Previously, the secondary nitroalkane 2-nitropropane, a strong hepatocarcinogen in rats, had been shown to induce the formation of 8-aminoguanine in both DNA and RNA of rat liver through a sulfotransferase-mediated pathway. This pathway was postulated to convert the carcinogen into an aminating species. To submit this postulate to further test, we examined liver proteins of rats treated with 2-nitropropane, other carcinogenic secondary nitroalkanes, or the related rat liver tumorigen acetoxime for the presence of 3-aminotyrosine, the expected product of tyrosine amination. Using ion-pair and/or cation-exchange high-performance liquid chromatography with electrochemical detection, we found that the liver cytosolic proteins of these animals contained 0.1-1.5 mol of 3-aminotyrosine/10(3) mol of tyrosine. Treatment with the noncarcinogenic primary nitroalkane 1-nitropropane or with other primary nitroalkanes did not produce an analogous increase in the aminated amino acid (level of detection estimated at approximately 0.01 mol/10(3) mol of tyrosine). ... In vitro studies with acetoxime-O-sulfonate and hydroxylamine-O-sulfonate showed that these proposed intermediates in the activation pathway of 2-nitropropane react with guanosine to give 8-aminoguanosine, N1-aminoguanosine, and 8-oxoguanosine and also react with tyrosine to give 3-aminotyrosine and 3-hydroxytyrosine. The in vitro amination and oxidation of guanosine at C8 were also produced by acetophenoxime-O-sulfonate and 2-heptanoxime-O-sulfonate. These results provide additional evidence for the production of a reactive species capable of aminating nucleic acids and proteins from 2-nitropropane and other carcinogenic secondary nitroalkanes by a pathway involving oxime- and hydroxylamine-O-sulfonates as intermediates.
Acetoxime and methylethyl ketoxime (MEKO) are tumorigenic in rodents, inducing liver tumors in male animals. The mechanisms of tumorigenicity for these compounds are not well defined. Oxidation of the oximes to nitronates of secondary-nitroalkanes, which are mutagenic and tumorigenic in rodents, has been postulated to play a role in the bioactivation of ketoximes. In these experiments, we have compared the oxidation of acetoxime and methylethyl ketoxime to corresponding nitronates in liver microsomes from different species. The oximes were incubated with liver microsomes from mice, rats, and several human liver samples. After tautomeric equilibration and extraction with n-hexane, 2-nitropropane and 2-nitrobutane were quantitated by GC/MS-NCI (limit of detection of 250 fmol/injection volume). In liver microsomes, nitronate formation from MEKO and acetoxime was dependent on time, enzymatically active proteins, and the presence of NADPH. Nitronate formation was increased in liver microsomes of rats pretreated with inducers of cytochrome P450 and reduced in the presence of inhibitors (n-octylamine and diethyldithiocarbamate). Rates of oxidation of MEKO (Vmax) were 1.1 nmol/min/mg (mice), 0.5 nmol/min/mg (humans), and 0.1 nmol/min/mg (rats). In addition to nitronates, several minor metabolites were also enzymatically formed (two diastereoisomers of 3-nitro-2-butanol, 2-hydroxy-3-butanone oxime and 2-nitro-1-butanol). Acetoxime was also metabolized to the corresponding nitronate at rates approximately 50% of those observed with MEKO oxidation in the three species examined. 2-Nitro-1-propanol was identified as a minor product formed from acetoxime. No sex differences in the capacity to oxidize acetoxime and MEKO were observed in the species examined. The observed results show that formation of sec-nitronates from ketoximes occurs slowly, but is not the only pathway involved in the oxidative biotransformation of these compounds. Due to the lack of sex-specific oxidative metabolism, other metabolic pathways or mechanisms of tumorigenicity not involving bioactivation may be involved in the sex-specific tumorigenicity of ketoximes in rodents.
The hepatocarcinogenicity of acetoxime has been tentatively linked with its metabolic oxidation to the potent genotoxicant and carcinogen propane 2-nitronate (P2-N). In order to test the hypothesis that acetoxime is metabolized to P2-N, the oxime (20 mM) was incubated with liver microsomes from mice, rats and two humans. Ion-pair HPLC analysis of the incubates afforded a peak that co-eluted with P2-N. P2-N exists in tautomeric equilibrium with 2-nitropropane (2-NP). Samples of the microsomal incubates, which had been adjusted to pH 5.5 and kept for 24 hr in order to allow maximal tautomeric equilibration of P2-N to 2-NP to occur, were extracted with hexane. GLC analysis of the extracts yielded a peak that co-eluted with 2-NP, and gave a mass spectrum identical to that of authentic 2-NP. The metabolite peak obtained on HPLC was isolated and its hexane extract contained also 2-NP when investigated by GLC. P2-N was found by HPLC in the urine of rats that had received acetoxime (3.36 mmol/kg i.p.). Hexane extracts of urine samples, which had been adjusted to pH 5.5 and left for 24 hr, contained 2-NP as demonstrated by GLC analysis. The results are consistent with the suggestion that the toxicity of acetoxime is associated with its biotransformation to P2-N.
IDENTIFICATION AND USE: Acetoxime is a solid. It is used in organic synthesis (intermediate), as a solvent for cellulose ethers, and as a primer for diesel fuels. HUMAN STUDIES: Acetoxime has been tested in vitro as an experimental medication for herpes infection. ANIMAL STUDIES: Acetoxime was tested for carcinogenicity by chronic administration in the drinking water to male and female rats. The dose of 1.0 g/liter was administered 5 days/week for 18 months (total dose, 6.2 -7.0 g/rat). Acetoxime induced benign hepatocellular adenomas in 80% of the males but did not produce tumors in the females. The 90 day-NOAEL of the test substance in rats by the oral route was 15 mg/kg bw/day in both sexes. No effects were observed in the reproductive organs or tissues up to the highest dose tested (50 mg/kg bw/day). Acetoxime was negative in the Ames test with TA97, TA98, TA100 and TA1535 with and without metabolic activation. Acetoxime was genotoxic in Drosophila melanogaster. When tested in vivo acetoxime was found to induce a specific pattern of base damage in rat liver DNA and RNA, including the induction of increased levels of 8-hydroxyguanine. Because acetoxime was a weaker carcinogen in female rats than male rats, its ability to induce damage in liver and kidney nucleic acids was examined in male and female rats 6 and 18 hr after administration. Significantly lower levels of 8-hydroxydeoxyguanosine, 8-hydroxyguanosine and other presumed modified nucleosides discernible by high-performance liquid chromatography with electrochemical detection were found in liver nucleic acids of female rats.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
副作用
神经毒素 - 其他中枢神经系统神经毒素
Neurotoxin - Other CNS neurotoxin
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Aren- und cyclopentadienyl-halbsandwichkomplexe des rutheniums mit oximaten, carboxylaten, iminen und azavinylidenen als liganden
作者：H. Werner、T. Daniel、W. Knaup、O. Nürnberg
DOI：10.1016/0022-328x(93)83372-3
日期：1993.12
The reaction of [C6H6Ru(PiPr3)Cl2] (1) with NaONCRR′ in the presence of KPF6 leads to the formation of the oximatoruthenium(II) complexes [C6H6Ru(η2-ONCRR′)(PiPr3)]PF6 (2–5) in 70–90% yield. Compound 5 (R Me, R′ tBu) reacts with HNCPh2 via ligand exchange to give [C6H6Ru(NCPh2)(Pi Pr3)]PF6 (8). The azavinylidene complex 8 has also been prepared from the acetatoruthenium derivative [C6H6Ru(η2-O2
在KPF 6存在下，[C 6 H 6 Ru（P i Pr 3）Cl 2 ]（1）与NaONCRR'的反应导致形成氧亚氨基钌（II）络合物[C 6 H 6 Ru（ η 2 -ONCRR'）（P我镨3）] PF 6（2 - 5）在70-90％的产率。化合物5（RMe中，R'吨卜）与HNCPh发生反应2通过配体交换，得到[C 6 H ^ 6的Ru（NCPh 2）（Pi Pr 3）] PF 6（8）。所述azavinylidene复杂8也被从acetatoruthenium衍生物制备[C 6 H ^ 6的Ru（η 2 -O 2 CCH 3）（P我镨3）] PF 6（6），其可以或者从可以得到1，CH 3 CO 2 Na和KPF 6或从治疗的5用过量的CH 3 CO 2 H的hexamethylbenzeneruthenium化合物的合成[C6我6的Ru（NCR' 2）PR 3 ]）PF
Stereospecific synthesis of 1,5-disubstituted tetrazoles from ketoximes via a Beckmann rearrangement facilitated by diphenyl phosphorazidate
A novel method for the stereospecificsynthesis of 1,5-disubstituted tetrazoles from ketoximes via the Beckmann rearrangement was developed using diphenyl phosphorazidate (DPPA) as both the oxime activator and azide source. Various ketoximes were transformed into the corresponding 1,5-disubstituted tetrazoles with exclusive trans-group migration and no E-Z isomerization of the ketoxime. This method
Drugs with high anticonvulsant and analgesic activities constituted by symmetrical .beta.-dialkoxyiminocycloalklene derivatives in which the imine double bonds are conjugated with the cyclic double bond or bonds belonging to one or more fused benzene rings. They correspond to the general formula I: ##STR1##
Stereoselective oxidation of alkanes with m-CPBA as an oxidant and cobalt complex with isoindole-based ligands as catalysts
作者：Oksana V. Nesterova、Maximilian N. Kopylovich、Dmytro S. Nesterov
DOI：10.1039/c6ra14382b
日期：——
substrates (>98% for cis-1,2-DMCH) and highest cis/trans ratio of tertiary alcohols (products) of 56, under mild conditions. The best achieved yields of tertiary cis-alcohols were of 13.7 and 50.5%, based on the substrate (cis-1,2-DMCH) and the oxidant (m-CPBA) respectively. Kinetic experiments, high bond and stereoselectivity parameters, kinetic isotopeeffect of 7.2(2) in the oxidation of cyclohexane, and
具有通式[M C 6 H 4 C（NH 2）NC（ONCMe 2）2 } 2 ]（NO 3）2的异吲哚核配体的两个配合物（M = Co表示1，M = Ni表示2）研究作为催化剂用于与轻度立体选择性氧化烷烃米氯过苯甲酸（米-CPBA）作为氧化剂和顺-1,2-二甲基环己烷（顺式-1,2- DMCH）作为主要模型底物。配合物1表现出显着的活性，并高度保留了底物的立体构型（顺式> 98％-1,2- DMCH）和最高的顺/反式的56（产品），在温和条件下的叔醇的比率。基于底物（顺式-1，2-DMCH）和氧化剂（m -CPBA），最佳的顺式叔醇收率分别为13.7和50.5％。动力学实验，高粘合和立体选择性的参数，在将环己烷氧化的7.2（2）动力学同位素效应，和掺入18从H 2 O 2 18 O支持Co的参与IV ø高价金属-氧中间体作为主要的C -H攻击物种。
[EN] AMINO PYRAZINE DERIVATIVES AS PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS<br/>[FR] DÉRIVÉS AMINÉS DE PYRAZINE UTILISABLES EN TANT QU'INHIBITEURS DE LA PHOSPHATIDYLINOSITOL 3-KINASE
申请人：NOVARTIS AG
公开号：WO2015162459A1
公开（公告）日：2015-10-29
The present invention provides compounds of formula (I) which inhibit the activity of PI 3-kinase gamma isoform, which are useful for the treatment of diseases mediated by the activation of PI 3-kinase gamma isoform.
