. Urine and feces samples were collected for 24, 48 or 72 hr and assayed for (14)C activity. Exhaled volatiles were collected in ethanol traps and analyzed. After 72 hr, the rats were /sacrificed/ and their skin removed and analyzed for (14)C activity. Approx 21-27% and 43 to 45% of the 2-chloronitrobenzene and 4-chloronitrobenzene doses, respectively, were eliminated in the urine over 72 hr. Approx 11 to 15% of the 2-chloronitrobenzene dose and 5 to 12% of the 4-chloronitrobenzene dose were excreted over 72 hr. Fecal excretion of 4-chloronitrobenzene showed a dose related incr which was statistically significant only when comparing the 65 mg/kg dose with the 0.65 mg/kg dose. Approx 27 to 32% of 2-chloronitrobenzene derived radioactivity and 13 to 15% of the 4-chloronitrobenzene derived (14)C activity were recovered in the ethanol traps. The amt of collected radioactivity did not depend on dose and consisted of unchanged 2-chloronitrobenzene or 4-chloronitrobenzene. ... An analysis of all (14)C data indicated that the dermal absorption of 2-chloronitrobenzene ... was linear over the entire dose range. Dermal absorption of 4-chloronitrobenzene was linear only after application of 0.65 and 6.5 mg/kg. /Results indicate/ that under the experimental conditions used at least 33 to 40% and 51 to 62% of the applied 2-chloronitrobenzene and 4-chloronitrobenzene doses, respectively, are absorbed from the skin of rats. ... Dermal absorption of 2-chloronitrobenzene is linear over the dose range 0.65 mg/kg to 65 mg/kg. Dermal absorption of 4-chloronitrobenzene is essentially unaffected by dose.
... The dermal absorption of the chemicals was compared, and the absorption, distribution, metabolism, and excretion were partially characterized following oral administration to male F344/N rats. Percutaneous absorption of [14C]-2-chloronitrobenzene and [14C]-4-chloronitrobenzene was demonstrated in rats. For doses ranging from 0.65 to 65 mg/kg of either chemical, 33%; to 40%; of 2-chloronitrobenzene and 51%; to 62%; of 4-chloronitrobenzene were absorbed under nonocclusive conditions. Oral absorption was somewhat higher than dermal absorption for both chemicals, and metabolism was complicated, with over 20 unidentified metabolites isolated from urine of rats given either 2- or 4-chloronitrobenzene.
1-Chloro-2-nitrobenzene, under appropriate conditions of exposure, is absorbed by the body both via the skin and the gastrointestinal tract as well as via the respiratory tract. Rat studies with labelled chemical show that 1-chloro-2-nitrobenzene absorption is 80% following oral administration and at least 40% after open dermal application. 0n 11 consecutive days, 65 mg 1-chloro-2-nitrobenzene/kg bw was administered by gavage to adult and to old rats. On days 1, 5, and 9 applied substance was labelled and urine and feces were collected in the following 96 hours. The adult rats excreted 71-74% of the dose in the urine and 20-27% of the dose in the feces. Excretion rate increased with the duration of treatment. Urinary excretion rate in the old rats consisted 71-85% of the dose and did not increase with the duration of treatment. The radioactivity level in the tissues were determined 72 hours after d9-treatment and shown to be found 5% of the dose in adult rats and 8% in the old rats. At very high doses, e.g. 200 mg/kg bw given orally, urinary excretion is delayed and fecal excretion is markedly suppressed. There is evidence to suggest involvement of the enterohepatic cycle, but there are no signs of accumulation of 1-chloro-2-nitrobenzene or one of its metabolites.
After oral administration of 100 mg 1-chloro-2-nitrobenzene/kg bw to rabbits 42% of the dose was excreted in the urine as glucuronides, 24% as sulfates, 7% as mercapturic acids and 9% as free 2-chloroaniline. Only 2-Chloroaniline (0.3%) could be detected in the feces. 48 hours after administration elimination was complete.
The present invention concerns novel compounds, their preparation and their uses, therapeutic uses in particular. More specifically it concerns derivative compounds having at least two aromatic cycles, their preparation and their uses, in particular in the area of human or animal health. These compounds have an affinity for the biological receptors of neuropeptide Y, NPY, present in the central and peripheral nervous systems. The compounds of the invention are preferably NPY antagonists, and more particularly antagonists of sub-type NPY Y1, and can therefore be used for the therapeutic or prophylactic treatment of any disorder involving NPY. The present invention also concerns pharmaceutical compositions containing said compounds, their preparation and their uses, as well as treatment methods using said compounds.
the preparation of a wide variety of π-extended near-infrared fluorescent rhodamine dyes. Using this strategy, seven rectilinearly π-extended rhodamines (RE1–RE7) that had fluorescence emission wavelengths in the near-infrared region were synthesized. RE1, RE3, and RE4 were lysosome targetable and showed good photostabilities. In addition, using dye RE1 as a precursor, we constructed a novel NIR fluorescent
由于减少了来自生物样品的干扰吸收和荧光，减少了散射并提高了组织穿透深度，近红外（NIR）染料在生物医学中引起了人们的极大兴趣。在这种情况下，我们报告了使用芳香族氢的独特分子内亲核取代（S N Ar H）策略合成直线π延伸的若丹明染料的方法。该策略利用了预先组织的芳族氨基氮与x吨离子中电子不足的碳之间的S N Ar H反应。S N Ar H本文提出的反应可在没有过渡金属催化剂的温和条件下进行，并且有望实现多种π扩展的近红外荧光若丹明染料的制备。使用这种策略，合成了在近红外区域具有荧光发射波长的七个直线π扩展的若丹明（RE1-RE7）。RE1，RE3和RE4可溶酶体靶向，并显示出良好的光稳定性。此外，我们以染料RE1为前体，构建了一种新型的NIR荧光开启探针（RE1-Cu），可用于检测Cu 2+ 在活细胞中的含量，证明了我们近红外功能荧光染料的价值。
Efficient one-pot transformation of aminoarenes to haloarenes using halodimethylisulfonium halides generated in situ
作者：Woonphil Baik、Wanqiang Luan、Hyun Joo Lee、Cheol Hun Yoon、Sangho Koo、Byeong Hyo Kim
DOI：10.1139/v05-026
日期：2005.3.1
Halodimethylsulfonium halide 1, which is readily formed in situ from hydrohaloic acid and DMSO, is a good nucleophilic halide. This activated nucleophilic halide rapidly converts aryldiazonium salt prepared in situ by the same hydrohaloic acid and nitrite ion to aryl chlorides, bromides, or iodides in good yield. The combined action of nitrite ion and hydrohaloic acid in DMSO is required for the direct transformation of aromatic amines, which results in the production of aryl halides within 1 h. Substituted compounds with electron-donating or -withdrawing groups or sterically hindered aromatic amines are also smoothly transformed to the corresponding aromatic halides. The only observed by-product is the deaminated arene (usually <7%). The isolated aryldiazonium salts can also be converted to the corresponding aryl halides using 1. The present method offers a facile, one-step procedure for transforming aminoarenes to haloarenes and lacks the environmental pollutants that usually accompany the Sandmeyer reaction using copper halides. Key words: aminoarenes, haloarenes, halodimethylsulfonium halide, halogenation, amination.
Highly chemoselective reduction of nitroarenes over non-noble metal nickel-molybdenum oxide catalysts
作者：Haigen Huang、Xueguang Wang、Xu Li、Chenju Chen、Xiujing Zou、Weizhong Ding、Xionggang Lu
DOI：10.1039/c6gc03141b
日期：——
Chemoselectivereduction of nitroarenes is an important transformation for the production of arylamines, which are the primary intermediates in the synthesis of pharmaceuticals, agrochemicals and dyes. Heterogeneous non-noble metal nickel-molybdenum...
through direct heating treatment of cobalt oxide precursors incipiently deposited over nanographite materials. Cobalt oxides are partially reduced to active zero‐valent metal species and the simultaneous formation of carbon layers over the nanoparticles protects them from oxidation and deactivation. This nanocatalyst performs excellently in chemoselective hydrogenation of some challenging nitroarenes with
