Induction of glandular stomach cancers in Helicobacter pylori-sensitive Mongolian gerbils treated with N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine in drinking water.

PubMed

Tatematsu, M; Yamamoto, M; Shimizu, N; Yoshikawa, A; Fukami, H; Kaminishi, M; Oohara, T; Sugiyama, A; Ikeno, T

1998-02-01

An animal model of stomach carcinogenesis was established using Mongolian gerbils with N-methyl-N-nitrosourea (MNU) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as the carcinogens. In addition, the sensitivity of these gerbils to Helicobacter pylori (H. pylori) was confirmed. One hundred and sixty specific pathogen-free male MGS/Sea animals, 7 weeks old, were treated with MNU in the drinking water (30 ppm for alternate weeks to give 10 weeks exposure, or 10 ppm or 3 ppm for 20 weeks continuous exposure), or given MNNG in the drinking water at 400 ppm or 200 ppm for 20 weeks, or orally inoculated with ATCC43504 H. pylori (1.7 x 10(8) CFUs/animal). Adenocarcinomas in the glandular stomach were found in 2 out of 12 effective animals (2/ 12) treated with 30 ppm MNU at week 20, although all were dead or moribund by week 30 due to MNU toxicity. At week 50, the incidences of gastric adenocarcinomas in groups treated with 10 ppm MNU, 3 ppm MNU, 400 ppm MNNG, and 200 ppm MNNG were 2/21 (9.5%), 1/23 (4.3%), 7/ 11 (63.6%), and 1/10 (10.0%). The lesions were generally well differentiated, although poorly differentiated adenocarcinoma was also found in a single gerbil in each of the 10 ppm MNU and 400 ppm MNNG groups. In control animals no tumors were found. In the infection study, the animals were killed at week 20, and H. pylori was detected in all cases, causing multiple erosions with marked inflammatory cell infiltration in the lamina propria and submucosa, and frequent formation of lymphoid follicles. Thus, MNU and MNNG in the drinking water induced neoplastic lesions in the glandular stomach epithelium of H. pylori-sensitive gerbils.

Crystal structure of N'-[(E)-(4-chloro-phen-yl)(phen-yl)methyl-idene]-4-methyl-benzene-sulfono-hydrazide.

PubMed

Balaji, J; Prabu, S; Xavier, J J F; Srinivasan, P

2015-01-01

The title compound, C20H17ClN2O2S, was obtained by a condensation reaction between 4-chloro-benzo-phenone and tosyl hydrazide. The plane of the methyl-substituted benzene ring forms dihedral angles of 20.12 (12) and 78.43 (13)° with those of the chlorine-substituted benzene ring and the benzene ring, respectively, with the last two rings forming a dihedral angle of 67.81 (13)°. The chlorine substituent was also found to be 0.868 (2):0.132 (2) disordered over these two rings. In the crystal, mol-ecules are linked through pairs of N-H⋯O hydrogen bonds, giving centrosymmetric cyclic dimers [graph set R 2 (2)(8)], which are linked by weak C-H⋯O and C-H⋯Cl inter-actions into a chain structure which extends along the a-axis direction.

Maleic Hydrazide Unsuitable for Controlling Height Growth of Green Ash and Shumard Oak Seedlings

Treesearch

F. T. Bonner

1965-01-01

In southern nurseries, hardwood seedlings often grow so large that they are difficult to lift and plant. In a study at the Southern Hardwoods Laboratory, maleic hydrazide (MH) was tested as a means of halting height growth when seedlings reach suitable size.

Determination of Glyphosate, Maleic Hydrazide, Fosetyl Aluminum, and Ethephon in Grapes by Liquid Chromatography/Tandem Mass Spectrometry.

PubMed

Chamkasem, Narong

2017-08-30

A simple high-throughput liquid chromatography/tandem mass spectrometry (LC-MS-MS) method was developed for the determination of maleic hydrazide, glyphosate, fosetyl aluminum, and ethephon in grapes using a reversed-phase column with weak anion-exchange and cation-exchange mixed mode. A 5 g test portion was shaken with 50 mM HOAc and 10 mM Na 2 EDTA in 1/3 (v/v) MeOH/H 2 O for 10 min. After centrifugation, the extract was passed through an Oasis HLB cartridge to retain suspended particulates and nonpolar interferences. The final solution was injected and directly analyzed in 17 min by LC-MS-MS. Two MS-MS transitions were monitored in the method for each target compound to achieve true positive identification. Four isotopically labeled internal standards corresponding to each analyte were used to correct for matrix suppression effects and/or instrument signal drift. The linearity of the detector response was demonstrated in the range from 10 to 1000 ng/mL for each analyte with a coefficient of determination (R 2 ) of ≥0.995. The average recovery for all analytes at 100, 500, and 2000 ng/g (n = 5) ranged from 87 to 111%, with a relative standard deviation of less than 17%. The estimated LOQs for maleic hydrazide, glyphosate, fosetyl-Al, and ethephon were 38, 19, 29, and 34 ng/g, respectively.

Infrared Fingerprints of nN → σ*NH Hyperconjugation in Hydrazides.

PubMed

Andrade, Laize A F; Silla, Josué M; Cormanich, Rodrigo A; Freitas, Matheus P

2017-12-01

An earlier study demonstrated that hyperconjugation operates in hydrazides by analyzing the N-H stretching mode in gas phase infrared (IR) spectroscopy, and then observing two very distinct bands corresponding to isolated isomers experiencing or not the n N → σ* N-H electron delocalization. The present work reports a chemical method to obtain insight on the hyperconjugation in hydrazide derivatives from solution IR spectroscopy. The analogous amides did not show a ν N-H red-shifted band, as the electron donor orbital in the above hyperconjugative interaction does not exist. In addition, the effect of electron withdrawing groups bonded to a nitrogen atom, namely the trifluoroacetyl and the methanesulfonyl groups, was analyzed on the conformational isomerism and on the ability to induce a stronger hyperconjugation in the resulting compounds.

Garlic and associated allyl sulfur components inhibit N-methyl-N-nitrosourea induced rat mammary carcinogenesis.

PubMed

Schaffer, E M; Liu, J Z; Green, J; Dangler, C A; Milner, J A

1996-04-19

Our previous studies demonstrated that dietary garlic powder supplementation inhibits N-nitrosamine induced DNA alkylation in liver and mammary tissue. The present studies compared the impact of dietary supplementation with garlic powder or two garlic constituents, water-soluble S-allyl cysteine (SAC) and oil-soluble diallyl disulfide (DADS), on the incidence of mammary tumorigenesis induced by N-methyl-N-nitrosourea (MNU). Female Sprague-Dawley rats were fed semi-purified casein based diets with or without supplements of garlic powder(20g/kg), SAC (57 micromol/kg) or DADS (57 micromol/kg) for 2 weeks prior to treatment with MNU (15 mg/kg body wt). Garlic powder, SAC and DADS supplementation significantly delayed the onset of mammary tumors compared to rats receiving the unsupplemented diet. Tumor incidence 23 weeks after MNU treatment was reduced by 76, 41 and 53% in rats fed garlic, SAC and DADS, respectively, compared to controls (P<0.05). Total tumor number was reduced 81, 35 and 65% by these supplements, respectively (P<0.05). In a separate study the quantity of mammary DNA alkylation occurring 3 h after MNU treatment was reduced in rats fed garlic, SAC or DADS (P<0.05). Specifically, O(6)-methylguanine adducts were reduced by 27, 18 and 23% in rats fed supplemental garlic, SAC and DADS, respectively, compared to controls. N(7)-Methylguanine adducts decreased by 48, 22 and 21% respectively, compared to rats fed the control diet. These studies demonstrate that garlic and associated allyl sulfur components, SAC and DADS, are effective inhibitors of MNU-induced mammary carcinogenesis.

Effects of Dietary Xanthophylls, Canthaxanthin and Astaxanthin on N-Methyl-N-nitrosourea-induced Rat Mammary Carcinogenesis.

PubMed

Yuri, Takashi; Yoshizawa, Katsuhiko; Emoto, Yuko; Kinoshita, Yuichi; Yuki, Michiko; Tsubura, Airo

Natural xanthophylls, canthaxanthin and astaxanthin are known to exhibit anticancer activity. However, the dietary effects of canthaxanthin and astaxanthin on N-methyl-N-nitrosourea (MNU)-induced mammary cancer remain controversial, and their mechanisms of action have not been clearly identified. Three-week-old female Sprague-Dawley rats were fed a xanthophyll-free (basal diet) diet or experimental diets containing canthaxanthin or astaxanthin (0.04% and 0.4%) for 5 weeks (until 8 weeks of age), after which all rats were provided the basal diet (n=15 each). Rats were administered MNU at 6 weeks of age, and the incidence of mammary tumors at 20 weeks of age was compared. The expression of adiponectin in mammary adipose tissues taken at 7 weeks of age was also compared. Compared to the basal diet group, the 0.4% (but not the 0.04%) astaxanthin diet significantly reduced the incidence of palpable mammary carcinoma (92% vs. 42%; p<0.05), while the low and high canthaxanthin diets produced no significant inhibition. Adiponectin immunoblotting showed significantly higher expression in the 0.4% astaxanthin diet group, while the other groups were similar to the basal diet group. High concentrations of astaxanthin suppress MNU-induced mammary carcinoma. Changes in adiponectin may be involved in the mechanism of action. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

[The biochemical mechanisms of the action of N-alkyl-N-nitrosoureas. The possible reasons for drug resistance to these compounds].

PubMed

Syrkin, A B; Gorbacheva, L B

1996-01-01

N-alkyl-N-nitrosoureas exhibit a wide spectrum of antitumor activity. They react as alkylating agents at nucleophilic sites in purine and pyrimidine moieties of DNA. The predominant site of this alkylation is N7 of guanine, which is followed by the site N3 of adenine and 06 of guanine. The formation and persistence of 0(6)-alkylguanine (0(6)-AG) may be of primary importance in cytotoxicity of the nitrosoureas. 0(6)-AG adducts of DNA of the tumor cells are repaired by protein 0(6)-alkylguanine-DNA transferase (0(6)-AGT) which transfers the alkyl group to internal cysteine residue being the acceptor protein for the alkyl group in an irreversible transfer reaction. 0(6)-AGT can protect the tumor cells against 0(6)-AG adducts by the way of inhibiting the formation of the DNA interstrand cross-links 0(6)-AGT plays an important role in the drug resistance because it repairs the DNA alkyl adducts at the 0(6) position of guanine. The 0(6)-AGT activity inversely correlates with the cytotoxic effect of the nitrosoureas. The agents like 0(6)-methylguanosine, 0(6)-methyl-2'-deoxyguanosine, and some 0(6)-benzylated guanine derivatives are effective inactivators of 0(6)-AGT, and thus can be used to enhance the cytotoxicity of N-nitrosoureas. The activation of 0(6)-AGT and other repairing enzymes such as alpha and beta DNA-polymerases as well as an increase in the level of reduced glutathione may be used in developing the resistance to the nitrosoureas.

Dual-Functional Hydrazide-Reactive and Anhydride-Containing Oligomeric Hydrogel Building Blocks.

PubMed

Kascholke, Christian; Loth, Tina; Kohn-Polster, Caroline; Möller, Stephanie; Bellstedt, Peter; Schulz-Siegmund, Michaela; Schnabelrauch, Matthias; Hacker, Michael C

2017-03-13

Biomimetic hydrogels are advanced biomaterials that have been developed following different synthetic routes. Covalent postfabrication functionalization is a promising strategy to achieve efficient matrix modification decoupled of general material properties. To this end, dual-functional macromers were synthesized by free radical polymerization of maleic anhydride with diacetone acrylamide (N-(1,1-dimethyl-3-oxobutyl)acrylamide) and pentaerythritol diacrylate monostearate. Amphiphilic oligomers (M n < 7.5 kDa) with anhydride contents of 7-20% offered cross-linking reactivity to yield rigid hydrogels with gelatinous peptides (E = 4-13 kPa) and good cell adhesion properties. Mildly reactive methyl ketones as second functionality remained intact during hydrogel formation and potential of covalent matrix modification was shown using hydrazide and hydrazine model compounds. Successful secondary dihydrazide cross-linking was demonstrated by an increase of hydrogel stiffness (>40%). Efficient hydrazide/hydrazine immobilization depending on solution pH, hydrogel ketone content as well as ligand concentration for bioconjugation was shown and reversibility of hydrazone formation was indicated by physiologically relevant hydrazide release over 7 days. Proof-of-concept experiments with hydrazido-functionalized hyaluronan demonstrated potential for covalent aECM immobilization. The presented dual-functional macromers have perspective as reactive hydrogel building blocks for various biomedical applications.

Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N-methyl-N-nitrosourea.

PubMed

Chapman, Katherine E; Hoffmann, George R; Doak, Shareen H; Jenkins, Gareth J S

2017-07-01

Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently. A hormetic-style dose-response following a 24h exposure to the alkylating agent N-methyl-N-nitrosourea (MNU) was observed in a previous study for HPRT mutagenesis in the human lymphoblastoid cell line AHH-1. A second recent study demonstrated a J-shaped dose-response for the induction of micronuclei by MNU in a 24h treatment in a similar test system. Following mechanistic investigations, it was hypothesized that p53 may be responsible for the observed hormetic phenomenon. As genotoxic carcinogens are a major causative factor of many cancers, consideration of hormesis in carcinogenesis could be important in safety assessment. The data examined here offer possible insights into hormesis, including its estimated prevalence, underlying mechanisms and lack of generalizability. Copyright © 2017 Elsevier B.V. All rights reserved.

Cell Fate of Müller Cells During Photoreceptor Regeneration in an N-Methyl-N-nitrosourea-Induced Retinal Degeneration Model of Zebrafish.

PubMed

Ogai, Kazuhiro; Hisano, Suguru; Sugitani, Kayo; Koriyama, Yoshiki; Kato, Satoru

2016-01-01

Zebrafish can regenerate several organs such as the tail fin, heart, central nervous system, and photoreceptors. Very recently, a study has demonstrated the photoreceptor regeneration in the alkylating agent N-methyl-N-nitrosourea (MNU)-induced retinal degeneration (RD) zebrafish model, in which whole photoreceptors are lost within a week after MNU treatment and then regenerated within a month. The research has also shown massive proliferation of Müller cells within a week. To address the question of whether proliferating Müller cells are the source of regenerating photoreceptors, which remains unknown in the MNU-induced zebrafish RD model, we employed a BrdU pulse-chase technique to label the proliferating cells within a week after MNU treatment. As a result of the BrdU pulse-chase technique, a number of BrdU(+) cells were observed in the outer nuclear layer as well as the inner nuclear layer. This implies that regenerating photoreceptors are derived from proliferating Müller cells in the zebrafish MNU-induced RD model.

Multiple programmed cell death pathways are involved in N-methyl-N-nitrosourea-induced photoreceptor degeneration.

PubMed

Reisenhofer, Miriam; Balmer, Jasmin; Zulliger, Rahel; Enzmann, Volker

2015-05-01

To identify programmed cell death (PCD) pathways involved in N-methyl-N-nitrosourea (MNU)-induced photoreceptor (PR) degeneration. Adult C57BL/6 mice received a single MNU i.p. injection (60 mg/kg bodyweight), and were observed over a period of 7 days. Degeneration was visualized by H&E overview staining and electron microscopy. PR cell death was measured by quantifying TUNEL-positive cells in the outer nuclear layer (ONL). Activity measurements of key PCD enzymes (calpain, caspases) were used to identify the involved cell death pathways. Furthermore, the expression level of C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), key players in endoplasmic reticulum (ER) stress-induced apoptosis, was analyzed using quantitative real-time PCR. A decrease in ONL thickness and the appearance of apoptotic PR nuclei could be detected beginning 3 days post-injection (PI). This was accompanied by an increase of TUNEL-positive cells. Significant upregulation of activated caspases (3, 9, 12) was found at different time periods after MNU injection. Additionally, several other players of nonconventional PCD pathways were also upregulated. Consequently, calpain activity increased in the ONL, with a maximum on day 7 PI and an upregulation of CHOP and GRP78 expression beginning on day 1 PI was found. The data indicate that regular apoptosis is the major cause of MNU-induced PR cell death. However, alternative PCD pathways, including ER stress and calpain activation, are also involved. Knowledge about the mechanisms involved in this mouse model of PR degeneration could facilitate the design of putative combinatory therapeutic approaches.

Studies on synthesis and anticancer activity of selected N-(2-fluoroethyl)-N-nitrosoureas.

PubMed

Johnston, T P; Kussner, C L; Carter, R L; Frye, J L; Lomax, N R; Plowman, J; Narayanan, V L

1984-11-01

An activated carbamate, 2-nitrophenyl (2-fluoroethyl)nitrosocarbamate (3), was used to advantage in the synthesis of the water-soluble (2-fluoroethyl)nitrosoureas 6a--d from 2-aminoethanol, (1 alpha, 2 beta, 3 alpha)-2-amino-1,3-cyclohexanediol, cis-2-hydroxycyclohexanol, and 2-amino-2-deoxy-D-glucose. In a variation of this method, 2,4,5-trichlorophenyl (2-fluoroethyl)carbamate (4) was used to prepare the urea from which the essentially water-insoluble N-(2,6-dioxo-3-piperidinyl)-N-(2-fluoroethyl)-N-nitrosourea (6e) was derived. The anticancer activity of these nitrosoureas was determined against the murine tumors B16 melanoma and Lewis lung carcinoma and found to be significant and comparable to their chloroethyl counterparts. On the basis of results from both systems, the dihydroxycyclohexyl derivative 6b may be the most effective.

Pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes of rats with mammary gland cancer induced by N-methyl nitrosourea.

PubMed

Carrera, M P; Ramírez-Expósito, M J; Valenzuela, M T; García, M J; Mayas, M D; Arias de Saavedra, J M; Sánchez, R; Pérez, M C; Martínez-Martos, J M

2005-02-01

Pyrrolidon carboxypeptidase is an omega-peptidase that hydrolyses N-terminal pyroglutamyl residues from biologically active peptides such as gonadotropin-releasing and thyrotrophin-releasing hormones. We previously described a decrease in both rat and human pyrrolidon carboxypeptidase activity with breast cancer, suggesting that gonadotropin-releasing hormone may be an important local intracrine, autocrine and/or paracrine hormonal factor in the pathogenesis of breast cancer while playing a role in the tumoral process. However, the other susceptible substrate of pyrrolidon carboxypeptidase, thyrotrophin-releasing hormone, may also be modified with breast cancer, supporting an association between breast cancer and thyroid disorders. The present work analyses soluble and membrane-bound pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes in N-methyl nitrosourea-induced breast cancer in rats. Our aim was to determine the possible relationship between gonadotropin-releasing hormone and thyrotrophin-releasing hormone regulation through pyrrolidon carboxypeptidase activity. We propose that pyrrolidon carboxypeptidase activity dysregulation at various local and systemic levels may participate in the initiation, promotion and progression of breast cancer induced in rat by N-methyl nitrosourea through the increase in gonadotropin-releasing hormone. Since pyrrolidon carboxypeptidase activity also acts on thyrotrophin-releasing hormone, the dysregulation of this enzyme's activity could indirectly affect hypothalamus-pituitary-thyroid axis function, and thus potentially represent a link between the diseases of thyroid and breast cancer.

Preventive effect of Oenothera rosea on N-methyl-N-nitrosourea-(NMU) induced gastric cancer in rats.

PubMed

Almora-Pinedo, Yuan; Arroyo-Acevedo, Jorge; Herrera-Calderon, Oscar; Chumpitaz-Cerrate, Víctor; Hañari-Quispe, Renán; Tinco-Jayo, Aldo; Franco-Quino, Cesar; Figueroa-Salvador, Linder

2017-01-01

Currently, gastric cancer (GC) is considered a public health problem worldwide. Using medicinal plants for the prevention of chronic diseases such as cancer constitutes new alternatives in traditional medicine. Oenothera rosea (OR) could be an option, but it needs to be evaluated. The main objective of this study was to evaluate the protective effect of OR extract on N-methyl-N-nitrosourea (NMU)-induced GC in rats. In total, 80 male Holtzman rats were randomized into five groups. Group A received the saline solution (5mL/kg), group B received NMU 500 μg/kg (cancer inductor) by oral administration for 16 weeks, and groups C, D, and E were treated with OR extract (100, 200, and 300 mg/kg, respectively) and NMU in order to evaluate the preventive effect on cancer induced by NMU for 16 weeks. Blood and histological samples of stomachs were collected to determine histopathological, biochemical, and hematological parameters between different experimental groups. Groups C, D, and E presented less histopathological changes such as anaplastic and hyperplastic cells, compared with group B. Hematological and biochemical parameters were recorded, and superoxide dismutase, malondialdehyde, and nitric oxide levels were statistically less than those of NMU group ( P <0.05, P <0.01, and P <0.01). Considering the histopathological signs and the antioxidant activity in vivo as well as hematological and biochemical parameters of ethanolic extract of OR, we concluded that its administration in rats has a protective effect on GC, which is induced experimentally. This species could be studied in clinical trials for patients with GC in the future.

Analysis of the expression level and methylation of tumor protein p53, phosphatase and tensin homolog and mutS homolog 2 in N-methyl-N-nitrosourea-induced thymic lymphoma in C57BL/6 mice.

PubMed

Huo, Xueyun; Li, Zhenkun; Zhang, Shuangyue; Li, Changlong; Guo, Meng; Lu, Jing; Lv, Jianyi; Du, Xiaoyan; Chen, Zhenwen

2017-10-01

Tumorigenesis is often caused by somatic mutation or epigenetic changes in genes that regulate aspects of cell death, proliferation and survival. Although the functions of multiple tumor suppressor genes have been well studied in isolation, how these genes cooperate during the progression of a single tumor remains unclear in numerous cases. The present study used N-methyl-N-nitrosourea (MNU), one of the most potent mutagenic nitrosourea compounds, to induce thymic lymphoma in C57BL/6J mice. Subsequently, the protein expression levels of phosphatase and tensin homolog (PTEN), transformation protein 53 and mutS homolog 2 (MSH2) were evaluated concomitantly in the thymus, liver, kidney and spleen of MNU-treated mice by western blotting. To determine whether changes in expression level were due to aberrant epigenetic regulation, the present study further examined the methylation status of each gene by MassARRAY analysis. During the tumorigenesis process of an MNU-induced single thymic lymphoma, the expression level of PTEN was revealed to be reduced in thymic lymphoma samples but not in normal or non-tumor thymus tissue samples. Furthermore, a marked reduction of P53 expression levels were demonstrated in thymic lymphomas and spleens with a metastatic tumor. Conversely, MSH2 upregulation was identified only in liver, kidney, and spleen samples that were infiltrated by thymic lymphoma cells. Furthermore, the present study revealed that a number of 5'-C-phosphate-G-3' sites located in the promoter of aberrantly expressed genes had significantly altered methylation statuses. These results improve the understanding of the course of mutagen-induced cancer, and highlight that epigenetic regulation may serve an important function in cancer.

Evaluation of the immunological cellular response of Cebus apella exposed to the carcinogen N-methyl-N-nitrosourea and treated with CANOVA®.

PubMed

Feio, Danielle Cristinne Azevedo; Muniz, José Augusto Pereira Carneiro; Montenegro, Raquel Carvalho; Burbano, Rommel Rodriguez; De Brito Junior, Lacy Cardoso; De Lima, Patrícia Danielle Lima

2014-01-01

The immune response modifier Canova® is a homeopathic remedy indicated for patients with depressed immune system, since this drug appears to increase adaptive immunity and induce an immune response against multiple and severe pathological conditions, including cancer. We evaluated the pattern of immune cellular response in non-human primates of the species Cebus apella exposed to N-methyl-N-nitrosourea (MNU) with and without Canova®. Twelve animals were divided into four groups, with three animals each: negative control and three experimental groups, MNU-alone (35 days); MNU (35 days)-plus-Canova® (3 days) and Canova®-alone (3 days). The animals received MNU orally and Canova® by three intravenous injections. Evaluation of the cellular immune response was performed by immunophenotyping of T-lymphocytes (CD4(+), CD8(+)), B-lymphocytes and natural killer cells. Analysis was also performed of the cell cycle. Our results suggest an increase of T-lymphocytes (CD4(+)CD3(+)) only in the Canova® group, while in the MNU-plus-Canova® group only B-lymphocytes increased. Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Preventive effect of Oenothera rosea on N-methyl-N-nitrosourea-(NMU) induced gastric cancer in rats

PubMed Central

Almora-Pinedo, Yuan; Arroyo-Acevedo, Jorge; Herrera-Calderon, Oscar; Chumpitaz-Cerrate, Víctor; Hañari-Quispe, Renán; Tinco-Jayo, Aldo; Franco-Quino, Cesar; Figueroa-Salvador, Linder

2017-01-01

Background Currently, gastric cancer (GC) is considered a public health problem worldwide. Using medicinal plants for the prevention of chronic diseases such as cancer constitutes new alternatives in traditional medicine. Oenothera rosea (OR) could be an option, but it needs to be evaluated. Aim The main objective of this study was to evaluate the protective effect of OR extract on N-methyl-N-nitrosourea (NMU)-induced GC in rats. Methods In total, 80 male Holtzman rats were randomized into five groups. Group A received the saline solution (5mL/kg), group B received NMU 500 μg/kg (cancer inductor) by oral administration for 16 weeks, and groups C, D, and E were treated with OR extract (100, 200, and 300 mg/kg, respectively) and NMU in order to evaluate the preventive effect on cancer induced by NMU for 16 weeks. Blood and histological samples of stomachs were collected to determine histopathological, biochemical, and hematological parameters between different experimental groups. Results Groups C, D, and E presented less histopathological changes such as anaplastic and hyperplastic cells, compared with group B. Hematological and biochemical parameters were recorded, and superoxide dismutase, malondialdehyde, and nitric oxide levels were statistically less than those of NMU group (P<0.05, P<0.01, and P<0.01). Conclusion Considering the histopathological signs and the antioxidant activity in vivo as well as hematological and biochemical parameters of ethanolic extract of OR, we concluded that its administration in rats has a protective effect on GC, which is induced experimentally. This species could be studied in clinical trials for patients with GC in the future. PMID:29270029

Nitrosamine-induced carcinogenesis. The alkylation of N-7 of guanine of nucleic acids of the rat by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate

PubMed Central

Swann, P. F.; Magee, P. N.

1971-01-01

1. The extent of ethylation of N-7 of guanine in the nucleic acids of rat tissue in vivo by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate was measured. 2. All compounds produced measurable amounts of 7-ethyl-guanine. 3. A single dose of diethylnitrosamine or N-ethyl-N-nitrosourea produced tumours of the kidney in the rat. Three doses of ethyl methanesulphonate produced kidney tumours, but a single dose did not. 4. A single dose of diethylnitrosamine produced twice as much ethylation of N-7 of guanine in DNA of kidney as did N-ethyl-N-nitrosourea. A single dose of both compounds induced kidney tumours, although of a different histological type. 5. A single dose of ethyl methanesulphonate produced ten times as much ethylation of N-7 of guanine in kidney DNA as did N-ethyl-N-nitrosourea without producing tumours. 6. The relevance of these findings to the hypothesis that alkylation of a cellular component is the mechanism of induction of tumours by nitroso compounds is discussed. PMID:5145908

Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats.

PubMed

McCormick, D L; Rao, K V; Dooley, L; Steele, V E; Lubet, R A; Kelloff, G J; Bosland, M C

1998-08-01

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar

Experimental induction of ovarian Sertoli cell tumors in rats by N-nitrosoureas.

PubMed Central

Maekawa, A; Onodera, H; Tanigawa, H; Furuta, K; Kanno, J; Ogiu, T; Hayashi, Y

1987-01-01

Spontaneous ovarian tumors are very rare in ACI, Wistar, F344 and Donryu rats; the few neoplasms found are of the granulosa/theca cell type. Ovarian tumors were also rare in these strains of rats when given high doses of N-alkyl-N-nitrosoureas continuously in the drinking water for their life-span; however, relatively high incidences of Sertoli cell tumors or Sertoli cell tumors mixed with granulosa cell tumors were induced in Donryu rats after administration of either a 400 ppm N-ethyl-N-nitrosourea solution in the drinking water for 4 weeks or as a single dose of 200 mg N-propyl-N-nitrosourea per kg body weight by stomach tube. Typical Sertoli cell tumors consisted of solid areas showing tubular formation. The tubules were lined by tall, columnar cells, with abundant, faintly eosinophilic, often vacuolated cytoplasm, and basally oriented, round nuclei, resembling seminiferous tubules in the testes. In some cases, Sertoli cell tumor elements were found mixed with areas of granulosa cells. The induction of ovarian Sertoli cell tumors in Donryu rats by low doses of nitrosoureas may provide a useful model for these tumors in man. Images PLATE 1. PLATE 2. PLATE 3. PLATE 4. PLATE 5. PLATE 6. PLATE 7. PLATE 8. PLATE 9. PLATE 10. PLATE 11. PLATE 12. PLATE 13. PLATE 14. PLATE 15. PLATE 16. PMID:3665856

Organ differences in the impact of p27(kip1) deficiency on carcinogenesis induced by N-methyl-N-nitrosourea.

PubMed

Ogawa, Kumiko; Murasaki, Toshiya; Sugiura, Satoshi; Nakanishi, Makoto; Shirai, Tomoyuki

2013-06-01

To evaluate the impact of p27 on carcinogenesis in various organs, N-methyl-N-nitrosourea (MNU), a direct-acting alkylating agent, was given to p27 knock-out mice. Groups of 20-40 male and female mice with null, hetero- or wild-type p27 alleles were given drinking water containing 240 ppm MNU or distilled water every other week for five cycles. The incidence and multiplicity of the induced proliferative lesions were then histologically evaluated at weeks 14 and 20. MNU treatment induced various lesions including squamous hyperplasia and squamous cell carcinoma in the forestomach, atypical hyperplasia and adenocarcinomas in the fundic and pyloric glands, adenomas and adenocarcinomas in the duodenum, malignant lymphomas in the thymus, liver, kidney and spleen and alveolar hyperplasia, adenomas, adenocarcinomas and malignant lymphomas in the lung. Although the incidences of the lesions in the forestomach, fundic and pyloric glands did not differ among the p27 genotypes, those of alveolar hyperplasia of the lung and malignant lymphoma of the thymus were significantly increased in p27-null males as compared with both wild- and hetero-type animals. Moreover, in both p27(+/+) and p27(+/-) cases, the rates for p27-positive cells were obviously increased in proliferative lesions of the pyloric gland and the lung. However, an increased rate of p27-positive cells was not observed in malignant lymphoma of the thymus. These findings suggest that p27 does not control the cell cycle equally in all organs affected by MNU-induced carcinogenesis. Copyright © 2011 John Wiley & Sons, Ltd.

The neurotoxic effects of N-methyl-N-nitrosourea on the electrophysiological property and visual signal transmission of rat's retina.

PubMed

Tao, Ye; Chen, Tao; Liu, Bei; Yang, Guo Qing; Peng, Guanghua; Zhang, Hua; Huang, Yi Fei

2015-07-01

The neurotoxic effects of N-methyl-N-nitrosourea (MNU) on the inner retinal neurons and related visual signal circuits have not been described in any animal models or human, despite ample morphological evidences about the MNU induced photoreceptor (PR) degeneration. With the helping of MEA (multielectrode array) recording system, we gained the opportunity to systemically explore the neural activities and visual signal pathways of MNU administrated rats. Our MEA research identified remarkable alterations in the electrophysiological properties and firstly provided instructive information about the neurotoxicity of MNU that affects the signal transmission in the inner retina. Moreover, the spatial electrophysiological functions of retina were monitored and found that the focal PRs had different vulnerabilities to the MNU. The MNU-induced PR dysfunction exhibited a distinct spatial- and time-dependent progression. In contrast, the spiking activities of both central and peripheral RGCs altered synchronously in response to the MNU administration. Pharmacological tests suggested that gap junctions played a pivotal role in this homogeneous response of RGCs. SNR analysis of MNU treated retina suggested that the signaling efficiency and fidelity of inner retinal circuits have been ruined by this toxicant, although the microstructure of the inner retina seemed relatively consolidated. The present study provided an appropriate example of MEA investigations on the toxicant induced pathological models and the effects of the pharmacological compounds on neuron activities. The positional MEA information would enrich our knowledge about the pathology of MNU induced RP models, and eventually be instrumental for elucidating the underlying mechanism of human RP. Copyright © 2015 Elsevier Inc. All rights reserved.

Spectroscopic investigation (FT-IR, FT-Raman), HOMO-LUMO, NBO, and molecular docking analysis of N-ethyl-N-nitrosourea, a potential anticancer agent

NASA Astrophysics Data System (ADS)

Singh, Priyanka; Islam, S. S.; Ahmad, Hilal; Prabaharan, A.

2018-02-01

Nitrosourea plays an important role in the treatment of cancer. N-ethyl-N-nitrosourea, also known as ENU, (chemical formula C3H7N3O2), is a highly potent mutagen. The chemical is an alkylating agent and acts by transferring the ethyl group of ENU to nucleobases (usually thymine) in nucleic acids. The molecular structure of N-ethyl-N-nitrosourea has been elucidated using experimental (FT-IR and FT-Raman) and theoretical (DFT) techniques. APT charges, Mulliken atomic charges, Natural bond orbital, Electrostatic potential, HOMO-LUMO and AIM analysis were performed to identify the reactive sites and charge transfer interactions. Furthermore, to evaluate the anticancer activity of ENU molecular docking studies were carried out against 2JIU protein.

Mutagenic synergism detected between dimethyl sulfate and X-rays but not found between N-methyl-N-nitrosourea and X-rays in the stamen hairs of Tradescantia clone BNL 4430.

PubMed

Shima, N; Ichikawa, S

1995-09-01

Mutagenic interactions with X-rays of two monofunctional alkylating agents, dimethyl sulfate (DMS) and N-methyl-N-nitrosourea (MNU), were studied in the stamen hairs of Tradescantia clone BNL 4430, a blue/pink heterozygote. The young inflorescence-bearing shoots with roots cultivated in the nutrient solution circulating growth chamber were used as tester plants. Synergism between two different mutagens was judged to have occurred when the mutation frequency observed after applying the two mutagens concurrently was statistically significantly higher than the mutation frequency expected from the additive effects of the two mutagens. Clear synergistic effects in inducing somatic pink mutations were detected with all combinations of doses of DMS and X-rays examined, even in a relatively low X-ray dose range (down to 299 mGy), resembling those confirmed earlier between ethyl methanesulfonate (EMS) and X-rays, but somewhat differing from the synergisms observed earlier between methyl methanesulfonate (MMS) and X-rays. On the other hand, no mutagenic synergism was detected between MNU and X-rays, even in a relatively high X-ray dose range (up to 862 mGy). The presence or absence of mutagenic synergisms of these alkylating agents with X-rays could be related to the action mechanism of each alkylating agent.

Enhancement by O6-benzyl-N2-acetylguanosine of N'-[2-chloroethyl]-N-[2-(methylsulphonyl)ethyl]-N'-nitrosourea therapeutic index on nude mice bearing resistant human melanoma.

PubMed Central

Debiton, E.; Cussac-Buchdhal, C.; Mounetou, E.; Rapp, M.; Dupuy, J. M.; Maurizis, J. C.; Veyre, A.; Madelmont, J. C.

1997-01-01

The exposure of cells to O6-benzyl-N2-acetylguanosine (BNAG) and several guanine derivatives is known to reduce the activity of O6-alkylguanine-DNA alkyltransferase (MGMT) and to enhance the sensitivity of Mer+ (methyl enzyme repair positive) tumour cells to chloroethylnitrosoureas (CENUs) in vitro and in vivo. High water solubility and the pharmacokinetic properties of BNAG make it a candidate for simultaneous administration with CENUs by the i.v. route in human clinical use. In vivo we have shown previously that BNAG significantly increases the efficiency of N'-[2-chloroethyl]-N-[2-(methylsulphonyl)ethyl]-N'-nitrosourea (cystemustine) against M4Beu melanoma cells (Mer+) through its cytostatic activity by the i.p. route, but also increases its toxicity. To investigate the toxicity of BNAG and cystemustine when administered simultaneously in mice, we compared the maximum tolerated dose and LD50 doses of cystemustine alone or in combination with 40 mg kg(-1) BNAG by the i.p. route. The toxicity of cystemustine was enhanced by a factor of almost 1.44 when combined with BNAG. To compare the therapeutic index of cystemustine alone and the cystemustine/BNAG combination, pharmacological tests were carried out in nude mice bearing Mer+ M4Beu human melanoma cells. Isotoxic doses were calculated using the 1.44 ratio. The treatments were administered three times by the i.v. route on days 1, 5 and 9 after s.c. inoculation of tumour cells. Although the toxicities of the treatments were equal, BNAG strongly enhanced tumour growth inhibition. These results demonstrate the increase of the therapeutic index of cystemustine by BNAG and justify the use of BNAG to enhance nitrosourea efficiency in vivo by i.v. co-injection. PMID:9365163

Cyanidin-3-glucoside extracted from mulberry fruit can reduce N-methyl-N-nitrosourea-induced retinal degeneration in rats.

PubMed

Lee, Seung Hee; Jeong, Eojin; Paik, Sun-Sook; Jeon, Ji Hyun; Jung, Sung Won; Kim, Hyun-Bok; Kim, Muyan; Chun, Myung-Hoon; Kim, In-Beom

2014-01-01

To investigate the effect of cyanidin-3-O-glucoside (C3G) on a rat retinal degeneration (RD) model. Experimental RD was induced in rats by the intraperitoneal injection of N-methyl-N-nitrosourea (MNU) at 50 mg/kg. C3G extracted from mulberry (Morus alba L.) fruit (50 mg/kg) was orally administered, daily for 1, 2 and 4 weeks after MNU injection. The effects of C3G administration on MNU-induced RD retinas were histologically and functionally assessed by hematoxylin and eosin staining and electroretinography (ERG), respectively. The degree of retinal injury in C3G-administered RD rats was evaluated by immunohistochemistry with an antibody against glial fibrillary acidic protein (GFAP). The preferential protective effect of C3G on scotopic vision was examined by western blot analysis. Marked loss of photoreceptors in the outer nuclear layer (ONL) was observed in RD rats at 2 and 4 weeks after MNU injection, while the ONL in the MNU-induced RD rats given C3G was relatively well preserved. Immunohistochemistry with anti-GFAP showed that retinal injury was also reduced in the retinas of the rats given C3G. Functional assessment by using ERG recordings showed that scotopic ERG responses were significantly increased in RD rats given C3G for 4 weeks (p < 0.01) compared with that of untreated RD rats. In the RD rats given short-term C3G (for 1 and 2 weeks), the increase in ERG responses was not significant. In addition, western blot analysis showed that rhodopsin level in the C3G-administered RD retinas significantly increased compared to that in the non-administered RD retinas (p < 0.05), whereas red/green opsin level did not show any significant difference. Long-term administration of C3G extracted from mulberry fruit could structurally reduce photoreceptor damage and functionally improve scotopic visual functions in the RD rat model induced by MNU.

Ex vivo culture of tumor cells from N-methyl-N-nitrosourea-induced bladder cancer in rats: Development of organoids and an immortalized cell line.

PubMed

Yoshida, Takahiro; Kates, Max; Sopko, Nikolai A; Liu, Xiaopu; Singh, Alok K; Bishai, William R; Joice, Gregory; McConkey, David J; Bivalacqua, Trinity J

2018-04-01

We ex vivo cultured primary tumor cells from N-methyl-N-nitrosourea (MNU)-induced bladder tumors in rats and established an immortalized cell line from them. Bladder tumors in rats were induced by instillation of MNU into the murine bladder. Primary tumor cells were prepared by the cancer-tissue originated spheroid method. An immortalized cell line was established by co-culture with fibroblasts. The cultured tumor cells were molecularly and functionally characterized by quantitative real-time polymerase chain reaction, Western blot, growth assay, and transwell migration assay. Primary tumor cells were successfully prepared as multicellular spheroids from MNU-induced bladder tumors. The differentiation marker expression patterns observed in the original tumors were largely retained in the spheroids. We succeeded in establishing a cell line from the spheroids and named it T-MNU-1. Although basal markers (CK14 and CK5) were enriched in T-MNU-1 compared to the spheroids, T-MNU-1 expressed both luminal and basal markers. T-MNU-1 was able to migrate through a transwell. Tumor cells in MNU-induced bladder tumors were successfully cultured ex vivo as organoids, and an immortalized cell line was also established from them. The ex vivo models offer a platform that enables analysis of intrinsic characteristics of tumor cells excluding influence of microenvironment in MNU-induced bladder tumors. Copyright © 2017 Elsevier Inc. All rights reserved.

Protective effect of zinc on N-methyl-N-nitrosourea and testosterone-induced prostatic intraepithelial neoplasia in the dorsolateral prostate of Sprague Dawley rats.

PubMed

Banudevi, Sivanantham; Elumalai, Perumal; Sharmila, Govindaraj; Arunkumar, Ramachandran; Senthilkumar, Kalimuthu; Arunakaran, Jagadeesan

2011-09-01

Previous studies have suggested that zinc exerts anticarcinogenic and antiproliferative effects against prostate cancer both in vitro and in rat ventral prostate. Zinc accumulation diminishes early in the course of prostate malignancy and it inhibits the growth of several carcinoma cells through induction of cell cycle arrest and apoptosis. In this study, we have investigated the influence of zinc on N-methyl-N-nitrosourea (MNU) and testosterone (T)-induced prostatic intraepithelial neoplasia in the dorsolateral prostate of Sprague Dawley (SD) rats. The results indicate that zinc plays an important role in prostate carcinogenesis. Increased tumor incidence was accompanied by a decrease in prostatic acid phosphatase activity, citrate, zinc, glutathione-S-transferase, reduced glutathione, p53, B-cell lymphoma protein (Bcl-2)-associated X protein and caspase-3 levels in MNU + T-treated rats. On the contrary, significantly increased phase I drug metabolizing enzyme activities, lipid peroxide, hydrogen peroxide, proliferating cell nuclear antigen, Bcl-2 and Bcl-X(L) protein levels were observed in the dorsolateral prostate of MNU + T-treated rats. Simultaneous zinc supplementation significantly reversed these effects in MNU + T-treated rats. Signs of dysplasia, a characteristic of prostatic intraepithelial neoplasia, were evident in the dorsolateral prostatic tissue sections by MNU + T administration. However, zinc supplementation has reversed these effects in the dorsolateral prostatic histoarchitecture. These results suggest that zinc may act as an essential trace element against MNU and testosterone-induced prostatic preneoplastic progression in SD rats.

The neurotoxic effects of N-methyl-N-nitrosourea on the electrophysiological property and visual signal transmission of rat's retina

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tao, Ye; Chen, Tao; Liu, Bei

The neurotoxic effects of N-methyl-N-nitrosourea (MNU) on the inner retinal neurons and related visual signal circuits have not been described in any animal models or human, despite ample morphological evidences about the MNU induced photoreceptor (PR) degeneration. With the helping of MEA (multielectrode array) recording system, we gained the opportunity to systemically explore the neural activities and visual signal pathways of MNU administrated rats. Our MEA research identified remarkable alterations in the electrophysiological properties and firstly provided instructive information about the neurotoxicity of MNU that affects the signal transmission in the inner retina. Moreover, the spatial electrophysiological functions of retinamore » were monitored and found that the focal PRs had different vulnerabilities to the MNU. The MNU-induced PR dysfunction exhibited a distinct spatial- and time-dependent progression. In contrast, the spiking activities of both central and peripheral RGCs altered synchronously in response to the MNU administration. Pharmacological tests suggested that gap junctions played a pivotal role in this homogeneous response of RGCs. SNR analysis of MNU treated retina suggested that the signaling efficiency and fidelity of inner retinal circuits have been ruined by this toxicant, although the microstructure of the inner retina seemed relatively consolidated. The present study provided an appropriate example of MEA investigations on the toxicant induced pathological models and the effects of the pharmacological compounds on neuron activities. The positional MEA information would enrich our knowledge about the pathology of MNU induced RP models, and eventually be instrumental for elucidating the underlying mechanism of human RP. - Highlights: • We systemically explored the neural activities and visual signal pathways of MNU administrated retinas. • The focal photoreceptors had different vulnerabilities to the MNU administration. �

[Synthesis of new nitrosoureas].

PubMed

Papadaki-Valiraki, A; Siatra-Papastaikoudi, T; Skaltsounis, A L; Roussakis, C

1989-01-01

Two chemical pathways were used for the synthesis of three new N'-(2-chloroethyl)-N-[2-(4-alkoxyphenylthio)ethyl]-N'-nitrosoureas and two new N'-(2-chloroethyl)-N)[2-(4-alkoxyphenyl-thio)ethyl]-N-nitrosoureas . The study of the cytotoxicity of the three N'-nitrosoureas, was carried out in two experimental models (P 388 and NSCLCN6).

The carcinogenicity of 1-methyl-3(p-bromophenyl)-1-nitrosourea (Br-MPNU).

PubMed

Warzok, R; Martin, J; Mendel, J; Thust, R; Schwarz, H

1983-01-01

In long-term experiments with Hooded rats the carcinogenic potential of 1-methyl-3(p-bromophenyl)-1-nitrosourea (Br-MPNU) could be demonstrated for the first time. Br-MPNU is formed also endogenously after combined administration of 1-methyl-3(p-bromophenyl)-urea (Br-MPU) and sodium nitrite. After repeated intragastric administration of 0.33 mmol Br-MPU and 0.73 mmol NaNO2 per kg b.w. papillomas and carcinomas of the forestomach developed in 83%. After repeated administration of 0.28 mmol Br-MPNU per kg b.w. these neoplasms were observed in 88%. The comparison of results obtained in similar experiments with 1-methyl-3-phenyl-1-nitrosourea shows that bromine substitution led to a reduction of the carcinogenic activity. The present paper is part of a complex program studying the interrelationships between structure, physico-chemical properties, mutagenicity and carcinogenicity of nitrosoureas.

Interrelationships among angiogenesis, proliferation, and apoptosis in the tumor microenvironment during N-methyl-N-nitrosourea androgen-induced prostate carcinogenesis in rats.

PubMed

Liao, Zhiming; Boileau, Thomas W-M; Erdman, John W; Clinton, Steven K

2002-10-01

Proliferation, apoptosis and angiogenesis are critical biologic processes altered during carcinogenesis. Surrogate biomarkers of these processes represent potential intermediate endpoints for short-term intervention studies with preventive and therapeutic agents. We examined the interrelationships among these processes during prostate carcinogenesis induced by N-methyl-N-nitrosourea (MNU) in male Wistar-Unilever rats. Immunohistochemical and digital image analysis techniques were used to evaluate the proliferation index, the apoptotic index and microvessel density (MVD) in tissue representing stages of prostate carcinogenesis. The proliferation index in the normal glandular epithelium of the prostate is lower than that observed in hyperplastic foci and atypical hyperplasia (P < 0.01) and is further increased in carcinoma (P < 0.01). Apoptosis in the normal prostate epithelium or hyperplastic lesions is lower than in adenocarcinoma (P < 0.01). In parallel to proliferation index, MVD increases as prostate cancer progresses. As tumors enlarge, we observed a predictable change in biomarker expression within the tumor microenvironment. We examined prostate tumors vertical line 1 cm in diameter and biomarker expression was quantified within the peripheral (outer 1-2 mm), central (perinecrotic) and intermediate (remaining) areas of each tumor. The proliferation index is higher (P < 0.01) in the intermediate area than either in the peripheral area or central area. Similarly, the vascular density in the intermediate area is higher (P < 0.01) than either in the peripheral or central area. The apoptotic index is higher (P < 0.05) in the central perinecrotic core than that in either the intermediate or the peripheral area. In conclusion, we observe that angiogenesis, proliferation and apoptosis are linked biological processes predictably altered temporally and spatially during prostate carcinogenesis in the MNU model. These biomarker changes are similar to those reported in

Cytostatic action of two nitrosoureas derived from cysteamine.

PubMed Central

Bourut, C.; Chenu, E.; Godenèche, D.; Madelmont, J. C.; Maral, R.; Mathé, G.; Meyniel, G.

1986-01-01

2-Chloroethyl nitrosocarbamoylcystamine or ICIG-1325 (CNCC) is a lipid-soluble isomeric mixture of nitrosoureas. Its dose-effect relationship on L1210 leukaemia is characterized by a large maximally efficient dose-range (MEDR), greater than that of other nitrosoureas. CNCC also demonstrated significant therapeutic activity on intracerebrally (i.c.) transplanted L1210 leukaemia and on six transplanted solid tumours, TM2 mammary carcinoma, M555 ovarian carcinoma, B16 melanoma, glioma 26, 3LL, Lewis lung carcinoma and colon 26 carcinoma. It was inactive on fibrosarcoma ICIG-Ci4. Its antitumour activity spectrum is wider than that of the related compounds 2-[3-(2-chloroethyl) 3-nitrosoureido]D-glucopyranose (CZT), (chloro-2-ethyl)-1(ribofuranosyl-isopropylidene-2'-3' paranitrobenzoate-5')-3 nitrosourea (RFCNU), and (chloro-2-ethyl)-1 (ribopyranosyl triacetate-2'-3'-4')-3 nitrosourea (RPCNU). A study of its metabolic disposition in animals has shown that CNCC undergoes extensive first-pass metabolism leading to the formation of four main plasma metabolites. These metabolites are water-soluble nitrosoureas that arose from the bioreduction of the disulphide bridge followed by the methylation and the oxidation of the thiol groups. Experimental screening was performed with these chemically synthesized metabolites. Both N'-(2-chloroethyl)-N-[2-(methylsulphinyl)ethyl]-N'-nitrosourea (CMSOEN2) and N'-(2-chloroethyl)-N-[2-(methylsulphonyl)ethyl]-N'-nitrosourea (CMSO2EN2) are very active on L1210 leukaemia grafted intraperitoneally (i.p.) and i.c., L40 leukaemia, B16 melanoma, glioma 26 and Lewis lung carcinoma. Their effectiveness is better than that of the parent compound CNCC. In addition,the percentage of mice cured after CMSOEN2 or CMSO2EN2 treatment is increased especially on B16 melanoma and glioma 26.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3801787

The Use of Maleic Hydrazide for Effective Hybridization of Setaria viridis

PubMed Central

Rizal, Govinda; Karki, Shanta; Garcia, Richard; Larazo, Nikki; Alcasid, Michael; Quick, William Paul

2015-01-01

An efficient method for crossing green foxtail (Setaria viridis) is currently lacking. S. viridis is considered to be the new model plant for the study of C4 system in monocots and so an effective crossing protocol is urgently needed. S. viridis is a small grass with C4-NADP (ME) type of photosynthesis and has the advantage of having small genome of about 515 Mb, small plant stature, short life cycle, multiple tillers, and profuse seed set, and hence is an ideal model species for research. The objectives of this project were to develop efficient methods of emasculation and pollination, and to speed up generation advancement. We assessed the response of S. viridis flowers to hot water treatment (48°C) and to different concentrations of gibberellic acid, abscisic acid, maleic hydrazide (MH), and kinetin. We found that 500 μM of MH was effective in the emasculation of S. viridis, whilst still retaining the receptivity of the stigma to pollination. We also report effective ways to accelerate the breeding cycle of S. viridis for research through the germination of mature as well as immature seeds in optimized culture media. We believe these findings will be of great interest to researchers using Setaria. PMID:25910193

Carcinogenicity of 1-methyl-3(p-chlorophenyl)-1-nitrosourea and its 1-methyl trideuterated derivative in rats.

PubMed

Schreiber, D; Martin, J; Mendel, J

1986-01-01

The carcinogenic activity of 1-methyl-3(p-chlorophenyl)-1-nitrosourea (Cl-MPNU) and its 1-methyl trideuterated analog (Cl-MPNU-d3) was compared by intragastric administration to hooded rats of equimolar doses of both compounds. A 100% frequency of forestomach tumors was observed in both groups. However, the mean latency period of the animals treated with Cl-MPNU-d3 was significantly longer (P less than 0.01). The results suggest the occurrence of a deuterium isotope effect in nitrosoureas but not as distinct as in nitrosamines.

Chemoselective room temperature E1cB N-N cleavage of oxazolidinone hydrazides from enantioselective aldehyde α-hydrazination: synthesis of (+)-1,4-dideoxyallonojirimycin.

PubMed

Ferreira, Jasmin; Rees-Jones, Sophie C M; Ramaotsoa, Valerie; Msutu, Ath'enkosi; Hunter, Roger

2016-02-07

Room temperature E1cB N-N cleavage of oxazolidinone hydrazides via N-alkylation with diethyl bromomalonate and potassium or caesium carbonate as base in acetonitrile is presented. The new method has a much improved chemoselectivity, which is illustrated by a concise total synthesis of the piperidine iminosugar (+)-1,4-dideoxyallonojirimycin.

Highly Efficient Release of Glycopeptides from Hydrazide Beads by Hydroxylamine Assisted PNGase F Deglycosylation for N-Glycoproteome Analysis.

PubMed

Huang, Junfeng; Wan, Hao; Yao, Yating; Li, Jinan; Cheng, Kai; Mao, Jiawei; Chen, Jin; Wang, Yan; Qin, Hongqiang; Zhang, Weibing; Ye, Mingliang; Zou, Hanfa

2015-10-20

Selective enrichment of glycopeptides from complex sample followed by cleavage of N-glycans by PNGase F to expose an easily detectable mark on the former glycosylation sites has become the popular protocol for comprehensive glycoproteome analysis. On account of the high enrichment specificity, hydrazide chemistry based solid-phase extraction of N-linked glycopeptides technique has sparked numerous interests. However, the enzymatic release of glycopeptides captured by hydrazide beads through direct incubation of the beads with PNGase F is not efficient due to the inherent steric hindrance effect. In this study, we developed a hydroxylamine assisted PNGase F deglycosylation (HAPD) method using the hydroxylamine to release glycopeptides captured on the hydrazide beads through the cleavage of hydrazone bonds by transamination followed with the PNGase F deglycosylation of the released glycopeptides in the free solution. Because of the homogeneous condition for the deglycosylation, the recovery of deglycosylated peptides (deglycopeptides) was improved significantly. It was found that 27% more N-glycosylation sites were identified by the HAPD strategy compared with the conventional method. Moreover, the ratio of identified N-terminal glycosylated peptides was improved over 5-fold.

Synthesis of hydrazide-functionalized hydrophilic polymer hybrid graphene oxide for highly efficient N-glycopeptide enrichment and identification by mass spectrometry.

PubMed

Bai, Haihong; Pan, Yiting; Guo, Cong; Zhao, Xinyuan; Shen, Bingquan; Wang, Xinghe; Liu, Zeyuan; Cheng, Yuanguo; Qin, Weijie; Qian, Xiaohong

2017-08-15

Protein N-glycosylation is one of the most important post-translational modifications, participating in many key biological and pathological processes. Large-scale and precise identification of N-glycosylated proteins and peptides is especially beneficial for understanding their biological functions and for discovery of new clinical biomarkers and therapeutic drug targets. However, protein N-glycosylation is microheterogeneous and low abundant in living organisms, therefore specific enrichment of N-glycosylated proteins/peptides before mass spectrometry analysis is a prerequisite. In this work, we developed a new type of polymer hybrid graphene oxide (GO) by in situ growth of hydrazide-functionalized hydrophilic polymer chains on the GO surface (GO-PAAH) for selective N-glycopeptide enrichment and identification by mass spectrometry. The densely attached and low steric hindrance hydrazide groups as well as the highly hydrophilic nature of GO-PAAH facilitate N-glycopeptide enrichment by the combination of hydrazide capturing and HILIC interaction. Taking advantage of the unique features of GO-PAAH, all of the three N-glycopeptides of bovine fetuin were successfully enriched and identified with significantly enhanced signal intensities from a digest mixture of bovine fetuin and bovine serum albumin at a mass ratio of 1:100, demonstrating the excellent enrichment selectivity of GO-PAAH. Furthermore, a total of 507 N-glycosylation sites and 480 N-glycopeptides in 232 N-glycoproteins were enriched and identified from 10μL of human serum by three replicates using this novel enrichment material, which is nearly two times higher than the commercial hydrazide resin based method (280 N-glycosylation sites, 261 N-glycopeptides and 144 N-glycoproteins in three experiments). Among the identified, 95 N-glycosylation sites were not reported in the Uniprot database, and 106 N-glycoproteins were disease related in the Nextprot database, indicating the potential of this new

Generation of N-Heterocycles via Tandem Reactions of N '-(2-Alkynylbenzylidene)hydrazides.

PubMed

Qiu, Guanyinsheng; Wu, Jie

2016-02-01

As a powerful synthon, N '-(2-alkynylbenzylidene)hydrazides have been utilized efficiently for the construction of N-heterocycles. Since N '-(2-alkynylbenzylidene)hydrazides can easily undergo intramolecular 6-endo cyclization promoted by silver triflate or electrophiles, the resulting isoquinolinium-2-yl amides can proceed through subsequent transformations including [3 + 2] cycloaddition, nucleophilic addition, and [3 + 3] cycloaddition. Several unexpected rearrangements via radical processes were observed in some cases, which afforded nitrogen-containing heterocycles with molecular complexity. Reactive partners including internal alkynes, arynes, ketenimines, ketenes, allenoates, and activated alkenes reacted through [3 + 2] cycloaddition and subsequent aromatization, leading to diverse H-pyrazolo[5,1-a]isoquinolines with high efficiency. Nucleophilic addition to the in situ generated isoquinolinium-2-yl amide followed by aromatization also produced H-pyrazolo[5,1-a]isoquinoline derivatives when terminal alkynes, carbonyls, enamines, and activated methylene compounds were used as nucleophiles. Isoquinoline derivatives were obtained when indoles or phosphites were employed as nucleophiles in the reactions of N '-(2-alkynylbenzylidene)hydrazides. A tandem 6-endo cyclization and [3 + 3] cycloaddition of cyclopropane-1,1-dicarboxylates with N '-(2-alkynylbenzylidene)hydrazides was observed as well. Small libraries of these compounds were constructed. Biological evaluation suggested that some compounds showed promising activities for inhibition of CDC25B, TC-PTP, HCT-116, and PTP1B. © 2015 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Increased phospho-AKT is associated with loss of the androgen receptor during the progression of N-methyl-N-nitrosourea-induced prostate carcinogenesis in rats.

PubMed

Liao, Zhiming; Wang, Shihua; Boileau, Thomas W-M; Erdman, John W; Clinton, Steven K

2005-07-01

Characterization of molecular events during N-methyl-N-nitrosourea (MNU)-induced rat prostate carcinogenesis enhances the utility of this model for the preclinical assessment of preventive strategies. Androgen independence is typical of advanced human prostate cancer and may occur through multiple mechanisms including the loss of androgen receptor (AR) expression and the activation of alternative signaling pathways. We examined the interrelationships between AR and p-AKT expression by immunohistochemical staining during MNU-androgen-induced prostate carcinogenesis in male Wistar-Unilever rats. Histone nuclear staining and image analysis was employed to assess parallel changes in chromatin and nuclear structure. The percentage of AR positive nuclei decreased (P < 0.01) as carcinogenesis progressed: hyperplasia (92%), atypical hyperplasia (92%), well-differentiated adenocarcinoma (57%), moderately-differentiated adenocarcinoma (19%), and poorly-differentiated adenocarcinoma (10%). Conversely, p-AKT staining increased significantly during carcinogenesis. Sparse staining was observed in normal tissues (0.2% of epithelial area) and hyperplastic lesions (0.1%), while expression increased significantly (P < 0.001) in atypical hyperplasia (7.6%), well-differentiated adenocarcinoma (16.7%), moderately-differentiated adenocarcinoma (19.6%), and poorly-differentiated adenocarcinoma (17.4%). In parallel, nuclear morphometry revealed increased nuclear size, greater irregularity, and lower DNA compactness as cancers became more poorly differentiated. In the MNU model, the progressive evolution of dominant tumor cell populations showing an increase in p-AKT in parallel with a decline in AR staining suggests that activation of AKT signaling may be one of several mechanisms contributing to androgen insensitivity during prostate cancer progression. Our observations mimic findings suggested by human studies and support the relevance of the MNU model in preclinical studies of

Optimal dose selection of N-methyl-N-nitrosourea for the rat comet assay to evaluate DNA damage in organs with different susceptibility to cytotoxicity.

PubMed

Kitamoto, Sachiko; Matsuyama, Ryoko; Uematsu, Yasuaki; Ogata, Keiko; Ota, Mika; Yamada, Toru; Miyata, Kaori; Funabashi, Hitoshi; Saito, Koichi

2015-07-01

The in vivo rodent alkaline comet assay (comet assay) is a promising technique to evaluate DNA damage in vivo. However, there is no agreement on a method to evaluate DNA damage in organs where cytotoxicity is observed. As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the comet assay, we examined DNA damage in the liver, stomach, and bone marrow of rats given three oral doses of N-methyl-N-nitrosourea (MNU) up to the maximum tolerated dose based on systemic toxicity. MNU significantly increased the % tail DNA in all the organs. Histopathological analysis showed no cytotoxic effect on the liver, indicating clearly that MNU has a genotoxic potential in the liver. In the stomach, however, the cytotoxic effects were very severe at systemically non-toxic doses. Low-dose MNU significantly increased the % tail DNA even at a non-cytotoxic dose, indicating that MNU has a genotoxic potential also in the stomach. Part of the DNA damage at cytotoxic doses was considered to be a secondary effect of severe cell damage. In the bone marrow, both the % tail DNA and incidence of micronucleated polychromatic erythrocytes significantly increased at non-hematotoxic doses, which were different from the non-cytotoxic doses for liver and stomach. These findings indicate that an optimal dose for detecting DNA damage may vary among organs and that careful attention is required to select an optimum dose for the comet assay based on systemic toxicity such as mortality and clinical observations. The present study shows that when serious cytotoxicity is suggested by increased % hedgehogs in the comet assay, histopathological examination should be included for the evaluation of a positive response. Copyright © 2015 Elsevier B.V. All rights reserved.

The effect of isoprenaline on induction of tumours by methyl nitrosourea in the salivary and mammary glands of female wistar rats.

PubMed Central

Parkin, R.; Neale, S.

1976-01-01

Pretreatment of rats with isoprenaline sulphate (IPR) stimulated DNA synthesis in both salivary and mammary gland tissues. Salivary gland tumours induced by N-methyl-N-nitrosourea (MNU) were observed for the first time in rats, but occurred only in IPR-pretreated animals given MNU during the period of IPR-stimulated DNA synthesis. The cumulative index of MNU-induced mammary tumours and the number of tumours per tumour-bearing rat were increased by IPR-pretreament only if the animals received MNU during the period of IPR-stimulated DNA synthesis. PMID:974007

New hydrazine and hydrazide quinoxaline 1,4-di-N-oxide derivatives: In silico ADMET, antiplasmodial and antileishmanial activity.

PubMed

Quiliano, Miguel; Pabón, Adriana; Ramirez-Calderon, Gustavo; Barea, Carlos; Deharo, Eric; Galiano, Silvia; Aldana, Ignacio

2017-04-15

We report the design (in silico ADMET criteria), synthesis, cytotoxicity studies (HepG-2 cells), and biological evaluation of 15 hydrazine/hydrazide quinoxaline 1,4-di-N-oxide derivatives against the 3D7 chloroquine sensitive strain and FCR-3 multidrug resistant strain of Plasmodium falciparum and Leishmania infantum (axenic amastigotes). Fourteen of derivatives are novel quinoxaline 1,4-di-N-oxide derivatives. Compounds 18 (3D7 IC 50 =1.40μM, FCR-3 IC 50 =2.56μM) and 19 (3D7 IC 50 =0.24μM, FCR-3 IC 50 =2.8μM) were identified as the most active against P. falciparum, and they were the least cytotoxic (CC 50 -values>241μM) and most selective (SI>86). None of the compounds tested against L. infantum were considered to be active. Additionally, the functional role of the hydrazine and hydrazide structures were studied in the quinoxaline 1,4-di-N-oxide system. Copyright © 2017 Elsevier Ltd. All rights reserved.

40 CFR 721.4080 - MNNG (N-methyl-N′-nitro-N-nitrosoguanidine).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false MNNG (N-methyl-Nâ²-nitro-N... Specific Chemical Substances § 721.4080 MNNG (N-methyl-N′-nitro-N-nitrosoguanidine). (a) Chemical substance and significant new use subject to reporting. (1) The chemical substance MNNG (N-methyl-N′-nitro-N...

40 CFR 721.4080 - MNNG (N-methyl-N′-nitro-N-nitrosoguanidine).

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false MNNG (N-methyl-Nâ²-nitro-N... Specific Chemical Substances § 721.4080 MNNG (N-methyl-N′-nitro-N-nitrosoguanidine). (a) Chemical substance and significant new use subject to reporting. (1) The chemical substance MNNG (N-methyl-N′-nitro-N...

A peptide N-terminal protection strategy for comprehensive glycoproteome analysis using hydrazide chemistry based method

PubMed Central

Huang, Junfeng; Qin, Hongqiang; Sun, Zhen; Huang, Guang; Mao, Jiawei; Cheng, Kai; Zhang, Zhang; Wan, Hao; Yao, Yating; Dong, Jing; Zhu, Jun; Wang, Fangjun; Ye, Mingliang; Zou, Hanfa

2015-01-01

Enrichment of glycopeptides by hydrazide chemistry (HC) is a popular method for glycoproteomics analysis. However, possible side reactions of peptide backbones during the glycan oxidation in this method have not been comprehensively studied. Here, we developed a proteomics approach to locate such side reactions and found several types of the side reactions that could seriously compromise the performance of glycoproteomics analysis. Particularly, the HC method failed to identify N-terminal Ser/Thr glycopeptides because the oxidation of vicinal amino alcohol on these peptides generates aldehyde groups and after they are covalently coupled to HC beads, these peptides cannot be released by PNGase F for identification. To overcome this drawback, we apply a peptide N-terminal protection strategy in which primary amine groups on peptides are chemically blocked via dimethyl labeling, thus the vicinal amino alcohols on peptide N-termini are eliminated. Our results showed that this strategy successfully prevented the oxidation of peptide N-termini and significantly improved the coverage of glycoproteome. PMID:25959593

Synergistic effects of N-ethyl-N-nitrosourea (an alkylating agent with a low Swain-Scott substrate constant) and X-rays in the stamen hairs of Tradescantia clone BNL 4430.

PubMed

Shima, N; Ichikawa, S

1997-01-01

The mutagenic interaction between N-ethyl-N-nitrosourea (ENU) and X-rays was tested in the stamen hairs of Tradescantia clone BNL 4430, a blue/pink heterozygote. ENU, a monofunctional alkylating agent with a low Swain-Scott substrate constant (s) of 0.26, exhibited a strong cytotoxicity. ENU-induced somatic pink mutation frequency per 10(4) hair-cell divisions increased with increasing ENU dose, with a slope of 1.243 on a log-log graph, the slope value being similar to that for X-ray-induced mutation frequency. Three out of five combined treatments with ENU and X-rays produced mutation frequencies significantly higher than those expected from the additive effects of the two mutagens. Clear synergistic effects were detected when relatively higher X-ray doses were applied, resembling those confirmed earlier between methyl methanesulfonate (MMS) and X-rays, although the s value for ENU is very much smaller than that (0.88) for MMS. It is therefore concluded that mutagenic interactions between alkylating agents and X-rays do not have any clear relationship with the s values.

Mixture genotoxicity of 2,4-dichlorophenoxyacetic acid, acrylamide, and maleic hydrazide on human Caco-2 cells assessed with comet assay.

PubMed

Syberg, Kristian; Binderup, Mona-Lise; Cedergreen, Nina; Rank, Jette

2015-01-01

Assessment of genotoxic properties of chemicals is mainly conducted only for single chemicals, without taking mixture genotoxic effects into consideration. The current study assessed mixture effects of the three known genotoxic chemicals, 2,4-dichlorophenoxyacetic acid (2,4-D), acrylamide (AA), and maleic hydrazide (MH), in an experiment with a fixed ratio design setup. The genotoxic effects were assessed with the single-cell gel electrophoresis assay (comet assay) for both single chemicals and the ternary mixture. The concentration ranges used were 0-1.4, 0-20, and 0-37.7 mM for 2,4-D, AA, and MH, respectively. Mixture toxicity was tested with a fixed ratio design at a 10:23:77% ratio for 2.4-D:AA:MH. Results indicated that the three chemicals yielded a synergistic mixture effect. It is not clear which mechanisms are responsible for this interaction. A few possible interactions are discussed, but further investigations including in vivo studies are needed to clarify how important these more-than-additive effects are for risk assessment.

Amides and Hydrazides from Amine and Hydrazine Hydrochlorides.

ERIC Educational Resources Information Center

Shama, Sami A.; Tran, Thuan L.

1978-01-01

This safe and efficient procedure for the synthesis of N-substituted amides and hydrazides is a modification of the Schotten-Bausmann procedure in which the amine or hydrazide is replaced by the corresponding hydrochloride salt, and the use of alkali is eliminated. (Author/BB)

Structure-based design of nitrosoureas containing tyrosine derivatives as potential antimelanoma agents.

PubMed

Gadjeva, Vesselina

2002-04-01

Two new nitrosoureas (TNUs), containing tyrosine derivatives as carriers of nitrosourea cytotoxic group have been synthesised. The physicochemical properties such as half-life time (tau(0.5)), alkylating and carbamoylating activities were determined. The nitrosoureas showed a higher inhibiting effect on the DOPA-oxidase activity of mushroom tyrosinase than that of the antitumour drug N'-cyclohexyl-N-(2-chloroethyl)-N-nitrosourea (lomustine, CCNU). In vitro cytotoxic effects of newly synthesised tyrosine containing nitrosoureas have been studied and compared to those of CCNU. A higher cytotoxicity to B16 melanoma cells than to YAC-1 and to lymphocytes was demonstrated for the tyrosine containing nitrosoureas in comparison with CCNU. Based on the results presented, we accept that a new trend for synthesis of more selective and less toxic nitrosourea derivatives as potential antimelanomic drugs might be developed.

N-methylated tryptamine derivatives in citrus genus plants: identification of N,N,N-trimethyltryptamine in bergamot.

PubMed

Servillo, Luigi; Giovane, Alfonso; Balestrieri, Maria Luisa; Cautela, Domenico; Castaldo, Domenico

2012-09-19

The occurrence of N-methylated tryptamine derivatives in bergamot plant (Citrus bergamia Risso et Poit) is reported for the first time. Interestingly, the most abundant of these substances is N,N,N-trimethyltryptamine, which has not been previously identified in any citrus plant. The N-methylated tryptamine derivatives were identified and quantitated in leaves, peel, juice, and seeds by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. N,N,N-Trimethyltryptamine was confirmed by MS(3) and comparison with the synthesized authentic standard. In addition, the study of the distribution of tryptophan, tryptamine, N-methyltryptamine, N,N-dimethyltryptamine, and N,N,N-trimethyltryptamine indicated that these compounds are differently expressed in the various tissues of the bergamot plant. Intriguingly, chemically synthesized N,N,N-trimethyltryptamine was reported to possess nicotine-like activity being a stimulant of parasympathetic ganglia by exerting its action on acetylcholine receptors. On this basis, the identification of N,N,N-trimethyltryptamine at a relatively high level in leaves suggests a possible role in a physiological mechanism of plant defense.

Anticlastogenic effect of Spirulina maxima extract on the micronuclei induced by maleic hydrazide in Tradescantia.

PubMed

Ruiz Flores, L Elvia; Madrigal-Bujaidar, Eduardo; Salazar, María; Chamorro, Germán

2003-02-07

The aim of this investigation was to determine if extracts of Spirulina maxima reduce the genotoxic damage induced by maleic hydrazide (MH) using the Tradescantia biosssay. Two types of extracts from the alga were prepared: an aqueous extract with two different concentrations, 100 and 500 mg/ml, and a second one, the extract of a 1% solution of dimethyl sulfoxide (DMSO) which corresponded to 100 mg/ml of the alga. The capacity of MH to induce micronuclei (MN) was initially established by administering 0.005, 0.01, and 0.015 mg/ml of the chemical to the Tradescantia inflorescences, and observing its effect after 24 h.The results of this experiment showed a significant MN increase with the two high concentrations tested, although no dose-response effect was observed. For the anticlastogenic assay, the extracts of Spirulina were applied to the inflorescences alone or immediately before the application of MH (0.01 mg/ml) and the induced MN were observed 24 h later. We found that none of the extracts increased the MN level with respect to the untreated plants; also, that MH more or less doubled the basal micronuclei frequency, and finally, that all tested extracts reduced the genotoxic damage caused by MH. The inhibitory indices obtained for the aqueous extracts (100 and 500 mg/ml) and for the DMSO extract were respectively 59, 85, and 56.3%. These data indicate that Spirulina is an anticlastogenic agent and suggest that it is advisable to extend studies on this matter using other biological models.

N-METHYL GROUPS IN BACTERIAL LIPIDS

PubMed Central

Goldfine, Howard; Ellis, Martha E.

1964-01-01

Goldfine, Howard (Harvard Medical School, Boston, Mass.), and Martha E. Ellis. N-methyl groups in bacterial lipids. J. Bacteriol. 87:8–15. 1964.—The ability of bacteria to synthesize lecithin was examined by measuring the incorporation of the methyl group of methionine into the water-soluble moieties obtained on acid hydrolysis of bacterial lipids. Of 21 species examined, mostly of the order Eubacteriales, only 2, Agrobacterium radiobacter and A. rhizogenes, incorporated the methyl group of methionine into lipid-bound choline. Evidence was also obtained for the formation of lipid-bound N-methylethanolamine and N,N′-dimethylethanolamine in these two organisms. Two other species, Clostridium butyricum and Proteus vulgaris, incorporated the methyl group of methionine into lipid-bound N-methylethanolamine, but did not appear to be able to further methylate these lipids to form lecithin. The results of this study lend further strength to the generalization that bacteria, with the exception of the genus Agrobacterium, are unable to synthesize lecithin. PMID:14102879

New cysteamine (2-chloroethyl)nitrosoureas. Synthesis and preliminary antitumor results.

PubMed

Madelmont, J C; Godeneche, D; Parry, D; Duprat, J; Chabard, J L; Plagne, R; Mathe, G; Meyniel, G

1985-09-01

Three chemical pathways were used for the synthesis of four new N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]- and N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N- or N'-nitrosoureas. These compounds are plasma metabolites of CNCC, a promising antineoplastic (2-chloroethyl)nitrosourea. Preliminary antitumor evaluation was performed against L1210 leukemia implanted intraperitoneally in mice. Among these compounds, two of them exhibited a greater antitumor activity compared to that of the parent mixture.

40 CFR 721.225 - 2-Chloro-N-methyl-N-substituted acetamide (generic name).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false 2-Chloro-N-methyl-N-substituted... Specific Chemical Substances § 721.225 2-Chloro-N-methyl-N-substituted acetamide (generic name). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance 2-chloro-N...

40 CFR 721.225 - 2-Chloro-N-methyl-N-substituted acetamide (generic name).

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false 2-Chloro-N-methyl-N-substituted... Specific Chemical Substances § 721.225 2-Chloro-N-methyl-N-substituted acetamide (generic name). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance 2-chloro-N...

40 CFR 721.1085 - Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Benzenamine,4,4â²-methylenebis[N-ethyl-N-methyl-. 721.1085 Section 721.1085 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1085 Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-. (a) Chemical...

40 CFR 721.1085 - Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Benzenamine,4,4â²-methylenebis[N-ethyl-N-methyl-. 721.1085 Section 721.1085 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1085 Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-. (a) Chemical...

Vapor Pressure of Methyl Salicylate and n-Hexadecane

DTIC Science & Technology

2014-01-01

VAPOR PRESSURE OF METHYL SALICYLATE AND N-HEXADECANE ECBC-TR-1184 David E. Tevault Leonard C. Buettner...REPORT TYPE Final 3. DATES COVERED (From - To) Mar 2000-Dec 2001 4. TITLE AND SUBTITLE Vapor Pressure of Methyl Salicylate and n-Hexadecane 5a...ABSTRACT Vapor pressure data are reported for O-hydroxybenzoic acid, methyl ester, more commonly known as methyl salicylate (MeS), and n-hexadecane in

40 CFR 721.4925 - Methyl n-butyl ketone.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Methyl n-butyl ketone. 721.4925... Substances § 721.4925 Methyl n-butyl ketone. (a) Chemical substance and significant new use subject to reporting. (1) The chemical substance methyl n-butyl ketone, CAS Number 591-78-6, is subject to reporting...

40 CFR 721.4925 - Methyl n-butyl ketone.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Methyl n-butyl ketone. 721.4925... Substances § 721.4925 Methyl n-butyl ketone. (a) Chemical substance and significant new use subject to reporting. (1) The chemical substance methyl n-butyl ketone, CAS Number 591-78-6, is subject to reporting...

N-(3-azidophenyl)-N-methyl-N'-([4-1H]- and [4-3H]-1-naphthyl)guanidine. A potent and selective ligand designed as a photoaffinity label for the phencyclidine site of the N-methyl-D-aspartate receptor.

PubMed

Gee, K R; Durant, G J; Holmes, D L; Magar, S S; Weber, E; Wong, S T; Keana, J F

1993-01-01

A novel radiolabeled photoaffinity ligand has been synthesized for the phencyclidine (PCP) site of the N-methyl-D-aspartate (NMDA) receptor. N-(3-Azidophenyl)-N-methyl-N'-([4-3H]-1-naphthyl)guanidine (13) was prepared with a specific activity of 25 Ci/mmol by diazotization of N-(3-aminophenyl)-N-methyl-N'-([4-3H]-1-naphthyl)guanidine (12) followed by treatment with sodium azide. Guanidine 12 was obtained by catalytic tritiation of N-(4-bromo-1-naphthyl)-N'-methyl-N'-(3-nitrophenyl)guanidine (11). The nontritiated analog 5 of 13 was prepared beginning with N-methyl-N'-1-naphthyl-N-(3-nitrophenyl)guanidine (9). The guanidines 9 and 11 were prepared in moderate yield by the aluminum chloride-catalyzed reaction of N-methyl-3-nitroaniline hydrochloride with 1-naphthylcyanamide and 4-bromo-1-naphthylcyanamide, respectively. Azide 5 showed high selectivity and affinity (IC50 = 100 nM vs [3H]MK801; 3000 nM vs [3H]ditolylguanidine) for the PCP site of the NMDA receptor in guinea pig brain homogenate. Photolabeling experiments with 13, however, failed to radiolabel a significant amount of receptor polypeptide.

Anionic polymer, poly(methyl vinyl ether-maleic anhydride)-coated beads-based capture of human influenza A and B virus.

PubMed

Sakudo, Akikazu; Baba, Koichi; Tsukamoto, Megumi; Sugimoto, Atsuko; Okada, Takashi; Kobayashi, Takanori; Kawashita, Norihito; Takagi, Tatsuya; Ikuta, Kazuyoshi

2009-01-15

An anionic magnetic beads-based method was developed for the capture of human influenza A and B viruses from nasal aspirates, allantoic fluid and culture medium. A polymer, poly(methyl vinyl ether-maleic anhydride) [poly(MVE-MA)], was used to endow magnetic beads with a negative charge and bioadhesive properties. After incubation with samples containing human influenza virus, the beads were separated from supernatants by applying a magnetic field. The adsorption [corrected] of the virus by the beads was confirmed by hemagglutinin assay, immunochromatography, Western blotting, egg infection, and cell infection. Successful capture was proved using 5 H1N1 influenza A viruses, 10 H3N2 influenza A viruses, and 6 influenza B viruses. Furthermore, the infectivity in chicken embryonated eggs and Madin-Darby canine kidney (MDCK) cells of the captured human influenza virus was similar to that of the total viral quantity of starting materials. Therefore, this method of capture using magnetic beads coated with poly(MVE-MA) can be broadly used for the recovery of infectious human influenza viruses.

Phenylethylamine N-methylation by human brain preparations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mosnaim, A.D.; Callaghan, O.H.; Wolf, M.E.

Alterations in the brain metabolism of biogenic amines has been postulated to play a role in the pathophysiology of several psychiatric disorders. There is some evidence suggesting schizogenic properties for some abnormal neuroamine methylated derivatives. The authors now report that postmortem human brain preparations, obtained from the putamen and thalamus, convert phenylethylamine (PEA) to its behaviorally active derivative N-methyl PEA, a reaction which is carried out by the 100,000 xg supernatant (in presence of 1 x 10 /sup -5/M pargyline) and enhanced by the addition of NADPH. PEA N-methylation occurred in schizophrenics as well as in sex and age matchedmore » controls. The formation of increased amounts of (/sup 3/H-) or (/sup 14/C-) N-methyl PEA when incubating either cold amine and /sup 3/H-SAM or 1-/sup 14/C PEA and cold SAM, respectively, indicates that SAM is a methyl group donor in this reaction. They will discuss the physiological and pharmacological implications of these results.« less

Highly sensitive sites for guanine-O6 ethylation in rat brain DNA exposed to N-ethyl-N-nitrosourea in vivo.

PubMed Central

Nehls, P; Rajewsky, M F; Spiess, E; Werner, D

1984-01-01

Brain chromosomal DNA isolated from fetal BDIX-rats 1 h after i.v. administration of the ethylating N-nitroso carcinogen N-ethyl-N-nitrosourea (75 micrograms/g body weight), statistically contained one molecule of O6-ethyl-2'-deoxyguanosine (O6-EtdGuo) per 81 micron of DNA, as determined in enzymatic DNA hydrolysates by competitive radio-immunoassay using a high-affinity anti-(O6-EtdGuo) monoclonal antibody (ER-6). After fragmentation of the DNA by the restriction enzyme AluI (average fragment length, Lav = 0.28 micron = 970 bp; length range, Lr = 1.87-0.02 micron = 6540 - 60 bp), a small (approximately 2%) fraction of DNA enriched in specific polypeptides tightly associated with DNA was separated from the bulk DNA by a glass fiber binding technique. As analyzed by immune electron microscopy, approximately 1% of the DNA molecules in this fraction contained clusters of 2-10 (O6-EtdGuo)-antibody binding sites (ABS). On the cluster-bearing fragments (Lav, 0.85 micron +/- 0.50 micron S.D.; corresponding to 2970 +/- 1760 bp) the average ABS-ABS interspace distance was 110 nm (= 390 bp; range approximately 9-600 nm), indicating a highly non-random distribution of O6-EtdGuo in target cell DNA. Images Fig. 2. PMID:6370677

Two-step iron(0)-mediated N-demethylation of N-methyl alkaloids.

PubMed

Kok, Gaik B; Pye, Cory C; Singer, Robert D; Scammells, Peter J

2010-07-16

A mild and simple two-step Fe(0)-mediated N-demethylation of a number of tertiary N-methyl alkaloids is described. The tertiary N-methylamine is first oxidized to the corresponding N-oxide, which is isolated as the hydrochloride salt. Subsequent treatment of the N-oxide hydrochloride with iron powder readily provides the N-demethylated amine. Representative substrates include a number of opiate and tropane alkaloids. Key intermediates in the synthesis of semisynthetic 14-hydroxy pharmaceutical opiates such as oxycodone and oxymorphone are also readily N-demethylated using this method.

Diverse spectrum of tumors in male Sprague-Dawley rats following single high doses of N-ethyl-N-nitrosourea (ENU).

PubMed Central

Stoica, G.; Koestner, A.

1984-01-01

In this study, 30-day-old male Sprague-Dawley rats, were inoculated intraperitoneally with a single dose of 45, 90, and 180 mg/kg of N-ethyl-N-Nitrosourea (ENU). A wide spectrum of neoplasms occurred. The most common tumors were those of the mammary gland and of the nervous system. Although the incidence of mammary tumors was highest in the two high-dose groups (90 and 180 mg/kg ENU), the incidence of neurogenic tumors was highest in the 45 mg/kg dose group. Mammary tumor development led to early death and precluded development of tumors of the nervous system, which require a longer latency period. A variety of neoplasms of other organs have been associated particularly with high doses of ENU, including ameloblastic tumors, carcinomas of the thyroid, prostate, kidney, pancreas, intestine, and lung, hemilymphatic tumors, and sarcomas. It is concluded that large doses of ENU are capable of expanding the tumor spectrum in young male rats beyond the target organs generally affected with lower doses, as described in earlier reports. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:6465287

Protective effects of folic acid on DNA damage and DNA methylation levels induced by N-methyl- N'-nitro- N-nitrosoguanidine in Kazakh esophageal epithelial cells.

PubMed

Chen, Y; Feng, H; Chen, D; Abuduwaili, K; Li, X; Zhang, H

2018-01-01

The protective effects of folic acid on DNA damage and DNA methylation induced by N-methyl- N'-nitro- N-nitrosoguanidine (MNNG) in Kazakh esophageal epithelial cells were investigated using a 3 × 3 factorial design trial. The cells were cultured in vitro and exposed to media containing different concentrations of folic acid and MNNG, after which growth indices were detected. DNA damage levels were measured using comet assays, and genome-wide DNA methylation levels (MLs) were measured using high-performance liquid chromatography. The DNA methylation of methylenetetrahydrofolate reductase (MTHFR) and folate receptor- α (FR α) genes was detected by bisulfite sequencing polymerase chain reaction (PCR). The results showed significant increases in tail DNA concentration, tail length, and Olive tail moment ( p < 0.01); a significant reduction of genome-wide DNA MLs ( p < 0.01); and an increase in the methylation frequencies of MTHFR and FR α genes. In particular, significant differences were observed in the promoter regions of both genes ( p < 0.01). Our study indicated that a reduction in folic acid concentration promotes DNA damage and DNA methylation in Kazakh esophageal epithelial cells upon MNNG exposure. Thus, sufficient folic acid levels could play a protective role against the damage induced by this compound.

INTERLABORATORY STUDY OF A THERMOSPRAY-LIQUID CHROMATOGRAPHIC/MASS SPECTROMETRIC METHOD FOR SELECTED N-METHYL CARBAMATES, N-METHYL CARBAMOYLOXIMES, AND SUBSTITUTED UREA PESTICIDES

EPA Science Inventory

A thermospray-liquid chromatographic/mass spectrometric (TS-LC/MS) method was evaluated in an interlaboratory study for determining 3 N-methyl carbamates (bendiocarb, carbaryl, and carbofuran), 3-N-methyl carbamoyloximes (aldicarb, methomyl, and oxamyl), 2 substituted urea pestic...

27 CFR 21.118 - Methyl n-butyl ketone.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Methyl n-butyl ketone. 21.118 Section 21.118 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU....118 Methyl n-butyl ketone. (a) Acidity (as acetic acid). 0.02 percent by weight, maximum. (b) Color...

21 CFR 500.1410 - N-methyl-2-pyrrolidone.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 6 2014-04-01 2014-04-01 false N-methyl-2-pyrrolidone. 500.1410 Section 500.1410 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Used in Food-Producing Animals § 500.1410 N-methyl-2-pyrrolidone. (a) Standard for residues. No...

21 CFR 500.1410 - N-methyl-2-pyrrolidone.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 6 2012-04-01 2012-04-01 false N-methyl-2-pyrrolidone. 500.1410 Section 500.1410 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Used in Food-Producing Animals § 500.1410 N-methyl-2-pyrrolidone. (a) Standard for residues. No...

27 CFR 21.118 - Methyl n-butyl ketone.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Methyl n-butyl ketone. 21.118 Section 21.118 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU....118 Methyl n-butyl ketone. (a) Acidity (as acetic acid). 0.02 percent by weight, maximum. (b) Color...

Assessment of the best N(3-) donors in preparation of [M(N)(PNP)]-based (M=(99m)Tc-; (188)Re) target-specific radiopharmaceuticals: Comparison among succinic dihydrazide (SDH), N-methyl-S-methyl dithiocarbazate (HDTCZ) and PEGylated N-methyl-S-methyl dithiocarbazate (HO2C-PEG600-DTCZ).

PubMed

Carta, Davide; Jentschel, Christian; Thieme, Stefan; Salvarese, Nicola; Morellato, Nicolò; Refosco, Fiorenzo; Ruzza, Paolo; Bergmann, Ralf; Pietzsch, Hans-Jurgen; Bolzati, Cristina

2014-08-01

Succinic dihydrazide (SDH), N-methyl-S-methyl dithiocarbazate (HDTCZ) and PEGylated N-methyl-S-methyl dithiocarbazate (HO2C-PEG600-DTCZ) are nitrido nitrogen atom donors employed for the preparation of nitride [M(N)]-complexes (M=(99m)Tc and (188)Re). This study aims to compare the capability and the efficiency of these three N(3-) group donors, in the preparation of [M(N)PNP]-based target-specific compounds (M=(99m)Tc, (188)Re; PNP=aminodiphosphine). For this purpose, three different kit formulations (SDH kit; HO2C-PEG600-DTCZ kit; HDTCZ kit) were assembled and used in the preparation of [M(N)(cys~)(PNP3)](0/+) complexes (cys~=cysteine derivate ligands). For each formulation, the radiochemical yield (RCY) of the [M(N)(~cys)(PNP3)] compounds, was determined by HPLC. The deviation of the percentage of RCY, due to changes in concentration of the N(3-) donors and of the exchanging ligand, was determined. For (99m)Tc, data clearly show that HDTCZ is the most efficient donor of N(3-); however, SDH is the most suitable nitrido nitrogen atom donor for the preparation of [(99m)Tc(N)(PNP)]-based target-specific agents with high specific activity. When HO2C-PEG600-DTCZ or HDTCZ are used in N(3-) donation, high amounts of the exchanging ligand (10(-4)M) were required for the formation of the final complex in acceptable yield. The possibility to use microgram amounts of HDTCZ also in [(188)Re(N)] preparation (0.050mg) reduces its ability to compete in ligand exchange reactions, minimizing the quantity of chelators required to obtain the final complex in high yield. This finding can be exploit for increasing the radiolabeling efficiency in [(188)Re(N)]-radiopharmaceutical preparations compared to the previously reported HDTCZ-based procedure, notwithstanding a purification process could be necessary to improve the specific activity of the complexes. Copyright © 2014 Elsevier Inc. All rights reserved.

Interstrand cross-linking of DNA by 1,3-bis(2-chloroethyl)-1-nitrosourea and other 1-(2-haloethyl)-1-nitrosoureas.

PubMed

Kohn, K W

1977-05-01

Bifunctional alkylating agents are known to cross-link DNA by simultaneously alkylating two guanine residues located on opposite strands. Despite this apparent requirement for bifunctionality, 1-(2-chloroethyl)-1-nitrosoureas bearing a single alkylating function were found to cross-link DNA in vitro. Cross-linking was demonstrated by showing inhibition of alkali-induced strand separation. Extensive cross-linking was observed in DNA treated with 1-(2-chloroethyl)-1-nitrosourea, 1,3-bis-(2-chloroethyl)-1-nitrosourea, and 1-(2-chloroethyl(-3-cyclohexyl-1-nitrosourea. The reaction occurs in two steps, an intital binding followed by a second step which can proceed after removal of unbound drug. It is suggested that the first step is chloroethylation of a nucleophilic site on one strand and that the second step involves displacement of Cl- by a nucleophilic site on the opposite strand, resulting in an ethyl bridge between the strands. Consistent with this possibility, 1-(2-fluoroethyl)-3-cyclohexyl-1-nitrosourea produced much less cross-linking, as expected from the known low activity of F-, compared with Cl-, as leaving group. 1-Methyl-1-nitrosourea, which is known to depurinate DNA, produced no detectable cross-linking.

Preclinical studies of steroid-linked nitrosoureas in murine pancreatic adenocarcinoma PANO2.

PubMed

Papageorgiou, A; Lialiaris, Th; Stergiou, E; Stergiou, I; Tsigris, C; Kourti, A; Geromichalos, G; Stravoravdi, P; Trafalis, D; Athanassiou, A E; Pitsas, A; Camoutsis, Ch

2008-01-01

In earlier studies, this laboratory carried out research on the synthesis and anticancer evaluation of hybrid compounds, which combine two molecules in one such as homo-aza-steroidal esters (HASE) of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline. In this combination, steroidal hormones are employed as carriers for transporting the alkylating agents to specific targeted tissues. Aiming to continue our research, we used alkylating agents, as nitrosoureas, instead of nitrogen mustards. In this work the N-[N- (2-chloroethyl)-N-nitroso-carbomoyl]-L-alanine (CNC-ala) has been used and was bound to 7 newly synthesized modified steroidal esters (carrier molecule) of nitrosourea and the hybrid molecules were tested for antitumor activity against PANO2 murine pancreatic adenocarcinoma. PANO2 adenocarcinoma was used in this study. C57Bl mice were used for chemotherapy evaluation. The activity was assessed from the inhibition of tumor growth and the oncostatic parameter T/C %. The antitumor activity displayed by 7 hybrid steroidal esters of nitrosourea was quite interesting. It was able to discern 4 of 7 compounds that exhibited considerable antitumor activity, increasing the lifespan of the tumor-bearing mice by inhibiting the tumor growth. The comparative study of 7 newly synthesized hybrid steroidal esters of nitrosourea shows that the antitumor effects of compound 7, which has an enlarged (7 carbon atoms) A-lactamic ring and nitrosourea esterified at the position 17, which seems to be the most appropriate for the connection of a DNA cross-linking amino acid derivative is superior.

Mapping N-linked Glycosylation Sites in the Secretome and Whole Cells of Aspergillus niger Using Hydrazide Chemistry and Mass Spectrometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Lu; Aryal, Uma K.; Dai, Ziyu

2012-01-01

Protein glycosylation is known to play an essential role in both cellular functions and the secretory pathways; however, little information is available on the dynamics of glycosylated N-linked glycosites of fungi. Herein we present the first extensive mapping of glycosylated N-linked glycosites in industrial strain Aspergillus niger by applying an optimized solid phase enrichment of glycopeptide protocol using hydrazide modified magnetic beads. The enrichment protocol was initially optimized using mouse plasma and A. niger secretome samples, which was then applied to profile N-linked glycosites from both the secretome and whole cell lysates of A. niger. A total of 847 uniquemore » N-linked glycosites and 330 N-linked glycoproteins were confidently identified by LC-MS/MS. Based on gene ontology analysis, the identified N-linked glycoproteins in the whole cell lysate were primarily localized in the plasma membrane, endoplasmic reticulum, golgi apparatus, lysosome, and storage vacuoles. The identified N-linked glycoproteins are involved in a wide range of biological processes including gene regulation and signal transduction, protein folding and assembly, protein modification and carbohydrate metabolism. The extensive coverage of glycosylated N-linked glycosites along with identification of partial N-linked glycosylation in those enzymes involving in different biochemical pathways provide useful information for functional studies of N-linked glycosylation and their biotechnological applications in A. niger.« less

40 CFR 721.2275 - N,N,N′,N′-Tetrakis(oxi-ranyl- methyl)-1,3-cyclohexane di-meth-anamine.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false N,N,Nâ²,Nâ²-Tetrakis(oxi-ranyl- methyl... Significant New Uses for Specific Chemical Substances § 721.2275 N,N,N′,N′-Tetrakis(oxi-ranyl- methyl)-1,3... chemical substance identified as N,N,N′,N′-tetrakis(oxiranylmethyl)-1,3-cyclohexanedimethanamine (P-84-7...

40 CFR 721.2275 - N,N,N′,N′-Tetrakis(oxi-ranyl- methyl)-1,3-cyclohexane di-meth-anamine.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false N,N,Nâ²,Nâ²-Tetrakis(oxi-ranyl- methyl... Significant New Uses for Specific Chemical Substances § 721.2275 N,N,N′,N′-Tetrakis(oxi-ranyl- methyl)-1,3... chemical substance identified as N,N,N′,N′-tetrakis(oxiranylmethyl)-1,3-cyclohexanedimethanamine (P-84-7...

Kinetic and analytic investigations on the formation of N-nitroso-N-methyl-N-cyclohexylamine from bromhexine and nitrite.

PubMed

Schmid, J; Daneck, K; Koss, F W; Eisenbrand, G; Schlemmer, K H

1988-09-01

Bromhexine (N-methyl-N-cyclohexyl-(2-amino-3,5-dibromobenzyl)-ammoniumhydr ochloride) forms N-nitroso-N-methyl-N-cyclohexylamine (NMCA) under the conditions of the WHO Nitrosation Assay Procedure (NAP-test). The formation kinetics of this compound was investigated. The formation of NMCA depends on the square of the nitrite concentration. The reaction has a narrow pH-optimum at pH 3. The reaction is quick: After 1 h about 70% of the maximum amount of NMCA is formed. To study this reaction kinetics sensitive assays with a detection limit up to 0.5 ng/ml NMCA were developed. The stability of the components of the system, especially that of NMCA and nitrite, were further studied. The latter is rather instable under conditions found in an acidic stomach.

Treatment of mycosis fungoides with topical nitrosourea compounds: Further studies.

PubMed

Zackheim, H S; Epstein, E H

1975-12-01

Twenty-six patients with mycosis fungoides were treated topically with three nitrosourea compounds: carmustine (BCNU), lomustine (CCNU), and 1-methyl-1-nitrosourea. A high percentage experienced good to excellent results. Remissions following treatment of individual lesions varied from one month to at least three years. Remissions following total body surface treatment varied from two weeks to at least four months. Two of 13 patients treated over the entire body suffered temporary bone marrow depression, indluding one with severe pancytopenia. This toxic effect was attributed to lomustine and was not seen in patients treated with carmustine alone. Thirteen patients highly allergic to mechlorethamine hydrochloride showed no cross-sensitivity to nitrosourea compounds. A primary irritant dermatitis occurred in about one half of the patients and telangiectasia in two. Two patients developed hypersensitivity to nitrosourea compounds. Carmustine is the preferred nitrosourea compound for topical therapy of mycosis fungoides.

Sequencing analysis of mutations induced by N-ethyl-N-nitrosourea at different sampling times in mouse bone marrow.

PubMed

Wang, Jianyong; Chen, Tao

2010-03-01

In our previous study (Wang et al., 2004, Toxicol. Sci. 82: 124-128), we observed that the cII gene mutant frequency (MF) in the bone marrow of Big Blue mice showed significant increase as early as day 1, reached the maximum at day 3 and then decreased to a plateau by day 15 after a single dose of carcinogen N-ethyl-N-nitrosourea (ENU) treatment, which is different from the longer mutation manifestation time and the constancy of MFs after reaching their maximum in some other tissues. To determine the mechanism underlying the quick increase in MF and the peak formation in the mutant manifestation, we examined the mutation frequencies and spectra of the ENU-induced mutants collected from different sampling times in this study. The cII mutants from days 1, 3 and 120 after ENU treatment were randomly selected from different animals. The mutation frequencies were 33, 217, 305 and 144 x 10(-6) for control, days 1, 3, and 120, respectively. The mutation spectra at days 1 and 3 were significantly different from that at day 120. Considering that stem cells are responsible for the ultimate MF plateau (day 120) and transit cells are accountable for the earlier MF induction (days 1 or 3) in mouse bone marrow, we conclude that transit cells are much more sensitive to mutation induction than stem cells in mouse bone marrow, which resulted in the specific mutation manifestation induced by ENU.

5-Bromo-N-methyl­pyrimidin-2-amine

PubMed Central

Yang, Qi; Xu, Ning; Zhu, Kai; Lv, Xiaoping; Han, Ping-fang

2012-01-01

In the title mol­ecule, C5H6BrN3, the pyrimidine ring is essentially planar, with an r.m.s. deviation of 0.007 Å. The Br and N atoms substituted to the pyrimidine ring are coplanar with the ring [displacements = 0.032 (1) and 0.009 (5) Å, respectively], while the methyl C atom lies 0.100 (15) Å from this plane with a dihedral angle between the pyrimidine ring and the methyl­amine group of 4.5 (3)°. In the crystal, C—H⋯N, C—H⋯Br and N—H⋯N hydrogen bonds link the mol­ecules into a two-dimensional network in the (011) plane. PMID:22259398

[Mammary gland tumor induction in rats by N-nitroso-N-methylurea and N-methyl-N1-nitro-N-nitrosoguanidine].

PubMed

Eliseev, V V; Vlasov, N N

1980-01-01

Cancer of the mammary gland was induced in female non-inbred rats under the local effect of N-nitroso-N-methylurea (NMU) and N-methyl-N-nitro-N-nitrosoguanidine (MNNG). During 10 weeks 2.5 mg of the substance in 0.2 ml of saline was injected in the region of the third mammary gland once a week. Under NMU exposure a primary tumor arose 3 months following the initiation of the experiment, the average latent period being 5.8 months, the incidence rate--76.7%. All tumors of this series were adenocarcinomas, in 5 cases there were noted sites of fibroadenomatosis with malignification along the tumor node margins. MNNG produced a primary tumor at the 7th month of the experiment, an average latent period--8.3 months, the incidence rate--56.7%. Tumors were mostly adenocarcinomas.

Modifying effects of lemongrass essential oil on specific tissue response to the carcinogen N-methyl-N-nitrosurea in female BALB/c mice.

PubMed

Bidinotto, Lucas T; Costa, Celso A R A; Costa, Mirtes; Rodrigues, Maria A M; Barbisan, Luís F

2012-02-01

Lemongrass (Cymbopogon citratus Stapf) essential oil has been used worldwide because of its ethnobotanical and medicinal usefulness. Regarding its medicinal usefulness, the present study evaluated the beneficial effects of lemongrass essential oil (LGEO) oral treatment on cell proliferation and apoptosis events and on early development of hyperplastic lesions in the mammary gland, colon, and urinary bladder induced by N-methyl-N-nitrosourea (MNU) in female BALB/c mice. The animals were allocated into three groups: G1, treated with LGEO vehicle for 5 weeks (five times per week); G2, treated with LGEO vehicle as for G1 and MNU (two injections each of 30 mg/kg of body weight at weeks 3 and 5); and G3, treated with LGEO (five times each with 500 mg/kg of body weight per week) and MNU as for G2. Twenty-four hours after the last MNU application, all animals were euthanized, and mammary glands, colon, and urinary bladder were collected for histological and immunohistochemical analysis. LGEO oral treatment significantly changed the indexes of apoptosis and/or cellular proliferation for the tissues analyzed. In particular, the treatment reduced the incidence of hyperplastic lesions and increased apoptosis in mammary epithelial cells. This increment in the apoptosis response may be related to a favorable balance in Bcl-2/Bax immunoreactivity in mammary epithelial cells. These findings indicate that LGEO presented a protective role against early MNU-induced mammary gland alterations in BALB/c mice.

40 CFR 721.1070 - Benzenamine, 4-methoxy-2-methyl-N-(3-methylphenyl).

Code of Federal Regulations, 2010 CFR

2010-07-01

... as benzenamine, 4-methoxy-2-methyl-N-(3-methylphenyl) (PMN P-01-152; CAS No. 93072-06-1) is subject... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Benzenamine, 4-methoxy-2-methyl-N-(3... Specific Chemical Substances § 721.1070 Benzenamine, 4-methoxy-2-methyl-N-(3-methylphenyl). (a) Chemical...

Immunity against mouse thymus-leukemia antigen (TL) protects against development of lymphomas induced by a chemical carcinogen, N-butyl-N-nitrosourea.

PubMed

Tsujimura, Kunio; Obata, Yuichi; Matsudaira, Yasue; Ozeki, Satoshi; Taguchi, Osamu; Nishida, Keiko; Okanami, Yuko; Akatsuka, Yoshiki; Kuzushima, Kiyotaka; Takahashi, Toshitada

2004-11-01

Mouse thymus-leukemia antigens (TL) are aberrantly expressed on T lymphomas in C57BL/6 (B6) and C3H/He (C3H) mice, while they are not expressed on normal T lymphocytes in these strains. When N-butyl-N-nitrosourea (NBU), a chemical carcinogen, was administered orally to B6 and C3H strains, lymphoma development was slower than in T3(b)-TL gene-transduced counterpart strains expressing TL ubiquitously as self-antigens, suggesting that anti-TL immunity may play a protective role. In addition, the development of lymphomas was slightly slower in C3H than in B6, which seems to be in accordance with the results of skin graft experiments indicating that both cellular and humoral immunities against TL were stronger in C3H than B6 mice. The interesting finding that B lymphomas derived from a T3(b)-TL transgenic strain (C3H background) expressing a very high level of TL were rejected in C3H, but not in H-2K(b) transgenic mice (C3H background), raises the possibility that TL-specific effector T cell populations are eliminated and/or energized to a certain extent by interacting with H-2K(b) molecules.

Nucleotide excision repair modulates the cytotoxic and mutagenic effects of N-n-butyl-N-nitrosourea in cultured mammalian cells as well as in mouse splenocytes in vivo.

PubMed

Bol, S A; van Steeg, H; van Oostrom, C T; Tates, A D; Vrieling, H; de Groot, A J; Mullenders, L H; van Zeeland, A A; Jansen, J G

1999-05-01

The butylating agent N-n-butyl-N-nitrosourea (BNU) was employed to study the role of nucleotide excision repair (NER) in protecting mammalian cells against the genotoxic effects of monofunctional alkylating agents. The direct acting agent BNU was found to be mutagenic in normal and XPA mouse splenocytes after a single i.p. treatment in vivo. After 25 and 35 mg/kg BNU, but not after 75 mg/ kg, 2- to 3-fold more hprt mutants were detected in splenocytes from XPA mice than from normal mice. Using O6-alkylguanine-DNA alkyltransferase (AGT)-deficient hamster cells, it was found that NER-deficient CHO UV5 cells carrying a mutation in the ERCC-2 gene were 40% more mutable towards lesions induced by BNU when compared with parental NER-proficient CHO AA8 cells. UV5 cells were 1.4-fold more sensitive to the cytotoxic effects of BNU compared with AA8 cells. To investigate whether this increased sensitivity of NER-deficient cells is modulated by AGT activity, cell survival studies were performed in human and mouse primary fibroblasts as well. BNU was 2.7-fold more toxic for mouse XPA fibroblasts compared with normal mouse fibroblasts. Comparable results were found for human fibroblasts. Taken together these data indicate that the role of NER in protecting rodent cells against the mutagenic and cytotoxic effects of the alkylating agent BNU depends on AGT.

Bioconversion of 6-(N-methyl-N-phenyl)aminomethyl androstane steroids by Nocardioides simplex.

PubMed

Sukhodolskaya, Galina; Fokina, Victoria; Shutov, Andrei; Nikolayeva, Vera; Savinova, Tatiana; Grishin, Yuri; Kazantsev, Alexey; Lukashev, Nikolay; Donova, Marina

2017-02-01

The newly synthesized (α/β)-diastereomers of 6-(N-methyl-N-phenyl)aminomethylandrost-4-ene-3,17-dione (5) and 6-(N-methyl-N-phenyl)aminomethylandrost-4-en-17β-ol-3-one (6) were firstly investigated as substrates for the whole cells of Nocardioides simplex VKM Ac-2033D in comparison with their unsubstituted analogs, - androst-4-ene-3,17-dione (1) and androst-4-en-17β-ol-3-one (2). 1(2)-Dehydroderivatives were identified as the major bioconversion products from all the substrates tested. When using the mixtures of (α/β)-stereoisomers of 5 and 6 as the substrates, only β-stereoisomers of the corresponding 1,4-diene-steroids were formed. Along with 1(2)-dehydrogenation, N. simplex VKM Ac-2033D promoted oxidation of the hydroxyl group at C-17 position of 6: both 6(α) and 6(β) were transformed to the corresponding 17-keto derivatives. No steroid core destruction was observed during the conversion of the 6-substituted androstanes 5 and 6, while it was significant when 1 or 2 was used as the substrate. The results suggested high potentials of N. simplex VKM Ac-2033D for the generation of novel 1(2)-dehydroanalogs. Copyright © 2016 Elsevier Inc. All rights reserved.

Alkylarylnitrosoureas--stability in aqueous solution, partition coefficient, alkylating activity and its relationship to SCE induction in Chinese hamster V 79-E cells.

PubMed

Mendel, J; Thust, R; Schwarz, H

1982-01-01

The alkylating activity, chemical stability in aqueous solution (pH 7.0; 37 degrees C), and partition coefficient (octanol/water) of the following compounds were determined: 1-methyl-3-phenyl-1-nitrosourea (MPNU), 1-ethyl-3-phenyl-1-nitrosourea (EPNU), 1-isopropyl-3-phenyl-1-nitrosourea (i-PrPNU), 1-methyl-3-(p-fluorophenyl)-1-nitrosourea (F-MPNU), 1-methyl-3-(p-chlorophenyl)-1-nitrosourea (Cl-MPNU), 1-methyl-3-(p-bromophenyl)-1-nitrosourea (Br-MPNU), 1,3-dimethyl-3-phenyl-1-nitrosourea (DMPNU), and 1-methyl-3-naphthyl-1-nitrosocarbamate (NCA). 1-Methyl-1-nitrosourea (MNU) and 1-ethyl-1-nitrosourea (ENU) were used for the comparison. THe rate of decomposition in aqueous solution is discussed concerning the influences of the substituents at the 1- and 3-N-atom. The mono- and disubstituted N-nitrosoureas showed a coarse correlation between alkylating activity and SCE induction in Chinese hamster V 79-E cells. On the other hand, this correlation is missing in the case of NCA, which is a potent SCE inducer despite relatively low alkylating activity. DMPNU is the strongest SCE inducer, but this compound shows a high stability in aqueous solution and, consequently, we were not able to detect an alkylating activity.

A new class of nitrosoureas. 4. Synthesis and antitumor activity of disaccharide derivatives of 3,3-disubstituted 1-(2-chloroethyl)-1-nitrosoureas.

PubMed

Tsujihara, K; Ozeki, M; Morikawa, T; Kawamori, M; Akaike, Y; Arai, Y

1982-04-01

A series of 33 N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of N-substituted glycosylamines has been prepared and tested for antitumor activities. The compounds were obtained by reaction of glycosylamines with isocyanate, followed by nitrosation with N2O4. Structure-activity relationships of these trisubstituted nitrosoureas were investigated by varying the N-substituents and disaccharide groups and by comparing them with the corresponding disubstituted analogues. A large number of the nitrosoureas bearing a maltosyl group exhibited strong antitumor activities against leukemia L1210 and Ehrlich ascites carcinoma, and 60-day survivors against leukemia L1210 were found at the optimal dose for these derivatives. In contrast, the lactosyl and the melibiosyl derivatives were almost inactive. The most interesting compound in this series, the 3-isobutyl-3-maltosyl derivative (37), was tested against leukemia L1210 by single and multiple treatment. Its therapeutic ratio (96.3) obtained by multiple treatment is 3 times larger than that (31.5) obtained by single treatment, suggesting a possible clinical utility of 37 by multiple treatment. The favorable effect of a maltosyl moiety in this class of compounds is discussed.

Decomposition reactions of (hydroxyalkyl) nitrosoureas and related compounds: possible relationship to carcinogenicity.

PubMed

Singer, S S

1985-08-01

(Hydroxyalkyl)nitrosoureas and the related cyclic carbamates N-nitrosooxazolidones are potent carcinogens. The decompositions of four such compounds, 1-nitroso-1-(2-hydroxyethyl)urea (I), 3-nitrosooxazolid-2-one (II), 1-nitroso-1-(2-hydroxypropyl)urea (III), and 5-methyl-3-nitrosooxazolid-2-one (IV), in aqueous buffers at physiological pH were studied to determine if any obvious differences in decomposition pathways could account for the variety of tumors obtained from these four compounds. The products predicted by the literature mechanisms for nitrosourea and nitrosooxazolidone decompositions (which were derived from experiments at pH 10-12) were indeed the products formed, including glycols, active carbonyl compounds, epoxides, and, from the oxazolidones, cyclic carbonates. Furthermore, it was shown that in pH 6.4-7.4 buffer epoxides were stable reaction products. However, in the presence of hepatocytes, most of the epoxide was converted to glycol. The analytical methods developed were then applied to the analysis of the decomposition products of some related dialkylnitrosoureas, and similar results were obtained. The formation of chemically reactive secondary products and the possible relevance of these results to carcinogenesis studies are discussed.

Spin labeled amino acid nitrosourea derivatives--synthesis and antitumour activity.

PubMed

Zheleva, A; Raikov, Z; Ilarionova, M; Todorov, D

1995-01-01

The synthesis of three spin labeled derivatives of N-[N'-(chloroethyl)-N'-nitrosocarbamoyl] amino acids is reported. The new nitrosoureas are obtained by condensation of the corresponding N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl] amino acid with 2,2,6,6-tetramethyl-1-oxyl-4-aminopiperidine using dicyclohexylcarbodiimide. Their chemical structures are confirmed by elemental analysis, IR, MS, and EPR spectroscopy. All newly synthesized compounds showed high antitumour activity against the lymphoid leukemia L1210 in BDF1 mice.

N-Acetylcarnosine and histidyl-hydrazide are potent agents for multitargeted ophthalmic therapy of senile cataracts and diabetic ocular complications.

PubMed

Babizhayev, Mark A; Guiotto, Andrea; Kasus-Jacobi, Anne

2009-01-01

In human diabetes, the deleterious effects of chronic hyperglycemia are the result of excessive nonenzymatic modification of proteins and phospholipids by glucose and its by-products leading to the formation of irreversible oxidized, aromatic, and fluorescent ligands known as advanced glycation end products. This glycation process has been associated with deleterious health effects. The present invention provides the potent inhibitors of protein glycation and AGEs formation, which are particularly advantageous for eyedrop delivery in the prevention and treatment of diabetes- and age-related pathologies. We proposed a deglycation system involving removal, by transglycation of sugar or aldehyde moieties from the Schiff bases by ophthalmic aldehyde scavenger L-carnosine derived from its ocular bioactivating sustained release prodrug 1% N-acetylcarnosine (NAC) lubricant eyedrops containing a mucoadhesive cellulose compound combined with corneal absorption promoters in drug delivery system. Carnosine analogs bearing the histidyl-hydrazide moiety were synthesized and patented in ophthalmic formulations with NAC bioactivating prodrug to moderate the enzymatic hydrolysis of a dipeptide by carnosinase (inhibited by a nonhydrolyzable substrate analog so that this keeps steadier levels of the drug active principle in the aqueous humor). Leucyl-histidylhydrazide peptidomimetic demonstrated the transglycation activity more pronounced than L-carnosine accounting for the ability of either molecule to reverse pre-existing, glycation-induced, cross-linking, and checking the nonenzymatic glycation cascade in the ophthalmic pathologies. The ophthalmic drug N-acetylcarnosine eye drop formulation with sustained time- release and increased absorption of L-carnosine in the aqueous humor (a prolonged effective dose) showed follow-up treatment efficacy for age-related cataracts for enrolled patients into the randomized double blind placebo controlled crossover clinical trial, and in over

TOXICITY OF TETRYL (N-METHYL-N,2,4,6-TETRANITROANILINE) IN F344 RATS

EPA Science Inventory

The toxicity of tetryl (N-methyl-N,2,4,6-tetranitroaniline) in male and female F344 rats was evaluated after adminstration in the diet for 14 or 90 days. The 14-day study diet concentrations used were 0, 500, 1250, 2000, 2500, and 5000 ppm; the 90-day study diet concentrations we...

Metal ion promoted hydrogels for bovine serum albumin adsorption: Cu(II) and Co(II) chelated poly[(N-vinylimidazole)-maleic acid].

PubMed

Pekel, Nursel; Salih, Bekir; Güven, Olgun

2005-05-10

Poly[(N-vinylimidazole)-maleic acid] (poly(VIm-MA)), copolymeric hydrogels were prepared by gamma-irradiating ternary mixtures of N-vinylimidazole-maleic acid-water in a (60)Co-gamma source. Cu(II) and Co(II) ions were chelated within the gels at pH=5.0. The maximum adsorption capacity of the gels were 3.71 mmol/g dry gel for Cu(II) and 1.25 mmol/g dry gel for Co(II) at pH=5.0. The swelling ratios of the gels were 1200% for poly(VIm-MA), 60 and 45% for Cu(II) and Co(II)-chelated poly(VIm-MA) gels at pH=5.0 in acetate buffer solution. These affinity gels with different swelling ratios for plain poly(VIm-MA), Cu(II)-, and Co(II)-chelated poly(VIm-MA), in acetate and phosphate buffers were used in the bovine serum albumin (BSA) adsorption/desorption studies in batch reactor. The maximum BSA adsorption capacities of the gels were 0.38 g/g dry gel for plain, 0.88 g/g dry gel for Cu(II)-chelated poly(VIm-MA) and 1.05 g/g dry gel for Co(II)-chelated poly(VIm-MA) gels. Adsorption capacity of BSA by the gels was reduced dramatically by increasing the ionic strength adjusted with NaCl. More than 95% of BSA were desorbed in 10 h in desorption medium containing 0.1M of EDTA for metal ion-chelated gels at pH=4.7.

40 CFR 721.1000 - Benzenamine, 3-chloro-2,6-dinitro-N,N-dipropyl-4-(tri-fluoro-methyl)-.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Benzenamine, 3-chloro-2,6-dinitro-N,N-dipropyl-4-(tri-fluoro-methyl)-. 721.1000 Section 721.1000 Protection of Environment ENVIRONMENTAL... Significant New Uses for Specific Chemical Substances § 721.1000 Benzenamine, 3-chloro-2,6-dinitro-N,N...

Generation of N-Ethyl-N-nitrosourea (ENU) Diabetes Models in Mice Demonstrates Genotype-specific Action of Glucokinase Activators*

PubMed Central

Fenner, Deborah; Odili, Stella; Hong, Hee-Kyung; Kobayashi, Yumiko; Kohsaka, Akira; Siepka, Sandra M.; Vitaterna, Martha H.; Chen, Pan; Zelent, Bogumil; Grimsby, Joseph; Takahashi, Joseph S.; Matschinsky, Franz M.; Bass, Joseph

2011-01-01

We performed genome-wide mutagenesis in C57BL/6J mice using N-ethyl-N-nitrosourea to identify mutations causing high blood glucose early in life and to produce new animal models of diabetes. Of a total of 13 new lines confirmed by heritability testing, we identified two semi-dominant pedigrees with novel missense mutations (GckK140E and GckP417R) in the gene encoding glucokinase (Gck), the mammalian glucose sensor that is mutated in human maturity onset diabetes of the young type 2 and the target of emerging anti-hyperglycemic agents that function as glucokinase activators (GKAs). Diabetes phenotype corresponded with genotype (mild-to-severe: Gck+/+ < GckP417R/+, GckK140E/+ < GckP417R/P417R, GckP417R/K140E, and GckK140E/K140E) and with the level of expression of GCK in liver. Each mutant was produced as the recombinant enzyme in Escherichia coli, and analysis of kcat and tryptophan fluorescence (I320/360) during thermal shift unfolding revealed a correlation between thermostability and the severity of hyperglycemia in the whole animal. Disruption of the glucokinase regulatory protein-binding site (GCKK140E), but not the ATP binding cassette (GCKP417R), prevented inhibition of enzyme activity by glucokinase regulatory protein and corresponded with reduced responsiveness to the GKA drug. Surprisingly, extracts from liver of diabetic GCK mutants inhibited activity of the recombinant enzyme, a property that was also observed in liver extracts from mice with streptozotocin-induced diabetes. These results indicate a relationship between genotype, phenotype, and GKA efficacy. The integration of forward genetic screening and biochemical profiling opens a pathway for preclinical development of mechanism-based diabetes therapies. PMID:21921030

4-Methyl-N-(1-methyl-1H-indazol-5-yl)benzene-sulfonamide.

PubMed

Chicha, Hakima; Oulemda, Bassou; Rakib, El Mostapha; Saadi, Mohamed; El Ammari, Lahcen

2013-01-01

In the title compound, C15H15N3O2S, the fused ring system is close to planar, the largest deviation from the mean plane being 0.030 (2) Å, and makes a dihedral angle of 48.84 (9)° with the benzene ring belonging to the methyl-benzene-sulfonamide moiety. In the crystal, mol-ecules are -connected through N-H⋯N hydrogen bonds and weak C-H⋯O contacts, forming a two-dimensional network parallel to (001).

The frequency of Pig-a mutant red blood cells in rats exposed in utero to N-ethyl-N-nitrosourea.

PubMed

Dobrovolsky, Vasily N; Heflich, Robert H; Ferguson, Sherry A

2012-07-01

The Pig-a assay has been developed as a rapid sensitive measure of gene mutation in adult rats; however, no data exist on its ability to detect mutation following in utero exposures or in neonatal animals. Pregnant Sprague-Dawley rats were treated daily on gestational days 12-18 with oral doses of 0, 6, or 12 mg/kg/day N-ethyl-N-nitrosourea (ENU); following parturition, the offspring and dams were monitored over a period of 5 months for the frequency of CD59-deficient erythrocytes as a marker of Pig-a mutation. Significant dose-related increases in Pig-a mutant red blood cells (RBCs) were observed in ENU-treated dams. However, only very weak increases in RBC Pig-a mutant frequency (MF) were noted in offspring treated in utero with the lower ENU dose. The higher ENU dose produced extremely variable responses in the offspring as a function of age, even among littermates, ranging from a steady low or moderately high Pig-a MF to a rapidly increasing or decreasing Pig-a MF. The manifestation kinetics of Pig-a mutant RBCs in the offspring suggest that the change from predominantly hepatic to predominantly bone marrow erythropoiesis that occurs during early development may have contributed to this variability. Our results indicate that using the RBC Pig-a model for mutation detection in animals treated in utero may require analysis of multiple offspring from the same litter to account for potential "jack pot" effects, and that detection of the earliest treatment effect (i.e., in neonates using the hepatic RBC fraction) may require optimization of blood processing. Published 2012 Wiley Periodicals, Inc.

Proline analogue of nitrosourea as a new cytotoxic prodrug.

PubMed

Stankiewicz-Kranc, Anna; Bielawska, Anna; Bielawski, Krzysztof; Skrzydlewska, Elzbieta

2009-11-01

Carmustine is frequently used as anticancer drug. High toxicity and low selectivity reduces the application of this drug. Though, there is a necessity to find new compounds characterized by similar therapeutic effects but a higher selectivity and safety. As a result, the proline analogue of nitrosourea, N-[N'-(2-bromophenyl)-N'-nitrosocarbamoyl]proline (AC), has been synthesized. The aim of this study was to compare the influence of carmustine and the proline analogue of nitrosourea on the antioxidant abilities of fibroblasts and leukemia cells, MOLT4. It was shown that carmustine as well as AC cause an increase in hydrogen peroxide concentration in normal and neoplastic cells. Incubation with both compounds led to a diminution of the activity of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and reductase. Changes in activity / level of antioxidant parameters were accompanied by augmentation of lipid and oxidative protein modifications. In conclusion, carmustine and AC cause changes in the antioxidative system of normal and MOLT4 cells and are a reason of oxidative stress formation.

Photoluminescence, chemiluminescence and anodic electrochemiluminescence of hydrazide-modified graphene quantum dots

NASA Astrophysics Data System (ADS)

Dong, Yongqiang; Dai, Ruiping; Dong, Tongqing; Chi, Yuwu; Chen, Guonan

2014-09-01

Single-layer graphene quantum dots (SGQDs) were refluxed with hydrazine (N2H4) to prepare hydrazide-modified SGQDs (HM-SGQDs). Compared with SGQDs, partial oxygen-containing groups have been removed from HM-SGQDs. At the same time, a lot of hydrazide groups have been introduced into HM-SGQDs. The introduced hydrazide groups provide HM-SGQDs with a new kind of surface state, and give HM-SGQDs unique photoluminescence (PL) properties such as blue-shifted PL emission and a relatively high PL quantum yield. More importantly, the hydrazide-modification made HM-SGQDs have abundant luminol-like units. Accordingly, HM-SGQDs exhibit unique and excellent chemiluminescence (CL) and anodic electrochemiluminescence (ECL). The hydrazide groups of HM-SGQDs can be chemically oxidized by the dissolved oxygen (O2) in alkaline solutions, producing a strong CL signal. The CL intensity is mainly dependent on the pH value and the concentration of O2, implying the potential applications of HM-SGQDs in pH and O2 sensors. The hydrazide groups of HM-SGQDs can also be electrochemically oxidized in alkaline solutions, producing a strong anodic ECL signal. The ECL intensity can be enhanced sensitively by hydrogen peroxide (H2O2). The enhanced ECL intensity is proportional to the concentration of H2O2 in a wide range of 3 μM to 500 μM. The detection limit of H2O2 was calculated to be about 0.7 μM. The results suggest the great potential applications of HM-SGQDs in the sensors of H2O2 and bio-molecules that are able to produce H2O2 in the presence of enzymes.Single-layer graphene quantum dots (SGQDs) were refluxed with hydrazine (N2H4) to prepare hydrazide-modified SGQDs (HM-SGQDs). Compared with SGQDs, partial oxygen-containing groups have been removed from HM-SGQDs. At the same time, a lot of hydrazide groups have been introduced into HM-SGQDs. The introduced hydrazide groups provide HM-SGQDs with a new kind of surface state, and give HM-SGQDs unique photoluminescence (PL) properties such

N-substituted methyl maleamates as larvicidal compounds against Aedes aegypti (Diptera: Culicidae).

PubMed

Harburguer, Laura; Gonzalez, Paula V; Gonzalez Audino, Paola; Zerba, Eduardo; Masuh, Héctor

2018-02-01

Severe human arboviral diseases can be transmitted by the mosquito Aedes aegypti (L.), including dengue, chikungunya, zika, and yellow fever. The use of larvicides in containers that can result as potential breeding places and cannot be eliminated is the main alternative in control programs. However, their continuous and widespread use caused an increase in insecticide-resistant populations of this mosquito. The aim of this study was to evaluate the effect of three N-substituted methyl maleamates as larvicides on Ae. aegypti, the N-propyl methyl maleamate (PMM), N-butyl methyl maleamate (BMM), and N-hexyl methyl maleamate (HMM). These compounds could have a different mode of action from those larvicides known so far. We evaluated the larva mortality after 1 and 24 h of exposure and we found that mortality was fast and occurs within the first 60 min. HMM was slightly more effective with LC 50 values of 0.7 and 0.3 ppm for 1 and 24 h of exposure and LC 95 of 11 and 3 ppm. Our results demonstrate that N-substituted methyl maleamates have insecticidal properties for the control of Ae. aegypti larvae. These compounds could become useful alternatives to traditional larvicides after studying their insecticidal mechanism as well as their toxicity towards non target organisms.

N-Methyl Inversion in Pseudo-Pelletierine

NASA Astrophysics Data System (ADS)

Vallejo-López, Montserrat; Ecija, Patricia; Cocinero, Emilio J.; Lesarri, Alberto; Basterretxea, Francisco J.; Fernández, José A.

2016-06-01

We have previously conducted rotational studies of several tropanes, since this bicyclic structural motif forms the core of different alkaloids of pharmaceutical interest. Now we report on the conformational properties and molecular structure of pseudo-pelletierine (9-methyl-9-azabicyclo[3.3.1]nonan-3-one), probed in a jet expansion with Fourier-transform microwave spectroscopy. Pseudo-pelletierine is an azabicycle with two fused six-membered rings, where the N-methyl group can produce inverting axial o equatorial conformations. The two conformations were detected in the rotational spectrum, recorded in the region 6-18 GHz. Unlike tropinone and N-methylpiperidone, where the most stable conformer is equatorial, the axial species was found dominant for pseudo-pelletierine. All monosubstituted isotopic species (13C, 15N and 18O) were identified for the axial conformer, leading to an accurate determination of the effective and substitution structures. An estimation of conformational populations was derived from relative intensities. The experimental results will be compared with ab initio (MP2) and DFT (M06-2X, B3LYP) calculations. E. J. Cocinero, A. Lesarri, P. Écija, J.-U. Grabow, J. A. Fernández, F. Castaño, Phys. Chem. Chem. Phys. 2010, 49, 4503 P. Écija, E. J. Cocinero, A. Lesarri, F. J. Basterretxea, J. A. Fernández, F. Castaño, Chem. Phys. Chem. 2013, 14, 1830 P. Écija, M. Vallejo-Lopez, I. Uriarte, F. J. Basterretxea, A. Lesarri, J. A. Fernández, E. J. Cocinero, submitted 2016

Crystal structure of 2-bromo-3-di­methyl­amino-N,N,N′,N′,4-penta­methyl-4-(tri­methyl­sil­yloxy)pent-2-eneamidinium bromide

PubMed Central

Tiritiris, Ioannis; Kress, Ralf; Kantlehner, Willi

2015-01-01

The reaction of the ortho­amide 1,1,1-tris­(di­methyl­amino)-4-methyl-4-(tri­methyl­sil­yloxy)pent-2-yne with bromine in benzene, yields the title salt, C15H33BrN3OSi+·Br−. The C—N bond lengths in the amidinium unit are 1.319 (6) and 1.333 (6) Å, indicating double-bond character, pointing towards charge delocalization within the NCN plane. The C—Br bond length of 1.926 (5) Å is characteristic for a C—Br single bond. Additionally, there is a bromine–bromine inter­action [3.229 (3) Å] present involving the anion and cation. In the crystal, weak C—H⋯Br inter­actions between the methyl H atoms of the cation and the bromide ions are present. PMID:26870498

Crystal structure and electrochemical properties of [Ni(bztmpen)(CH3CN)](BF4)2 {bztmpen is N-benzyl-N,N',N'-tris-[(6-methyl-pyridin-2-yl)meth-yl]ethane-1,2-di-amine}.

PubMed

Chen, Lin; Ren, Gan; Guo, Yakun; Sang, Ge

2017-06-01

The mononuclear nickel title complex (acetonitrile-κ N ){ N -benzyl- N , N ', N '-tris-[(6-methyl-pyridin-2-yl)meth-yl]ethane-1,2-di-amine}-nickel(II) bis-(tetra-fluor-ido-borate), [Ni(C 30 H 35 N 5 )(CH 3 CN)](BF 4 ) 2 , was prepared from the reaction of Ni(BF 4 ) 2 ·6H 2 O with N -benzyl- N , N ', N '-tris-[(6-methyl-pyridin-2-yl)meth-yl]ethane-1,2-di-amine ( bztmpen ) in aceto-nitrile at room temperature. With an open site occupied by the aceto-nitrile mol-ecule, the nickel(II) atom is chelated by five N-atom sites from the ligand and one N atom from the ligand, showing an overall octa-hedral coordination environment. Compared with analogues where the 6-methyl substituent is absent, the bond length around the Ni 2+ cation are evidently longer. Upon reductive dissociation of the acetro-nitrile mol-ecule, the title complex has an open site for a catalytic reaction. The title complex has two redox couples at -1.50 and -1.80 V ( versus F c +/0 ) based on nickel. The F atoms of the two BF 4 - counter-anions are split into two groups and the occupancy ratios refined to 0.611 (18):0.389 (18) and 0.71 (2):0.29 (2).

N.m.r. studies of the conformation of analogues of methyl beta-lactoside in methyl sulfoxide-d6.

PubMed

Rivera-Sagredo, A; Jiménez-Barbero, J; Martín-Lomas, M

1991-12-16

The 1H- and 13C-n.m.r. spectra of solutions of methyl beta-lactoside (1), all of its monodeoxy derivatives (2, 3, 6-10), the 3-O-methyl derivative (4), and methyl 4-O-beta-D-galactopyranosyl-D-xylopyranoside (5) in methyl sulfoxide-d6 have been analysed. The n.O.e.'s and specific desheildings indicate similar distributions of low-energy conformers, comparable to those in aqueous solution. The major conformer has torsion angles phi H and psi H of 49 degrees and 5 degrees, respectively, with contributions of conformers with phi/psi 24 degrees/-59 degrees, 22 degrees/32 degrees, and 6 degrees/44 degrees.

Sage Gene Expression Profiles Characterizing Cure

DTIC Science & Technology

2005-10-01

achieved in haematological malignancies. In addition, tumour cell lines showed a log-linear dose re- sponse when exposed to alkylating agents [26,27...direct carcinogen, N-methyl nitrosourea (NMU) and an indirect carcinogen, 7,12- dimethylbenzanthracene each depend upon the estrous cycle phase at the...a single dose of N-methyl-N- nitrosourea . Cancer Res 45: 3042–3047, 1995 8. Nagasawa H, Yanai R, Taniguchi H: Importance of mammary gland DNA synthesis

2-chloroethanol formation as evidence for a 2-chloroethyl alkylating intermediate during chemical degradation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea.

PubMed

Reed, D J; May, H E; Boose, R B; Gregory, K M; Beilstein, M A

1975-03-01

Chemical degradation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea or 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea in buffer under physiological conditions resulted in the formation of a significant quantity of 2-chlorethanol (18 to 25% of the initial nitrosourea concentration). Other degradation products observed included acetaldehyde (5 to 10%), vinyl chloride (1 to 2%), ethylene (1 to 2%), and cyclohexylamine (32%), but not 1,3-dicyclohexylurea. The 2-chlorethyl moiety of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea was trapped with halide ions, CI-, BR-, and I-, to form the corresponding dihaloethanes which were identified by gas chromatography-mass spectrometry techniques. High-pressure liquid chromatographic procedures were developed for the separation and quantiation of the nitrosoureas and many of their degradation products. It is postulated that a new mode of 1(2-chloreoethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea degradation can occur that is not the loss of the chloro group as chloride ion, but the loss of the N-3 hydrogen as a proton. Then the corresponding isocyanate and 2-chloroethyidiazene hydroxide are formed, with the latter intermidiate becoming an alkylating species, possibly in part as a 2-chloroethyl carbonium ion.

Control of box C/D snoRNP assembly by N6-methylation of adenine.

PubMed

Huang, Lin; Ashraf, Saira; Wang, Jia; Lilley, David Mj

2017-09-01

N 6 -methyladenine is the most widespread mRNA modification. A subset of human box C/D snoRNA species have target GAC sequences that lead to formation of N 6 -methyladenine at a key trans Hoogsteen-sugar A·G base pair, of which half are methylated in vivo The GAC target is conserved only in those that are methylated. Methylation prevents binding of the 15.5-kDa protein and the induced folding of the RNA Thus, the assembly of the box C/D snoRNP could in principle be regulated by RNA methylation at its critical first stage. Crystallography reveals that N 6 -methylation of adenine prevents the formation of trans Hoogsteen-sugar A·G base pairs, explaining why the box C/D RNA cannot adopt its kinked conformation. More generally, our data indicate that sheared A·G base pairs (but not Watson-Crick base pairs) are more susceptible to disruption by N 6 mA methylation and are therefore possible regulatory sites. The human signal recognition particle RNA and many related Alu retrotransposon RNA species are also methylated at N6 of an adenine that forms a sheared base pair with guanine and mediates a key tertiary interaction. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

N-Methyl Inversion and Accurate Equilibrium Structures in Alkaloids: Pseudopelletierine.

PubMed

Vallejo-López, Montserrat; Écija, Patricia; Vogt, Natalja; Demaison, Jean; Lesarri, Alberto; Basterretxea, Francisco J; Cocinero, Emilio J

2017-11-21

A rotational spectroscopy investigation has resolved the conformational equilibrium and structural properties of the alkaloid pseudopelletierine. Two different conformers, which originate from inversion of the N-methyl group from an axial to an equatorial position, have been unambiguously identified in the gas phase, and nine independent isotopologues have been recorded by Fourier-transform microwave spectroscopy in a jet expansion. Both conformers share a chair-chair configuration of the two bridged six-membered rings. The conformational equilibrium is displaced towards the axial form, with a relative population in the supersonic jet of N axial /N equatorial ≈2/1. An accurate equilibrium structure has been determined by using the semiexperimental mixed-estimation method and alternatively computed by quantum-chemical methods up to the coupled-cluster level of theory. A comparison with the N-methyl inversion equilibria in related tropanes is also presented. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

N,N,N′,N′-Tetra­methyl­guanidinium tetra­phenyl­borate

PubMed Central

Tiritiris, Ioannis

2012-01-01

In the title salt, C5H14N3 +·C24H20B−, the C—N bond lengths in the central CN3 unit are 1.3322 (11), 1.3385 (12) and 1.3422 (12) Å, indicating partial double-bond character. The central C atom is bonded to the three N atoms in a nearly ideal trigonal-planar geometry [N—C—N angles = 119.51 (8), 119.81 (9) and 120.69 (8)°] and the positive charge is delocalized in the CN3 plane. The bond lengths between the N atoms and the terminal methyl groups all have values close to a typical single bond [1.4597 (12)–1.4695 (13) Å]. The crystal packing is caused by electrostatic inter­actions between cations and anions. PMID:23476307

Structural and spectroscopic characterization of methyl isocyanate, methyl cyanate, methyl fulminate, and acetonitrile N-oxide using highly correlated ab initio methods.

PubMed

Dalbouha, S; Senent, M L; Komiha, N; Domínguez-Gómez, R

2016-09-28

Various astrophysical relevant molecules obeying the empirical formula C 2 H 3 NO are characterized using explicitly correlated coupled cluster methods (CCSD(T)-F12). Rotational and rovibrational parameters are provided for four isomers: methyl isocyanate (CH 3 NCO), methyl cyanate (CH 3 OCN), methyl fulminate (CH 3 ONC), and acetonitrile N-oxide (CH 3 CNO). A CH 3 CON transition state is inspected. A variational procedure is employed to explore the far infrared region because some species present non-rigidity. Second order perturbation theory is used for the determination of anharmonic frequencies, rovibrational constants, and to predict Fermi resonances. Three species, methyl cyanate, methyl fulminate, and CH 3 CON, show a unique methyl torsion hindered by energy barriers. In methyl isocyanate, the methyl group barrier is so low that the internal top can be considered a free rotor. On the other hand, acetonitrile N-oxide presents a linear skeleton, C 3v symmetry, and free internal rotation. Its equilibrium geometry depends strongly on electron correlation. The remaining isomers present a bend skeleton. Divergences between theoretical rotational constants and previous parameters fitted from observed lines for methyl isocyanate are discussed on the basis of the relevant rovibrational interaction and the quasi-linearity of the molecular skeleton.

Structural and spectroscopic characterization of methyl isocyanate, methyl cyanate, methyl fulminate, and acetonitrile N-oxide using highly correlated ab initio methods

NASA Astrophysics Data System (ADS)

Dalbouha, S.; Senent, M. L.; Komiha, N.; Domínguez-Gómez, R.

2016-09-01

Various astrophysical relevant molecules obeying the empirical formula C2H3NO are characterized using explicitly correlated coupled cluster methods (CCSD(T)-F12). Rotational and rovibrational parameters are provided for four isomers: methyl isocyanate (CH3NCO), methyl cyanate (CH3OCN), methyl fulminate (CH3ONC), and acetonitrile N-oxide (CH3CNO). A CH3CON transition state is inspected. A variational procedure is employed to explore the far infrared region because some species present non-rigidity. Second order perturbation theory is used for the determination of anharmonic frequencies, rovibrational constants, and to predict Fermi resonances. Three species, methyl cyanate, methyl fulminate, and CH3CON, show a unique methyl torsion hindered by energy barriers. In methyl isocyanate, the methyl group barrier is so low that the internal top can be considered a free rotor. On the other hand, acetonitrile N-oxide presents a linear skeleton, C3v symmetry, and free internal rotation. Its equilibrium geometry depends strongly on electron correlation. The remaining isomers present a bend skeleton. Divergences between theoretical rotational constants and previous parameters fitted from observed lines for methyl isocyanate are discussed on the basis of the relevant rovibrational interaction and the quasi-linearity of the molecular skeleton.

(E)-4-Meth­oxy-N′-[(6-methyl-4-oxo-4H-chromen-3-yl)methyl­idene]benzo­hydrazide monohydrate

PubMed Central

Ishikawa, Yoshinobu; Watanabe, Kohzoh

2014-01-01

In the title hydrate, C19H16N2O4·H2O, the 4H-chromen-4-one segment is slightly twisted, with a dihedral angle between the two six-membered rings of 3.30 (5)°. The dihedral angles between the plane of the pyran­one ring and the hydrazide plane and between the planes of the pyran­one ring and the benzene ring of the p-meth­oxy­benzene unit are 26.69 (4) and 2.23 (3)°, respectively. The mol­ecule is connected to the solvent water mol­ecule by an N—H⋯O hydrogen bond. In the crystal, there are π–π stacking inter­actions between centrosymmetrically related pyran­one rings [centroid–centroid distance = 3.5394 (9) Å], as well as bridges formed by the water mol­ecules via O—H⋯O hydrogen bonds. PMID:25161570

Top-Contact Pentacene-Based Organic Thin Film Transistor (OTFT) with N, N'-Bis(3-Methyl Phenyl)- N, N'-Diphenyl Benzidine (TPD)/Au Bilayer Source-Drain Electrode

NASA Astrophysics Data System (ADS)

Borthakur, Tribeni; Sarma, Ranjit

2018-01-01

A top-contact Pentacene-based organic thin film transistor (OTFT) with N, N'-Bis (3-methyl phenyl)- N, N'-diphenyl benzidine (TPD)/Au bilayer source-drain electrode is reported. The devices with TPD/Au bilayer source-drain (S-D) electrodes show better performance than the single layer S-D electrode OTFT devices. The field-effect mobility of 4.13 cm2 v-1 s-1, the on-off ratio of 1.86 × 107, the threshold voltage of -4 v and the subthreshold slope of .27 v/decade, respectively, are obtained from the device with a TPD/Au bilayer source-drain electrode.

Cinnamic acid hydrogen bonds to isoniazid and N'-(propan-2-ylidene)isonicotinohydrazide, an in situ reaction product of isoniazid and acetone.

PubMed

Sarcevica, Inese; Orola, Liana; Veidis, Mikelis V; Belyakov, Sergey

2014-04-01

A new polymorph of the cinnamic acid-isoniazid cocrystal has been prepared by slow evaporation, namely cinnamic acid-pyridine-4-carbohydrazide (1/1), C9H8O2·C6H7N3O. The crystal structure is characterized by a hydrogen-bonded tetrameric arrangement of two molecules of isoniazid and two of cinnamic acid. Possible modification of the hydrogen bonding was investigated by changing the hydrazide group of isoniazid via an in situ reaction with acetone and cocrystallization with cinnamic acid. In the structure of cinnamic acid-N'-(propan-2-ylidene)isonicotinohydrazide (1/1), C9H8O2·C9H11N3O, carboxylic acid-pyridine O-H···N and hydrazide-hydrazide N-H···O hydrogen bonds are formed.

Crystal structure of {2,6-bis-[(di-methyl-amino)-meth-yl]phenyl-κ3N,C1,N'}(bromido/chlorido)-mercury(II).

PubMed

Gupta, Anand; Singh, Harkesh B; Butcher, Ray J

2017-11-01

In the mol-ecular structure of the title compound, {2,6-bis-[(di-methyl-amino)-meth-yl]phenyl-κ 3 N , C 1 , N '}[bromido/chlorido-(0.30/0.70)]mercury(II)-{2,6-bis-[(di-methyl-amino)-meth-yl]phenyl-κ 3 N , C 1 , N '}[bromido/chlorido-(0.24/0.76)]mer-cury(II) (1/1), [HgBr 0.30 Cl 0.70 (C 12 H 19 N 2 )]·[HgBr 0.24 Cl 0.76 (C 12 H 19 N 2 )], there are two mol-ecules in the asymmetric unit of formula L Hg X { L = 2,6-bis-[(di-methyl-amino)-meth-yl]phenyl and X = Cl/Br}. In each mol-ecule, the halide site is mixed Cl/Br, with occupancies of 0.699 (7):0.301 (7) and 0.763 (7):0.237 (7), respectively. The two mol-ecules are linked into dimers by a combination of Hg⋯Hg [Hg⋯Hg = 3.6153 (3) Å] and C-H⋯Cl and C-H⋯π inter-actions.

Nitrosoureas: a review of experimental antitumor activity.

PubMed

Schabel, F M

1976-06-01

The chemical class of drugs known as the nitrosoureas are a recently developed group of very active alkylating-agent anticancer drugs which are best represented by BCNU, CCNU, and methyl-CCNU (meCCNU). The nitrosoureas are among the most active, if not the most active, anticancer drugs both quantitatively (log kill of sensitive tumor cells in vivo) and qualitatively (spectrum of mouse, rat, and hamster tumors responding to treatment). Therapeutic anticancer activity of the nitrosoureas has been consistently observed with oral as well as parenteral administration. The nitrosoureas are clearly the most active group of anticancer drugs observed against experimental meningeal leukemias and intracerebrally implanted transplantable primary tumors of central nervous system origin (eg, gliomas, ependymoblastomas, and astrocytomas in mice and hamsters). The nitrosoureas have been observed to be less than additive in lethal toxicity for vital normal cells in the mouse in combination with representatives of the other major classes of anticancer agents, eg, purine antagonists, pyrimidine antagonists, inhibitors of DNA polymerase(s) or ribonucleotide reductase(s), mitotic inhibitors, drugs that bind to or intercalate with DNA, and other alkylating agents. Therapeutic synergism against one or more transplantable or spontaneous tumors of mice, rats, or hamsters with one of several nitrosoureas in two-drug combinations with representatives of most of the major classes of anticancer agents listed above has been reported. With a number of advanced-stages mouse tumors, generally considered to be refractory to treatment with most anticancer agents, long-term cures have been obtained with combination-drug or combined-modality (surgery plus chemotherapy) treatment. The demonstrated lack of cross-resistance of several leukemias and solid tumors of mice selected for resistance to BCNU, meCCNU, or other alkylating agents suggests that the widely held opinion that all alkylating agents are

Resistance of Salmonella typhimurium TA 1535 to O6-guanine methylation and mutagenesis induced by low doses of N-methyl-N'-nitro-N-nitrosoguanidine: an apparent constitutive repair activity.

PubMed

Guttenplan, J B; Milstein, S

1982-01-01

Salmonella tester strains which are reverted by base-pair substitution mutagens are relatively insensitive to the mutagenic effects of N-methyl-N-nitroso compounds. One reason for this insensitivity is the ability of these strains to withstand low doses of these compounds before they become sensitive to their mutagenic effects. In this report it is shown that mutagenesis induced by treatment of Salmonella typhimurium TA 1535 with N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) in buffer is biphasic with a low sensitivity range at low doses where little mutagenesis occurs, followed by a high sensitivity range whose onset begins after an apparent threshold dose has been exceeded. levels of O6-methylguanine (O6-MeG) in the DNA extracted from the bacteria follow a similar dose-response curve suggesting a dependency of mutagenesis on O6-MeG. In contrast, levels of 7-methylguanine (7-MeG) in the DNA increase linearly with dose. O6-MeG was undetectable at the lowest dose of MNNG whereas 7-MeG was readily detectable. Although such resistance to O6-alkylation has been demonstrated in MNNG- pretreated (adapted) E. coli, it has not been reported in unpretreated cells. Then isolated DNA was treated with MNNG a linear dose-response in the generation of O6-MeG was observed. The lack of O6-MeG in DNA isolated from MNNG treated cells after low doses is attributed to a saturable, constitutive repair activity in the bacteria. An attempt to observe the removal of O6-MeG from the bacteria after exposure to a short challenge dose of N-nitroso-N-methylurea (NMU) followed by a subsequent incubation in buffer was unsuccessful, probably because all the repair occurred within the time necessary to treat and lyse the cells.

Synthesis and characterization of 3-acetoxy-2-methyl-N-(phenyl)benzamide and 3-acetoxy-2-methyl-N-(4- methylphenyl)benzamide

NASA Astrophysics Data System (ADS)

Kırca, Başak Koşar; Çakmak, Şükriye; Kütük, Halil; Odabaşoğlu, Mustafa; Büyükgüngör, Orhan

2018-01-01

This study treats about two successfully synthesized secondary amide compounds 3-Acetoxy-2-methyl-N-(phenyl)benzamide, I and 3-Acetoxy-2-methyl-N-(4-methylphenyl)benzamide, II. Compounds were characterized by FTIR, 1H NMR, 13C NMR and X-ray single crystal diffraction analysis techniques. Single crystal X-ray diffraction analyses show that while I crystallized in the orthorhombic system with space group Pbca, II crystallized in the triclinic system with space group P-1 and the asymmetric unit of II consists of two crystallographically independent molecules. Lattice constants are a = 7.9713 (3) Å, b = 9.5059 (3) Å, c = 37.1762 (2) Å, Z = 8 for I and a = 7.5579 (8) Å, b = 8.8601 (8) Å, c = 23.363 (3) Å, α = 97.011 (9) °, β = 96.932 (9)°, γ = 90.051 (8)°, Z = 4 for II. Crystallographic studies also show that the supramolecular structures were stabilized by intramolecular, intermolecular hydrogen bonds and Csbnd H … π interactions for both compounds. Characteristic amide bonds were observed in IR and NMR spectra.

40 CFR 414.70 - Applicability; description of the bulk organic chemicals subcategory.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., Calcium Salt Maleic Anhydride Methacrylic Acid *Methacrylic Acid Esters Methane Methyl Ethyl Ketone Methyl Methacrylate Methyl Tert-Butyl Ether Methylisobutyl Ketone *n-Alkanes n-Butyl Alcohol n-Butylacetate n... Acid Nylon Salt Oxalic Acid *Oxo Aldehydes—Alcohols Pentaerythritol Pentane *Pentenes *Petroleum...

40 CFR 414.70 - Applicability; description of the bulk organic chemicals subcategory.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., Calcium Salt Maleic Anhydride Methacrylic Acid *Methacrylic Acid Esters Methane Methyl Ethyl Ketone Methyl Methacrylate Methyl Tert-Butyl Ether Methylisobutyl Ketone *n-Alkanes n-Butyl Alcohol n-Butylacetate n... Acid Nylon Salt Oxalic Acid *Oxo Aldehydes—Alcohols Pentaerythritol Pentane *Pentenes *Petroleum...

40 CFR 414.70 - Applicability; description of the bulk organic chemicals subcategory.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., Calcium Salt Maleic Anhydride Methacrylic Acid *Methacrylic Acid Esters Methane Methyl Ethyl Ketone Methyl Methacrylate Methyl Tert-Butyl Ether Methylisobutyl Ketone *n-Alkanes n-Butyl Alcohol n-Butylacetate n... Acid Nylon Salt Oxalic Acid *Oxo Aldehydes—Alcohols Pentaerythritol Pentane *Pentenes *Petroleum...

40 CFR 414.70 - Applicability; description of the bulk organic chemicals subcategory.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., Calcium Salt Maleic Anhydride Methacrylic Acid *Methacrylic Acid Esters Methane Methyl Ethyl Ketone Methyl Methacrylate Methyl Tert-Butyl Ether Methylisobutyl Ketone *n-Alkanes n-Butyl Alcohol n-Butylacetate n... Acid Nylon Salt Oxalic Acid *Oxo Aldehydes—Alcohols Pentaerythritol Pentane *Pentenes *Petroleum...

Design synthesis and structure-activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands.

PubMed

Deekonda, Srinivas; Rankin, David; Davis, Peg; Lai, Josephine; Vanderah, Todd W; Porecca, Frank; Hruby, Victor J

2016-01-15

Here, we report the design, synthesis and structure activity relationship of novel small molecule opioid ligands based on 5-amino substituted (tetrahydronaphthalen-2-yl)methyl moiety with N-phenyl-N-(piperidin-2-yl)propionamide derivatives. We synthesized various molecules including amino, amide and hydroxy substitution on the 5th position of the (tetrahydronaphthalen-2-yl)methyl moiety. In our further designs we replaced the (tetrahydronaphthalen-2-yl)methyl moiety with benzyl and phenethyl moiety. These N-phenyl-N-(piperidin-2-yl)propionamide analogues showed moderate to good binding affinities (850-4 nM) and were selective towards the μ opioid receptor over the δ opioid receptors. From the structure activity relationship studies, we found that a hydroxyl substitution at the 5th position of (tetrahydronapthalen-2yl)methyl group, ligands 19 and 20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand 19 showed potent agonist activities 75±21 nM, and 190±42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue 20 showed good agonist activities in MVD assays 170±42 nM, in contrast to its binding affinity results. Copyright © 2015 Elsevier Ltd. All rights reserved.

Efficient and Selective N-Methylation of Nitroarenes under Mild Reaction Conditions.

PubMed

Pedrajas, Elena; Sorribes, Iván; Guillamón, Eva; Junge, Kathrin; Beller, Matthias; Llusar, Rosa

2017-09-21

Herein, we report a straightforward protocol for the preparation of N,N-dimethylated amines from readily available nitro starting materials using formic acid as a renewable C 1 source and silanes as reducing agents. This tandem process is efficiently accomplished in the presence of a cubane-type Mo 3 PtS 4 catalyst. For the preparation of the novel [Mo 3 Pt(PPh 3 )S 4 Cl 3 (dmen) 3 ] + (3 + ) (dmen: N,N'-dimethylethylenediamine) compound we have followed a [3+1] building block strategy starting from the trinuclear [Mo 3 S 4 Cl 3 (dmen) 3 ] + (1 + ) and Pt(PPh 3 ) 4 (2) complexes. The heterobimetallic 3 + cation preserves the main structural features of its 1 + cluster precursor. Interestingly, this catalytic protocol operates at room temperature with high chemoselectivity when the 3 + catalyst co-exists with its trinuclear 1 + precursor. N-heterocyclic arenes, double bonds, ketones, cyanides and ester functional groups are well retained after N-methylation of the corresponding functionalized nitroarenes. In addition, benzylic-type as well as aliphatic nitro compounds can also be methylated following this protocol. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dibromidobis(N,N,N′,N′-tetra­methyl­thio­urea-κS)cadmium(II)

PubMed Central

Nawaz, Sidra; Sadaf, Sana; Fettouhi, Mohammed; Fazal, Atif; Ahmad, Saeed

2010-01-01

In the title compound, [CdBr2(C5H12N2S)2], the CdII atom lies on a twofold rotation axis. It exhibits a distorted tetra­hedral coordination environment defined by two S atoms of two tetra­methyl­thio­urea (tmtu) ligands and two bromide ions. The crystal structure is consolidated by C—H⋯N and C—H⋯S hydrogen bonds. PMID:21588180

Novel pyrrolinones as N-methyl-D-aspartate receptor antagonists.

PubMed

Poschenrieder, Hermann; Stachel, Hans-Dietrich; Höfner, Georg; Mayer, Peter

2005-04-01

A series of oximes, deriving from 2-arylidene-pyrroline-3,4-diones (7, 8, 22, 23) has been prepared. The presence of tautomers in their solutions has been established by spectroscopic means. The compounds reacted with diazomethane chiefly by N-methylation forming nitrones (10, 11). The analogously prepared 2-arylidene-4-nitropyrrolin-3-ones (12, 13, 24, 25), formally derived from nitrotetramic acids, yielded nitronic acid esters (14, 15, 26) upon reaction with diazomethane. The structures were elucidated by spectral evidence and-in the case of compounds 10 and 20b-by X-ray diffraction analysis. The binding affinity of some of the new compounds toward the N-methyl-d-aspartate (NMDA) (glycine site) receptor has been measured thus providing the basis for further structure-activity relationship studies. Oxime 8b showed the highest binding potency (Ki= 9.2 microM).

Computational Study of Environmental Effects on Torsional Free Energy Surface of N-Acetyl-N'-methyl-L-alanylamide Dipeptide

ERIC Educational Resources Information Center

Carlotto, Silvia; Zerbetto, Mirco

2014-01-01

We propose an articulated computational experiment in which both quantum mechanics (QM) and molecular mechanics (MM) methods are employed to investigate environment effects on the free energy surface for the backbone dihedral angles rotation of the small dipeptide N-Acetyl-N'-methyl-L-alanylamide. This computation exercise is appropriate for an…

Crystal structure of N-[3-(di­methyl­aza­nium­yl)prop­yl]-N′,N′,N′′,N′′-tetra­methyl-N-(N,N,N′,N′-tetra­methyl­form­am­id­in­ium­yl)­guanidinium dibromide hydroxide monohydrate

PubMed Central

Tiritiris, Ioannis; Kantlehner, Willi

2015-01-01

The asymmetric unit of the title hydrated salt, C15H37N6 3+·2Br−·OH−·H2O, contains one cation, three partial-occupancy bromide ions, one hydroxide ion and one water mol­ecule. Refinement of the site-occupancy factors of the three disordered bromide ions converges with occupancies 0.701 (2), 0.831 (2) and 0.456 (2) summing to approximately two bromide ions per formula unit. The structure was refined as a two-component inversion twin with volume fractions 0.109 (8):0.891 (8) for the two domains. The central C3N unit of the bis­amidinium ion is linked to the aliphatic propyl chain by a C—N single bond. The other two bonds in this unit have double-bond character as have the four C—N bonds to the outer NMe2 groups. In contrast, the three C—N bonds to the central N atom of the (di­methyl­aza­nium­yl)propyl group have single-bond character. Delocalization of the two positive charges occurs in the N/C/N and C/N/C planes, while the third positive charge is localized on the di­methyl­ammonium group. The crystal structure is stabilized by O—H⋯O, N—H⋯Br, O—H⋯Br and C—H⋯Br hydrogen bonds, forming a three-dimensional network. PMID:26870507

Insight into the theoretical and experimental studies of 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone N(4)-methyl-N(4)- phenylthiosemicarbazone - A potential NLO material

NASA Astrophysics Data System (ADS)

Sangeetha, K. G.; Aravindakshan, K. K.; Safna Hussan, K. P.

2017-12-01

The synthesis, geometrical parameters, spectroscopic studies, optimised molecular structure, vibrational analysis, Mullikan population analysis, MEP, NBO, frontier molecular orbitals and NLO effects of 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone N-(4)-methyl-N-(4)-phenylthiosemicarbazone, C25H23N5OS (L1) have been communicated in this paper. A combined experimental and theoretical approach was used to explore the structure and properties of the compound. For computational studies, Gaussian 09 program was used. Starting geometry of molecule was taken from X-ray refinement data and has been optimized by using DFT (B3LYP) method with the 6-31+G (d, p) basis sets. NBO analysis gave insight into the strongly delocalized structure, responsible for the nonlinearity and hence the stability of the molecule. Frontier molecular orbitals have been defined to forecast the global reactivity descriptors of L1. The computed first-order hyperpolarizability (β) of the compound is 2 times higher than that of urea and this account for its nonlinear optical property. Simultaneously, a molecular docking study of the compound was performed using GLIDE Program. For this, three biological enzymes, histone deacetylase, ribonucleotide reductase and DNA methyl transferase, were selected as receptor molecules.

40 CFR 721.2275 - N,N,N′,N′-Tetrakis(oxi-ranyl- methyl)-1,3-cyclohexane di-meth-anamine.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false N,N,Nâ²,Nâ²-Tetrakis(oxi-ranyl- methyl)-1,3-cyclohexane di-meth-anamine. 721.2275 Section 721.2275 Protection of Environment ENVIRONMENTAL...-cyclohexane di-meth-anamine. (a) Chemical substances and significant new uses subject to reporting. (1) The...

40 CFR 721.2275 - N,N,N′,N′-Tetrakis(oxi-ranyl- methyl)-1,3-cyclohexane di-meth-anamine.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false N,N,Nâ²,Nâ²-Tetrakis(oxi-ranyl- methyl)-1,3-cyclohexane di-meth-anamine. 721.2275 Section 721.2275 Protection of Environment ENVIRONMENTAL...-cyclohexane di-meth-anamine. (a) Chemical substances and significant new uses subject to reporting. (1) The...

40 CFR 721.2275 - N,N,N′,N′-Tetrakis(oxi-ranyl- methyl)-1,3-cyclohexane di-meth-anamine.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false N,N,Nâ²,Nâ²-Tetrakis(oxi-ranyl- methyl)-1,3-cyclohexane di-meth-anamine. 721.2275 Section 721.2275 Protection of Environment ENVIRONMENTAL...-cyclohexane di-meth-anamine. (a) Chemical substances and significant new uses subject to reporting. (1) The...

Synthesis, Characterization, and Anti-Cancer Activity of Some New N'-(2-Oxoindolin-3-ylidene)-2-propylpentane hydrazide-hydrazones Derivatives.

PubMed

El-Faham, Ayman; Farooq, Muhammad; Khattab, Sherine N; Abutaha, Nael; Wadaan, Mohammad A; Ghabbour, Hazem A; Fun, Hoong-Kun

2015-08-13

Eight novel N'-(2-oxoindolin-3-ylidene)-2-propylpentane hydrazide-hydrazone derivatives 4a-h were synthesized and fully characterized by IR, NMR ((1)H-NMR and (13)C-NMR), elemental analysis, and X-ray crystallography. The cyto-toxicity and in vitro anti-cancer evaluation of the prepared compounds have been assessed against two different human tumour cell lines including human liver (HepG2) and leukaemia (Jurkat), as well as in normal cell lines derived from human embryonic kidney (HEK293) using MTT assay. The compounds 3e, 3f, 4a, 4c, and 4e revealed promising anti-cancer activities in tested human tumour cells lines (IC50 values between 3 and 7 μM) as compared to the known anti-cancer drug 5-Fluorouracil (IC50 32-50 μM). Among the tested compounds, 4a showed specificity against leukaemia (Jurkat) cells, with an IC50 value of 3.14 μM, but this compound was inactive in liver cancer and normal cell lines.

4-Methyl-N-(1-methyl-1H-indazol-5-yl)benzene­sulfonamide

PubMed Central

Chicha, Hakima; Oulemda, Bassou; Rakib, El Mostapha; Saadi, Mohamed; El Ammari, Lahcen

2013-01-01

In the title compound, C15H15N3O2S, the fused ring system is close to planar, the largest deviation from the mean plane being 0.030 (2) Å, and makes a dihedral angle of 48.84 (9)° with the benzene ring belonging to the methyl­benzene­sulfonamide moiety. In the crystal, mol­ecules are ­connected through N—H⋯N hydrogen bonds and weak C—H⋯O contacts, forming a two-dimensional network parallel to (001). PMID:24427093

Methyl N-phenyl carbamate synthesis from aniline and methyl formate: carbon recycling to chemical products.

PubMed

Yalfani, Mohammad S; Lolli, Giulio; Müller, Thomas E; Wolf, Aurel; Mleczko, Leslaw

2015-02-01

Methyl N-phenyl carbamate was synthesized from aniline by using methyl formate as a green and efficient carbonylating agent. High yields were obtained at milder reaction conditions compared to the conventional CO/CH3 OH route. Studies on the reaction sequence led to suggest an alternative and more efficient route to the carbamate via formanilide as intermediate. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

New method to measure the carbamoylating activity of nitrosoureas by electron paramagnetic resonance spectroscopy.

PubMed

Gadzheva, V; Ichimori, K; Raikov, Z; Nakazawa, H

1997-08-01

A new method for measuring the carbamoylating activity of nitrosoureas and isocyanates using electron paramagnetic resonance (EPR) spectroscopy is described. The extent and time course of carbamoylation reaction of chloroethyl isocyanate and a series of 9 nitrosoureas toward amino group of 4-amino-2,2,6,6-tetramethyl-piperidine-1-oxyl were examined with both the EPR method and the HPLC method which has been proposed by Brubaker et al. [Biochem. Pharmacol. 35:2359 (1986)]. Spin-labeled nitrosoureas we synthesized are included in this study since they have less toxicity or more efficiency than commercially available drug in some cases. The concentration of carbamoylated product was easily determined with the EPR spectra. There is a very high correlation (r = 0.982, t = 2.58, N = 10, p < 0.001) between the EPR and HPLC methods. Spin-labeled nitrosoureas showed lower carbamoylating activity than non-labeled analogues. The carbamoylating activity for these nitrosourea depended on the reactivity of isocyanate intermediate and almost independent of their half life. This rapid and simple EPR method is suitable for the detailed investigation of the rate and extent of carbamoylation reaction.

Demonstration of hydrazide tagging for O-glycans and a central composite design of experiments optimization using the INLIGHT™ reagent.

PubMed

King, Samuel R; Hecht, Elizabeth S; Muddiman, David C

2018-02-01

The INLIGHT™ strategy for N-linked glycan derivatization has been shown to overcome many of the challenges associated with glycan analysis. The hydrazide tag reacts efficiently with the glycans, increasing their non-polar surface area, allowing for reversed-phase separations and increased ionization efficiency. We have taken the INLIGHT™ strategy and adopted it for use with O-linked glycans. A central composite design was utilized to find optimized tagging conditions (45% acetic acid, 0.1 μg/μL tag concentration, 37 C, 1.75 h). Derivatization at optimized conditions was much quicker than any hydrazide derivatization strategy used previously. Human immunoglobulin A (IgA) and bovine submaxillary mucin (BSM) were then deglycosylated through hydrazinolysis and the removed glycans were tagged under optimum conditions. XIC of tagged glycans and MS2 data show successful hydrazide tagging of O-linked glycans for the first time. Graphical abstract The INLIGHT™ hydrazide tag was optimized using a central composite design for derivatization of O-linked glycans. Two glycoprotein standards were deglycosylated through hydrazinolysis and tagged at the optimized conditions. MS/MS data shows INLIGHT™ derivatization of glycans demonstrating successful hydrazide tagging of O-glycans for the first time.

Cyclic mu-opioid receptor ligands containing multiple N-methylated amino acid residues.

PubMed

Adamska-Bartłomiejczyk, Anna; Janecka, Anna; Szabó, Márton Richárd; Cerlesi, Maria Camilla; Calo, Girolamo; Kluczyk, Alicja; Tömböly, Csaba; Borics, Attila

2017-04-15

In this study we report the in vitro activities of four cyclic opioid peptides with various sequence length/macrocycle size and N-methylamino acid residue content. N-Methylated amino acids were incorporated and cyclization was employed to enhance conformational rigidity to various extent. The effect of such modifications on ligand structure and binding properties were studied. The pentapeptide containing one endocyclic and one exocyclic N-methylated amino acid displayed the highest affinity to the mu-opioid receptor. This peptide was also shown to be a full agonist, while the other analogs failed to activate the mu opioid receptor. Results of molecular docking studies provided rationale for the explanation of binding properties on a structural basis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Preparation, electrochemical and spectral properties of free-base and manganese N-methyl-pyridylethynyl porphyrins.

PubMed

Lin, Ching-Yao; Chen, Yen-Chuan; Yao, Chi-Wen; Huang, Sung-Chou; Cheng, Yi-Hui

2008-02-14

Two series of free-base and manganese N-methyl-pyridylethynyl-5,15-biphenyl porphyrins were synthesized, and their UV-Visible, electrochemical and spectro-electrochemical properties were studied. Cyclic voltammetry experiments showed positive shifts in the reduction potentials and the UV-Visible spectra showed significant red-shifts in the absorption wavelengths of these porphyrins, indicating the effects of N-methyl-pyridylethynyl substituents.

N-(1-Allyl-1H-indazol-5-yl)-4-methyl-benzene-sulfonamide.

PubMed

Chicha, Hakima; Rakib, El Mostapha; Abderrafia, Hafid; Saadi, Mohamed; El Ammari, Lahcen

2013-11-30

The asymmetric unit of the title compound, C17H17N3O2S, contains two independent mol-ecules linked by an N-H⋯O hydrogen bond. The mol-ecules show different conformations. In the first mol-ecule, the fused five- and six-membered ring system is almost perpendicular to the plane through the atoms forming the allyl group, as indicated by the dihedral angle of 85.1 (4)°. The dihedral angle with the methyl-benzene-sulfonamide group is 78.8 (1)°. On the other hand, in the second mol-ecule, the dihedral angles between the indazole plane and the allyl and methyl-benzene-sulfonamide groups are 80.3 (3) and 41.5 (1)°, respectively. In the crystal, mol-ecules are further linked by N-H⋯N and C-H⋯O hydrogen bonds, forming a three-dimensional network.

Crystal structures of isomeric 3,5-di-chloro-N-(2,3-di-methyl-phen-yl)benzene-sulfonamide, 3,5-di-chloro-N-(2,6-di-methyl-phen-yl)benzene-sulfonamide and 3,5-di-chloro-N-(3,5-di-methyl-phen-yl)benzene-sulfonamide.

PubMed

Shakuntala, K; Naveen, S; Lokanath, N K; Suchetan, P A

2017-05-01

The crystal structures of three isomeric compounds of formula C 14 H 13 Cl 2 NO 2 S, namely 3,5-di-chloro- N -(2,3-di-methyl-phen-yl)-benzene-sulfonamide (I), 3,5-di-chloro- N -(2,6-di-methyl-phen-yl)benzene-sulfonamide (II) and 3,5-di-chloro- N -(3,5-di-methyl-phen-yl)benzene-sulfonamide (III) are described. The mol-ecules of all the three compounds are U-shaped with the two aromatic rings inclined at 41.3 (6)° in (I), 42.1 (2)° in (II) and 54.4 (3)° in (III). The mol-ecular conformation of (II) is stabilized by intra-molecular C-H⋯O hydrogen bonds and C-H⋯π inter-actions. The crystal structure of (I) features N-H⋯O hydrogen-bonded R 2 2 (8) loops inter-connected via C (7) chains of C-H⋯O inter-actions, forming a three-dimensional architecture. The structure also features π-π inter-actions [ Cg ⋯ Cg = 3.6970 (14) Å]. In (II), N-H⋯O hydrogen-bonded R 2 2 (8) loops are inter-connected via π-π inter-actions [inter-centroid distance = 3.606 (3) Å] to form a one-dimensional architecture running parallel to the a axis. In (III), adjacent C (4) chains of N-H⋯O hydrogen-bonded mol-ecules running parallel to [010] are connected via C-H⋯π inter-actions, forming sheets parallel to the ab plane. Neighbouring sheets are linked via offset π-π inter-actions [inter-centroid distance = 3.8303 (16) Å] to form a three-dimensional architecture.

Crystal structure of N,N,N′,N′,N′′,N′′-hexa­methyl­guanidinium cyanate 1.5-hydrate

PubMed Central

Tiritiris, Ioannis; Kantlehner, Willi

2015-01-01

The title hydrated salt, C7H18N3 +·OCN−.1.5H2O, was synthesized starting from N,N,N′,N′,N′′,N′′-hexa­methyl­guanidinium chloride by a twofold anion-exchange reaction. The asymmetric unit contains two cations, two cyanate anions and three water mol­ecules. One cation shows orientational disorder and two sets of N-atom positions were found related by a 60° rotation, with an occupancy ratio of 0.852 (6):0.148 (6). The C—N bond lengths in both guanidin­ium ions range from 1.329 (2) to 1.358 (10) Å, indicating double-bond character, pointing towards charge delocalization within the NCN planes. Strong O—H⋯N hydrogen bonds between the crystal water mol­ecules and the cyanate ions and strong O—H⋯O hydrogen bonds between the water mol­ecules are present, resulting in a two-dimensional hydrogen bonded network running parallel to the (001) plane. The hexa­methyl­guanidinium ions are packed in between the layers built up by water mol­ecules and cyanate ions. PMID:26870506

Bis[μ-N-(tert-butyl­dimethyl­silyl)-N-(pyridin-2-ylmeth­yl)amido]­bis­[methyl­cobalt(II)

PubMed Central

Malassa, Astrid; Agthe, Christine; Görls, Helmar; Westerhausen, Matthias

2012-01-01

The green title complex, [Co2(CH3)2(C12H21N2Si)2], was obtained from bis­{[μ-N-tert-butyl­dimethyl­silyl-N-(pyridin-2-ylmeth­yl)amido]­chloridocobalt(II)} and methyl­lithium in diethyl ether at 195 K via a metathesis reaction. The dimeric cobalt(II) complex exhibits a crystallographic center of inversion in the middle of the Co2N2 ring (average Co—N = 2.050 Å). The CoII atom shows a distorted tetra­hedral coordination sphere. The exocyclic Co—N bond length to the pyridyl group shows a similar value of 2.045 (4) Å. The exocyclic methyl group has a rather long Co—C bond length of 2.019 (5) Å. PMID:22969464

Spin labelled nitrosoureas and triazenes and their non-labelled clinically used analogues--a comparative study on their physicochemical properties and antimelanomic effects.

PubMed

Zheleva, A M; Gadjeva, V G

2001-01-16

Physicochemical properties, such as half life time (tau0.5), alkylating and carbamoylating activity and in vivo antimelanomic effects against B16 melanoma of spin labeled (containing nitroxyl free radical moiety) amino acid nitrosoureas, synthesized in our laboratory, have been studied and compared to those of the antitumor drug N'-cyclohexyl-N-(2-chloroethyl)-N-nitrosourea (lomustine, CCNU). We have shown that the introduction of amino acid moieties and the replacement of cyclohexylamine with nitroxyl moiety leads to a faster decomposition, higher alkylating, lower carbamoylating activity, better antimelanomic activity and lower general toxicity, when compared to those of CCNU. It was also established that spin labeled triazenes, previously synthesized by us, were more stable in phosphate saline than their nonlabeled analogue, 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (dacarbazine, DTIC). A higher cytotoxicity to B16 melanoma cells than to YAC-1 and lymphocytes was demonstrated for all spin labeled triazenes, in comparison with DTIC. An assumption has been made to explain the lower general toxicity of the spin labeled nitrosoureas compared to that of CCNU. Based on the results presented, we accept that a new trend for synthesis of more selective and less toxic nitrosourea and triazene derivatives as potential antimelanomic drugs might be developed.

COMPARISON OF ACUTE NEUROBEHAVIORAL EFFECTS OF N-METHYL CARBAMATE INSECTICIDES.

EPA Science Inventory

The acute neurobehavioral and cholinesterase (ChE)-inhibiting effects of N-methyl carbamate insecticides have not been systematically compared. We evaluated five carbamates - carbaryl (CB), propoxur (PP), oxamyl (OM), methomyl (MM), and methiocarb (MC). Adult male Long-Evans ra...

Tyramine Pathways in Citrus Plant Defense: Glycoconjugates of Tyramine and Its N-Methylated Derivatives.

PubMed

Servillo, Luigi; Castaldo, Domenico; Giovane, Alfonso; Casale, Rosario; D'Onofrio, Nunzia; Cautela, Domenico; Balestrieri, Maria Luisa

2017-02-01

Glucosylated forms of tyramine and some of its N-methylated derivatives are here reported for the first time to occur in Citrus genus plants. The compounds tyramine-O-β-d-glucoside, N-methyltyramine-O-β-d-glucoside, and N,N-dimethyltyramine-O-β-d-glucoside were detected in juice and leaves of sweet orange, bitter orange, bergamot, citron, lemon, mandarin, and pomelo. The compounds were identified by mass spectrometric analysis, enzymatic synthesis, and comparison with extracts of Stapelia hirsuta L., a plant belonging to the Apocynaceae family in which N,N-dimethyltyramine-O-β-d-glucoside was identified by others. Interestingly, in Stapelia hirsuta we discovered also tyramine-O-β-d-glucoside, N-methyltyramine-O-β-d-glucoside, and the tyramine metabolite, N,N,N-trimethyltyramine-O-β-glucoside. However, the latter tyramine metabolite, never described before, was not detected in any of the Citrus plants included in this study. The presence of N-methylated tyramine derivatives and their glucosylated forms in Citrus plants, together with octopamine and synephrine, also deriving from tyramine, supports the hypothesis of specific biosynthetic pathways of adrenergic compounds aimed to defend against biotic stress.

Synthesis, structural, optical and thermal properties of N-methyl-N-aryl benzamide organic single crystals grown by a slow evaporation technique

NASA Astrophysics Data System (ADS)

Prabukanthan, P.; Lakshmi, R.; Harichandran, G.; Kumar, C. Sudarsana

2018-03-01

The organic materials, N-methyl-N-aryl benzamides were synthesized from benzoylation of N-methyl-4-nitrobenzenamine (MNBA) using suitably substituted benzoyl chlorides. The products were purified by recrystallization and their single crystal were grown by a slow evaporation technique. The crystals were characterized by FTIR, UV-Vis-NIR, 1H &13C NMR, and single & powder X-ray diffraction. Thermal stability of the crystals was studied by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Dielectric and NLO properties of MNPB, FMNPB and MMNPB crystals were studied. The second harmonic generation (SHG) has been confirmed by the Kurtz powder test for all these crystals and the SHG efficiency of MMNPB crystal was found to be 2.25 times higher than that of KDP crystal.

DOSE-RESPONSE MODELING FOR THE ASSESSMENT OF CUMULATIVE RISK DUE TO EXPOSURE TO N-METHYL CARBAMATE PESTICIDES

EPA Science Inventory

The US EPAs N-Methyl Carbamate Cumulative Risk Assessment (NMCRA) assesses the effect on acetylcholine esterase (AChE) activity of exposure to 10 N-methyl carbamate (NMC) pesticides through dietary, drinking water, and residential exposures.

N-mustard analogs of S-adenosyl-L-methionine as biochemical probes of protein arginine methylation.

PubMed

Hymbaugh Bergman, Sarah J; Comstock, Lindsay R

2015-08-01

Nucleosomes, the fundamental building blocks of eukaryotic chromatin, undergo post-synthetic modifications and play a major role in the regulation of transcriptional processes. Combinations of these modifications, including methylation, regulate chromatin structure, determining its different functional states and playing a central role in differentiation. The biological significance of cellular methylation, particularly on chromatin, is widely recognized, yet we know little about the mechanisms that link biological methylation events. To characterize and fully understand protein methylation, we describe here novel N-mustard analogs of S-adenosyl-l-methionine (SAM) as biochemical tools to better understand protein arginine methylation events using protein arginine methyltransferase 1 (PRMT1). Specifically, azide- and alkyne-functionalized N-mustard analogs serve as cofactor mimics of SAM and are enzymatically transferred to a model peptide substrate in a PRMT1-dependent fashion. Once incorporated, the resulting alkynes and azides can be modified through chemoselective ligations, including click chemistry and the Staudinger ligation. These results readily demonstrate the feasibility of utilizing N-mustard analogs as biochemical tools to site-specifically label substrates of PRMT1 and serve as an alternative approach to study protein methylation events. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Radiosynthesis and radiopharmacological evaluation of [N-methyl-11C]Org 34850 as a glucocorticoid receptor (GR)-binding radiotracer.

PubMed

Wuest, Frank; Kniess, Torsten; Henry, Brian; Peeters, Bernardus W M M; Wiegerinck, Peter H G; Pietzsch, Jens; Bergmann, Ralf

2009-02-01

The radiosynthesis of [N-methyl-(11)C]Org 34850 as a potential brain glucocorticoid receptor (GR)-binding radiotracer is described. The radiosynthesis was accomplished via N-methylation of the corresponding desmethyl precursor with [(11)C]methyl triflate in a remotely controlled synthesis module to give the desired compound in a radiochemical yield of 23+/-5% (decay-corrected, based upon [(11)C]CO(2)) at a specific activity of 47+/-12 GBq/micromol (n=15) at the end-of-synthesis (EOS). The radiochemical purity after semi-preparative HPLC purification exceeded 95%. The total synthesis time was 35-40 min after end-of-bombardment (EOB). The radiotracer is rapidly metabolized in rat plasma leading to the formation of two more hydrophilic metabolites as the major metabolites. Radiopharmacological evaluation involving biodistribution and small animal PET imaging in normal Wistar rats showed that the compound [N-methyl-(11)C]Org 34850 is not able to sufficiently penetrate the blood-brain barrier. Therefore, compound [N-methyl-(11)C]Org 34850 seems not to be a suitable PET radiotracer for imaging rat brain GRs. However, involvement of Pgp or species differences requires further clarification to establish whether the radiotracer [N-methyl-(11)C]Org 34850 may still represent a suitable candidate for imaging GRs in humans.

Glycerol as a Building Block for Prochiral Aminoketone, N-Formamide, and N-Methyl Amine Synthesis.

PubMed

Dai, Xingchao; Rabeah, Jabor; Yuan, Hangkong; Brückner, Angelika; Cui, Xinjiang; Shi, Feng

2016-11-23

Prochiral aminoketones are key intermediates for the synthesis of optically active amino alcohols, and glycerol is one of the main biomass-based alcohols available in industry. In this work, glycerol was catalytically activated and purposefully converted with amines to generate highly valuable prochiral aminoketones, as well as N-formamides and N-methyl amines, over CuNiAlO x catalyst. The catalyst structure can be anticipated as nano-Ni species on or in CuAlO x via the formation of nano- Cu-Ni alloy particles. This concept may present a novel and valuable methodology for glycerol utilization. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The cocrystal rac-1-[(N,4-dimethylbenzenesulfonamido)methyl]-2-(diphenylphosphoryl)ferrocene-rac-1-[(N,4-dimethylbenzenesulfonamido)methyl]-2-(diphenylphosphanyl)ferrocene (0.45/0.55).

PubMed

Wei, Muh Mei; Audin, Catherine; Manoury, Eric; Deydier, Eric; Daran, Jean Claude

2014-03-01

As part of our interest in the synthesis and catalytic applications of chiral (diphenylphosphanyl)ferrocene ligands, we designed a number of P,N-containing ligands for use in asymmetric transfer hydrogenation (ATH). During the synthetic procedure to obtain rac-1-[(N,4-dimethylbenzenesulfonamido)methyl]-2-(diphenylphosphanyl)ferrocene, the title compound, [Fe(C5H5)(C26H25NO2PS)]0.55 · [Fe(C5H5)(C26H25NO3PS)]0.45, was obtained as a by-product. It is composed of a ferrocene group disubstituted by a partially oxidized diphenylphosphanyl group, as confirmed by (31)P NMR analysis, and an (N,4-dimethylbenzenesulfonamido)methyl substituent. Owing to the partially oxidized diphenylphosphanyl group, it is best to view the crystal as being composed of a mixture of non-oxidized and oxidized phosphane, so it can be regarded as a cocrystal. It is also a racemate. To the best of our knowledge, the P=O distance [1.344 (4) Å] is the shortest observed for related (diphenylphosphoryl)ferrocene compounds. The packing is stabilized by weak C-H...O interactions, forming R2(2)(10) hydrogen-bonding motifs, which build up a chain along the c axis.

75 FR 58315 - Hazardous Waste Management System; Identification and Listing of Hazardous Waste; Direct Final...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-24

... benzene, ethyl ether, methyl isobutyl ketone, n-butyl alcohol, cyclohexane, methanol. F005 Toluene, methyl... alcohol. U147 Maleic anhydride. U154 Methanol. U159 Methyl ethyl ketone. U161 Methyl isobutyl ketone. U213..., methyl isobutyl ketone, n-butyl alcohol, cyclohexane, methanol. F005 Toluene, methyl ethyl ketone, carbon...

Solubility and diffusivity of N{sub 2}O and CO{sub 2} in (diethanolamine + N-methyldiethanolamine + water) and in (diethanolamine + 2-amino-2-methyl-1-propanol + water)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, M.H.; Lee, W.C.

1996-05-01

Acid gases such as CO{sub 2} and H{sub 2}S are frequently removed from natural gas, synthetic natural gas, and other process gas streams by means of absorption into aqueous alkanol-amine solutions. The solubility and diffusivity of N{sub 2}O in (diethanolamine + N-methyldiethanolamine + water) and in (diethanolamine + 2-amino-2-methyl-1-propanol + water) were measured at (30, 35, and 40)C and at atmospheric pressure. Five (diethanolamine + N-methyldiethanolamine + water) and four (diethanolamine + 2-amino-2-methyl-1-propanol + water) systems were studied. The total amine mass percent in all cases was 30. A solubility apparatus was used to measure the solubility of N{sub 2}Omore » in amine solutions. The diffusivity was measured by a wetted wall column absorber. The N{sub 2}O analogy was used to estimate the solubility and diffusivity of CO{sub 2} in (diethanolamine + N-methyldiethanolamine + water) and in (diethanolamine + 2-amino-2-methyl-1-propanol + water).« less

Oxygenated N-Acyl Alanine Methyl Esters (NAMEs) from the Marine Bacterium Roseovarius tolerans EL-164.

PubMed

Bruns, Hilke; Herrmann, Jennifer; Müller, Rolf; Wang, Hui; Wagner Döbler, Irene; Schulz, Stefan

2018-01-26

The marine bacterium Roseovarius tolerans EL-164 (Rhodobacteraceae) can produce unique N-acylalanine methyl esters (NAMEs) besides strucutrally related N-acylhomoserine lactones (AHLs), bacterial signaling compounds widespread in the Rhodobacteraceae. The structures of two unprecedented NAMEs carrying a rare terminally oxidized acyl chain are reported here. The compounds (Z)-N-16-hydroxyhexadec-9-enoyl-l-alanine methyl ester (Z9-16-OH-C16:1-NAME, 3) and (Z)-N-15-carboxypentadec-9-enoyl-l-alanine methyl ester (16COOH-C16:1-NAME, 4) were isolated, and the structures were determined by NMR and MS experiments. Both compounds were synthesized to prove assignments and to test their biological activity. Finally, non-natural, structurally related Z9-3-OH-C16:1-NAME (18) was synthesized to investigate the mass spectroscopy of structurally related NAMEs. Compound 3 showed moderate antibacterial activity against microorganisms such as Bacillus, Streptococcus, Micrococcus, or Mucor strains. In contrast to AHLs, quorum-sensing or quorum-quenching activity was not observed.

Stimulation of Methanogenesis by Aldicarb and Several Other N-Methyl Carbamate Pesticides †

PubMed Central

Kiene, Ronald P.; Capone, Douglas G.

1986-01-01

Aldicarb and several other N-methyl carbamate pesticides stimulated methane production in anaerobic salt marsh soils and organic-rich aquifer soils. Stimulation was biological and linearly related to the amount of carbamate added. Of the four carbamates studied, methomyl gave the greatest stimulation followed by carbaryl, aldicarb, and baygon. The percent conversions [(moles of CH4 in excess of control/mole of carbamate added) × 100] for methomyl, carbaryl, aldicarb, and baygon were 88, 57, 40, and 11, respectively. Using aldicarb as a model carbamate, we found that monomethylamine (MA) accumulated in sediments as a result of aldicarb addition. MA arises from the N-methyl carbamoyl portion of the carbamates as a result of presumptive biological hydrolysis. MA levels decreased as CH4 production was stimulated, and 2-bromoethane sulfonic acid (a specific inhibitor of mathanogenesis) partially inhibited the loss of MA. These findings suggest that N-methyl carbamates are readily hydrolyzed to MA in the presence of an active microbial population under anaerobic conditions and that methanogenesis is stimulated as a result of the consumption of MA by methanogenic bacteria. PMID:16347082

DNA methylation of ESR-1 and N-33 in colorectal mucosa of patients with ulcerative colitis (UC).

PubMed

Arasaradnam, Ramesh P; Khoo, Kevin; Bradburn, Mike; Mathers, John C; Kelly, Seamus B

2010-07-01

Epigenetic marking such as DNA methylation influence gene transcription and chromosomal stability and may also be affected by environmental exposures. Few studies exist on alteration in DNA methylation profiles (genomic and gene specific methylation) in patients with Ulcerative Colitis (UC) and no studies exist that assess its relationship with lifestyle exposures. The methylation level of both ESR-1 and N-33 genes were significantly higher in UC subjects compared with controls (7.9% vs. 5.9%; p = 0.015 and 66% vs. 9.3%; p < 0.001 respectively). There was no detectable difference in global DNA methylation between patients with UC and age and sex matched controls. No associations between indices of DNA methylation and anthropometric measures or smoking patterns were detected. To assess genomic methylation and promoter methylation of the ESR-1 (oestrogen receptor-1) and N-33 (tumor suppressor candidate-3) genes in the macroscopically normal mucosa of UC patients as well as to investigate effects of anthropometric and lifestyle exposures on DNA methylation. Sixty eight subjects were recruited (24 UC and 44 age and sex matched controls). Colorectal mucosal biopsies were obtained and DNA was extracted. Genomic DNA methylation was quantified using the tritium-labelled cytosine extension assay (3[H] dCTP) while gene specific methylation was quantified using the COBRA method. For the first time, we have shown increased methylation in the promoter regions of the putative tumor suppressor gene N-33 in macroscopically normal mucosa of patients with UC. In addition, we have confirmed that methylation of ESR-1 promoter is higher in UC patients compared with age and sex matched controls. These findings suggest that inactivation through methylation of the putative tumor suppressor genes N-33 and ESR-1 may not be associated with colorectal carcinogenesis in UC.

Enzymatic hydrolysis of cellulose pretreated with ionic liquids and N-methyl Morpholine N-Oxide

NASA Astrophysics Data System (ADS)

Yau Li, Elizabeth

The effect of N-methyl Morpholine N-Oxide (NMMO), 1-ethyl-3-methyl-imidazolium acetate ([Emim]Ac) and 1-ethyl-3-methyl-imidazolium diethyl phosphate ([Emim]DEP) on pretreatment and enzymatic hydrolysis of dissolving pulp was studied. X-ray diffraction measurements of regenerated cellulose from these solvents showed that solvent pretreatment reduces the crystallinity of cellulose. However, crystallinity might not be a major factor affecting the in-situ enzymatic hydrolysis of cellulose in these solvents. Although regenerated cellulose from [Emim]DEP showed the lowest crystallinity index (˜15%), in-situ enzymatic hydrolysis of cellulose dissolved in NMMO showed the highest cellulose conversion (68% compared to 65% for [Emim]Ac and 37% for [Emim]DEP at enzyme loading of 122 FPU/g). Moreover, results showed that enzymes could tolerate up to NMMO concentration of 100 g/L and still yield full conversion of cellulose. Since it is not necessary to remove all the NMMO, less amount of water will be required for the washing step and thus the process will be more economical. The HCH-1 model was used in an attempt to model the enzymatic hydrolysis of cellulose in NMMO. With the incorporation of NMMO inhibition and a factor to account for unreacted cellulose, the model was able to correlate the experimental data of the enzymatic hydrolysis of cellulose (6.68 g/L) at various NMMO concentrations (0, 50, 100, 150 and 250 g/L). However, the experimental results also suggest that NMMO might be deactivating the enzymes rather than inhibiting them. More studies need to be done at varying cellulose, NMMO and enzyme concentrations to find the exact nature of this deactivation of NMMO.

4-(Di­methyl­amino)­pyridinium trichlorido[4-(di­methyl­amino)­pyridine-κN]cobaltate(II)

PubMed Central

Guenifa, Fatiha; Hadjadj, Nasreddine; Zeghouan, Ouahida; Bendjeddou, Lamia; Merazig, Hocine

2013-01-01

In the anion of the title compound, (C7H11N2)[CoCl3(C7H10N2)], the CoII ion is coordinated by one N atom from a 4-(di­methyl­amino)­pyridine (DMAP) ligand and three Cl atoms, forming a CoNCl3 polyhedron with a distorted tetra­hedral geometry. In the crystal, cations and anions are linked via weak N—H⋯Cl and C—H⋯Cl hydrogen bonds. Double layers of complex anions stack along the b- axis direction, which alternate with double layers of 4-(di­methyl­amino)-pyridinium cations. PMID:24046560

Crystal structure of di-μ-chlorido-bis-(chlorido-{N1,N1-diethyl-N4-[(pyridin-2-yl-κN)methyl-idene]benzene-1,4-di-amine-κN4}mercury(II)).

PubMed

Faizi, Md Serajul Haque; Dege, Necmi; Goleva, Kateryna

2017-06-01

The title dinuclear mercury(II) complex, [Hg 2 Cl 4 (C 16 H 19 N 3 ) 2 ], synthesized from the pyridine-derived Schiff base ( E )- N 1 , N 1 -diethyl- N 4 -[(pyridin-2-yl)methyl-idene]benzene-1,4-di-amine (DPMBD), has inversion symmetry. The five-coordinated Hg II atoms have distorted square-pyramidal stereochemistry comprising two N-atom donors from bidentate chelate BPMBD ligands and three Cl-atom donors, two bridging and one monodentate. The dihedral angle between the benzene and the pyridine rings in the BPMBD ligand is 7.55 (4)°. In the crystal, the dinuclear mol-ecules are linked by weak C-H⋯Cl hydrogen bonds, forming zigzag ribbons lying parallel to [001]. Also present in the structure are π-π inter-actions between benzene and pyridine rings [minimum ring-centroid separation = 3.698 (8) Å].

Streptozotocin Diabetes CORRELATION WITH EXTENT OF DEPRESSION OF PANCREATIC ISLET NICOTINAMIDE ADENINE DINUCLEOTIDE

PubMed Central

Anderson, Tom; Schein, Philip S.; McMenamin, Mary G.; Cooney, David A.

1974-01-01

The diabetogenic activity of streptozotocin has been correlated with a reduction in pyridine nucleotide synthesis in the mouse pancreatic islet. To determine the specificity of this reduction for diabetogenicity, a comparative study of streptozotocin, its cytotoxic moiety, 1-methyl-1-nitrosourea, and alloxan was performed. Streptozotocin administered intraperitoneally (i.p.) producd a dose-related reduction in islet NAD which was proportional to the degree of diabetogenicity. A diabetogenic dose, 200 mg/kg, attained a peak plasma N-nitroso intact streptozotocin concentration of 0.224 μmol/ml and reduced the mean islet NAD from a control of 0.78 to 0.15 pmol. At borderline, 150 mg/kg, and nondiabetogenic, 100 mg/kg, doses, plasma concentrations reached 0.161 and 0.136 μmol/ml, and NAD was 0.36 and 0.86 pmol/islet, respectively. 1-Methyl-1-nitrosourea, 100 mg/kg, attained a maximum N-nitroso intact 1-methyl-1-nitrosourea concentration of 0.162 μmol/ml and reduced the mean NAD to 0.58 pmol/islet, and was nondiabetogenic; 200 mg/kg attained a peak plasma concentration of 0.344 μmol/ml and depressed NAD to 0.38 pmol/islet, and was inconsistently diabetogenic. Islet NAD of 0.4 pmol/islet or greater is required for integrity of the beta cell. A diabetogenic dose of alloxan, 500 mg/kg, did not depress NAD, 0.85 pmol/islet, therefore confirming that its mechanism of diabetogenicity differs from that of streptozotocin. In vivo uptake of [methyl-14C]streptozotocin by islets was 3.8 times that of [methyl-14C]-1-methyl-1-nitrosourea, whereas uptake by the exocrine pancreas favored 1-methyl-1-nitrosourea over streptozotocin 2.4:1. The decreased islet uptake of 1-methyl-1-nitrosourea correlates with the 3.5 times increased molar dosage required to produce islet NAD depression comparable to that of streptozotocin, 150 mg/kg. These studies indicate that the glucose carrier of streptozotocin facilitates uptake of its cytotoxic group, 1-methyl-1-nitrosourea, into islets. PMID

Investigation of TRPV1 loss-of-function phenotypes in TRPV1 Leu206Stop mice generated by N-ethyl-N-nitrosourea mutagenesis.

PubMed

Christoph, Thomas; Kögel, Babette; Schiene, Klaus; Peters, Thomas; Schröder, Wolfgang

2018-06-02

N-ethyl-N-nitrosourea (ENU) random mutagenesis was used to generate a mouse model for the analysis of the transient receptor potential vanilloid 1 (TRPV1) cation channel. A transversion from T→A in exon 4 led to a Leu206Stop mutation generating a loss-of-function mutant. The TRPV1 agonist capsaicin was used to analyze functional and nociceptive parameters in vitro and in vivo in TRPV1 Leu206Stop mice and congenic C3HeB/FeJ controls. Capsaicin-induced [Ca 2+ ] i changes in small diameter DRG neurons were significantly diminished in TRPV1 Leu206Stop mice and administration of capsaicin induced neither hypothermia nor nocifensive behaviour in vivo. TRPV1 Leu206Stop mice were tested in the spinal nerve ligation of mononeuropathic pain and developed mechanical hypersensitivity two weeks after nerve injury. In the open field test, a significant increase in spontaneous locomotion was detected in TRPV1 Leu206Stop mice as compared to wildtype controls. TRPV1 knockout mice have been reported to carry a similar phenotype regarding capsaicin-evoked responses in vitro and in vivo. However, in contrast to TRPV1 Leu206Stop mice, TRPV1 knockout mice did not differ in spontaneous locomotion as compared to congenic C57BL/6 mice, suggesting subtle ENU-dependent or independent strain differences between TRPV1 Leu206Stop mice and their wildtype controls. In summary, these data revealed a target-related (i.e. capsaicin-evoked) phenotype of TRPV1 Leu206Stop mice closely resembling that of published TRPV1 knockout mice. However, since ENU-mutant mice are congenic with the mouse strain initially used in random mutagenesis, direct phenotypic comparison with the respective wildtype controls is possible, and the time-consuming backcrossing in lines with targeted mutations is avoided. Copyright © 2018 Elsevier Inc. All rights reserved.

Altered IFN-γ-mediated immunity and transcriptional expression patterns in N-Ethyl-N-nitrosourea-induced STAT4 mutants confer susceptibility to acute typhoid-like disease.

PubMed

Eva, Megan M; Yuki, Kyoko E; Dauphinee, Shauna M; Schwartzentruber, Jeremy A; Pyzik, Michal; Paquet, Marilène; Lathrop, Mark; Majewski, Jacek; Vidal, Silvia M; Malo, Danielle

2014-01-01

Salmonella enterica is a ubiquitous Gram-negative intracellular bacterium that continues to pose a global challenge to human health. The etiology of Salmonella pathogenesis is complex and controlled by pathogen, environmental, and host genetic factors. In fact, patients immunodeficient in genes in the IL-12, IL-23/IFN-γ pathway are predisposed to invasive nontyphoidal Salmonella infection. Using a forward genomics approach by N-ethyl-N-nitrosourea (ENU) germline mutagenesis in mice, we identified the Ity14 (Immunity to Typhimurium locus 14) pedigree exhibiting increased susceptibility following in vivo Salmonella challenge. A DNA-binding domain mutation (p.G418_E445) in Stat4 (Signal Transducer and Activator of Transcription Factor 4) was the causative mutation. STAT4 signals downstream of IL-12 to mediate transcriptional regulation of inflammatory immune responses. In mutant Ity14 mice, the increased splenic and hepatic bacterial load resulted from an intrinsic defect in innate cell function, IFN-γ-mediated immunity, and disorganized granuloma formation. We further show that NK and NKT cells play an important role in mediating control of Salmonella in Stat4(Ity14/Ity14) mice. Stat4(Ity14/Ity14) mice had increased expression of genes involved in cell-cell interactions and communication, as well as increased CD11b expression on a subset of splenic myeloid dendritic cells, resulting in compromised recruitment of inflammatory cells to the spleen during Salmonella infection. Stat4(Ity14/Ity14) presented upregulated compensatory mechanisms, although inefficient and ultimately Stat4(Ity14/Ity14) mice develop fatal bacteremia. The following study further elucidates the pathophysiological impact of STAT4 during Salmonella infection.

Dopaminergic neurotoxicity of S-ethyl N,N-dipropylthiocarbamate (EPTC), molinate, and S-methyl-N,N-diethylthiocarbamate (MeDETC) in Caenorhabditis elegans

PubMed Central

Caito, Samuel W.; Valentine, William M.; Aschner, Michael

2013-01-01

Epidemiological studies corroborate a correlation between pesticide use and Parkinson’s disease (PD). Thiocarbamate and dithiocarbamate pesticides are widely used and produce neurotoxicity in the peripheral nervous system. Recent evidence from rodent studies suggests that these compounds also cause dopaminergic (DAergic) dysfunction and altered protein processing, two hallmarks of PD. However, DAergic neurotoxicity has yet to be documented. We assessed DAergic dysfunction in Caenorhabditis elegans (C. elegans) to investigate the ability of thiocarbamate pesticides to induce DAergic neurodegeneration. Acute treatment with either S-ethyl N,N-dipropylthiocarbamate (EPTC), molinate, or a common reactive intermediate of dithiocarbamate and thiocarbamate metabolism, S-methyl-N,N-diethylthiocarbamate (MeDETC), to gradual loss of DAergic cell morphology and structure over the course of 6 days in worms expressing green fluorescent protein (GFP) under a DAergic cell specific promoter. HPLC analysis revealed decreased DA content in the worms immediately following exposure to MeDETC, EPTC, and molinate. Additionally, worms treated with the three test compounds showed a drastic loss of DAergic-dependent behavior over a time course similar to changes in DAergic cell morphology. Alterations in the DAergic system were specific, as loss of cell structure and neurotransmitter content was not observed in cholinergic, glutamatergic, or GABAergic systems. Overall, our data suggest that thiocarbamate pesticides promote neurodegeneration and DAergic cell dysfunction in C. elegans, and may be an environmental risk factor for PD. PMID:23786526

Carbon Nanotubes Reinforced Maleic Anhydride-Modified Xylan-g-Poly(N-isopropylacrylamide) Hydrogel with Multifunctional Properties

PubMed Central

Liu, Xinxin; Song, Tao; Chang, Minmin; Meng, Ling; Wang, Xiaohui; Sun, Runcang; Ren, Junli

2018-01-01

Introducing multifunctional groups and inorganic material imparts xylan-based hydrogels with excellent properties, such as responsiveness to pH, temperature, light, and external magnetic field. In this work, a composite hydrogel was synthesized by introducing acid treated carbon nanotubes (AT-CNTs) into the maleic anhydride modified xylan grafted with poly(N-isopropylacrylamide) (MAX-g-PNIPAM) hydrogels network. It was found that the addition of AT-CNTs affected the MAX-g-PNIPAM hydrogel structure, the swelling ratio and mechanical properties, and imparted the hydrogel with new properties of electrical conductivity and near infrared region (NIR) photothermal conversion. AT-CNTs could reinforce the mechanical properties of MAX-g-PNIPAM hydrogels, being up to 83 kPa for the compressive strength when the amount was 11 wt %, which was eight times than that of PNIPAM hydrogel and four times than that of MAX-g-PNIPAM hydrogel. The electroconductibility was enhanced by the increase of AT-CNTs amounts. Meanwhile, the composite hydrogel also exhibited multiple shape memory and NIR photothermal conversion properties, and water temperature was increased from 26 °C to 56 °C within 8 min under the NIR irradiation. Thus, the AT-CNTs reinforced MAX-g-PNIPAM hydrogel possessed promising multifunctional properties, which offered many potential applications in the fields of biosensors, thermal-arrest technology, and drug-controlled release. PMID:29495611

Carbon Nanotubes Reinforced Maleic Anhydride-Modified Xylan-g-Poly(N-isopropylacrylamide) Hydrogel with Multifunctional Properties.

PubMed

Liu, Xinxin; Song, Tao; Chang, Minmin; Meng, Ling; Wang, Xiaohui; Sun, Runcang; Ren, Junli

2018-02-28

Introducing multifunctional groups and inorganic material imparts xylan-based hydrogels with excellent properties, such as responsiveness to pH, temperature, light, and external magnetic field. In this work, a composite hydrogel was synthesized by introducing acid treated carbon nanotubes (AT-CNTs) into the maleic anhydride modified xylan grafted with poly(N-isopropylacrylamide) (MAX-g-PNIPAM) hydrogels network. It was found that the addition of AT-CNTs affected the MAX-g-PNIPAM hydrogel structure, the swelling ratio and mechanical properties, and imparted the hydrogel with new properties of electrical conductivity and near infrared region (NIR) photothermal conversion. AT-CNTs could reinforce the mechanical properties of MAX-g-PNIPAM hydrogels, being up to 83 kPa for the compressive strength when the amount was 11 wt %, which was eight times than that of PNIPAM hydrogel and four times than that of MAX-g-PNIPAM hydrogel. The electroconductibility was enhanced by the increase of AT-CNTs amounts. Meanwhile, the composite hydrogel also exhibited multiple shape memory and NIR photothermal conversion properties, and water temperature was increased from 26 °C to 56 °C within 8 min under the NIR irradiation. Thus, the AT-CNTs reinforced MAX-g-PNIPAM hydrogel possessed promising multifunctional properties, which offered many potential applications in the fields of biosensors, thermal-arrest technology, and drug-controlled release.

N-Methyl-D-Aspartate Receptor Activation May Contribute to Glufosinate Neurotoxicity

EPA Science Inventory

N-Methyl-D-aspartate Receptor Activation May Contribute to Glufosinate Neurotoxicity Glufosinate (GLF) at high levels in mammals causes convulsions through a mechanism that is not completely understood. The structural similarity of GLF to glutamate (GLU) implicates the glutamate...

Structure of human IFIT1 with capped RNA reveals adaptable mRNA binding and mechanisms for sensing N1 and N2 ribose 2′-O methylations

PubMed Central

Laudenbach, Beatrice Theres; Martínez-Montero, Saúl; Cencic, Regina; Habjan, Matthias; Pichlmair, Andreas; Damha, Masad J.; Pelletier, Jerry; Nagar, Bhushan

2017-01-01

IFIT1 (IFN-induced protein with tetratricopeptide repeats-1) is an effector of the host innate immune antiviral response that prevents propagation of virus infection by selectively inhibiting translation of viral mRNA. It relies on its ability to compete with the translation initiation factor eIF4F to specifically recognize foreign capped mRNAs, while remaining inactive against host mRNAs marked by ribose 2′-O methylation at the first cap-proximal nucleotide (N1). We report here several crystal structures of RNA-bound human IFIT1, including a 1.6-Å complex with capped RNA. IFIT1 forms a water-filled, positively charged RNA-binding tunnel with a separate hydrophobic extension that unexpectedly engages the cap in multiple conformations (syn and anti) giving rise to a relatively plastic and nonspecific mode of binding, in stark contrast to eIF4E. Cap-proximal nucleotides encircled by the tunnel provide affinity to compete with eIF4F while allowing IFIT1 to select against N1 methylated mRNA. Gel-shift binding assays confirm that N1 methylation interferes with IFIT1 binding, but in an RNA-dependent manner, whereas translation assays reveal that N1 methylation alone is not sufficient to prevent mRNA recognition at high IFIT1 concentrations. Structural and functional analysis show that 2′-O methylation at N2, another abundant mRNA modification, is also detrimental for RNA binding, thus revealing a potentially synergistic role for it in self- versus nonself-mRNA discernment. Finally, structure-guided mutational analysis confirms the importance of RNA binding for IFIT1 restriction of a human coronavirus mutant lacking viral N1 methylation. Our structural and biochemical analysis sheds new light on the molecular basis for IFIT1 translational inhibition of capped viral RNA. PMID:28251928

Development of ferret as a human lung cancer model by injecting4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

USDA-ARS?s Scientific Manuscript database

Development of new animal lung cancer models that are relevant to human lung carcinogenesis is important for lung cancer research. Previously we have shown the induction of lung tumor in ferrets (Mustela putorius furo) exposed to both tobacco smoke and a tobacco carcinogen (4-(N-methyl-N-nitrosamino...

Nonparaneoplastic anti-N-methyl-D-aspartate receptor encephalitis: a case series of four children.

PubMed

Raha, Sarbani; Gadgil, Pradnya; Sankhla, Charulata; Udani, Vrajesh

2012-04-01

A rare, severe form of immune-mediated encephalitis recently has been described, associated with antibodies against N-methyl-D-aspartate receptors. It is reported mostly in women with ovarian tumors. Nonparaneoplastic presentations are less common. We describe four children with a neuropsychiatric and extrapyramidal syndrome associated with the presence of anti-N-methyl-D-aspartate receptor antibodies in cerebrospinal fluid and serum, without evidence of neoplasia. Three children recovered completely after immunomodulatory therapy, i.e., intravenous immunoglobulin and/or steroids, methylprednisolone, and/or adrenocorticotrophic hormone. Copyright © 2012 Elsevier Inc. All rights reserved.

N-hexane inhalation during pregnancy alters DNA promoter methylation in the ovarian granulosa cells of rat offspring.

PubMed

Li, Hong; Liu, Jin; Sun, Yan; Wang, Wenxiang; Weng, Shaozheng; Xiao, Shihua; Huang, Huiling; Zhang, Wenchang

2014-08-01

The N-hexane-induced impact on the reproductive system of the offspring of animals exposed to n-hexane has caused great concern. Pregnant Wistar rats inhaled 500, 2 500 or 12 500 ppm n-hexane during gestational days 1-20. Clinical characteristics and developmental indices were observed. Ovarian granulosa cells were extracted from F1 rats, the number of follicles was determined in ovarian slices and promoter methylation was assessed using MeDIP-Chip. Several methods were used to analyze the scanned genes, including the Gene Ontology Consortium tools, the DAVID Functional Annotation Clustering Tool, hierarchical clustering and KEGG pathway analysis. The results indicated that the live pups/litter ratio was significantly lowest in the 12 500 ppm group. A significant decrease in secondary follicles and an increase in atresic follicles were observed in the 12 500 ppm group. The number of shared demethylated genes was higher than that of the methylated genes, and the differentially methylated genes were enriched in cell death and apoptosis, cell growth and hormone regulation. The methylation profiles of the offspring from the 500 ppm and control groups were different from those of the 2500 and 12 500 ppm groups. Furthermore, the methylation status of genes in the PI3K-Akt and NF-kappa B signaling pathways was changed after n-hexane exposure. The Cyp11a1, Cyp17a1, Hsd3b1, Cyp1a1 and Srd5a1 promoters were hypermethylated in the n-hexane-exposed groups. These results indicate that the developmental toxicity of n-hexane in F1 ovaries is accompanied by the altered methylation of promoters of genes associated with apoptotic processes and steroid hormone biosynthesis. Copyright © 2013 John Wiley & Sons, Ltd.

Combined exposure to X-irradiation followed by N-ethyl-N-nitrosourea treatment alters the frequency and spectrum of Ikaros point mutations in murine T-cell lymphoma.

PubMed

Kakinuma, Shizuko; Nishimura, Mayumi; Amasaki, Yoshiko; Takada, Mayumi; Yamauchi, Kazumi; Sudo, Satomi; Shang, Yi; Doi, Kazutaka; Yoshinaga, Shinji; Shimada, Yoshiya

2012-09-01

Ionizing radiation is a well-known carcinogen, but its potency may be influenced by other environmental carcinogens, which is of practical importance in the assessment of risk. Data are scarce, however, on the combined effect of radiation with other environmental carcinogens and the underlying mechanisms involved. We studied the mode and mechanism of the carcinogenic effect of radiation in combination with N-ethyl-N-nitrosourea (ENU) using doses approximately equal to the corresponding thresholds. B6C3F1 mice exposed to fractionated X-irradiation (Kaplan's method) followed by ENU developed T-cell lymphomas in a dose-dependent manner. Radiation doses above an apparent threshold acted synergistically with ENU to promote lymphoma development, whereas radiation doses below that threshold antagonized lymphoma development. Ikaros, which regulates the commitment and differentiation of lymphoid lineage cells, is a critical tumor suppressor gene frequently altered in both human and mouse lymphomas and shows distinct mutation spectra between X-ray- and ENU-induced lymphomas. In the synergistically induced lymphomas, we observed a low frequency of LOH and an inordinate increase of Ikaros base substitutions characteristic of ENU-induced point mutations, G:C to A:T at non-CpG, A:T to G:C, G:C to T:A and A:T to T:A. This suggests that radiation doses above an apparent threshold activate the ENU mutagenic pathway. This is the first report on the carcinogenic mechanism elicited by combined exposure to carcinogens below and above threshold doses based on the mutation spectrum of the causative gene. These findings constitute a basis for assessing human cancer risk following exposure to multiple carcinogens. Copyright © 2012 Elsevier B.V. All rights reserved.

Towards optimizing the sequence of bevacizumab and nitrosoureas in recurrent malignant glioma.

PubMed

Wiestler, Benedikt; Radbruch, Alexander; Osswald, Matthias; Combs, Stephanie E; Jungk, Christine; Winkler, Frank; Bendszus, Martin; Unterberg, Andreas; Platten, Michael; Wick, Wolfgang; Wick, Antje

2014-03-01

Studies on the monoclonal VEGF-A antibody bevacizumab gave raise to questions regarding the lack of an overall survival benefit, the optimal timing in the disease course and potential combination and salvage therapies. We retrospectively assessed survival, radiological progression type on bevacizumab and efficacy of salvage therapies in 42 patients with recurrent malignant gliomas who received bevacizumab and nitrosourea sequentially. 15 patients received bevacizumab followed by nitrosourea at progression and 27 patients vice versa. Time to treatment failure, defined as time from initiation of one to failure of the other treatment, was similar in both groups (9.6 vs. 9.2 months, log rank p = 0.19). Progression-free survival on nitrosoureas was comparable in both groups, while progression-free survival on bevacizumab was longer in the group receiving bevacizumab first (5.3 vs. 4.1 months, log rank p = 0.03). Survival times were similar for patients with grade III (n = 9) and grade IV (n = 33) tumors. Progression-free survival on bevacizumab for patients developing contrast-enhancing T1 progression was longer than for patients who displayed a non-enhancing T2 progression. However, post-progression survival times after bevacizumab failure were not different. Earlier treatment with bevacizumab was not associated with better outcome in this series. The fact that earlier as compared to later bevacizumab treatment does not result in a different time to treatment failure highlights the challenge for first-line or recurrence trials with bevacizumab to demonstrate an overall survival benefit if crossover of bevacizumab-naïve patients after progression occurs.

Rotationally inelastic scattering of methyl radicals with Ar and N{sub 2}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tkáč, Ondřej; Orr-Ewing, Andrew J., E-mail: a.orr-ewing@bristol.ac.uk; Ma, Qianli

2015-01-07

The rotationally inelastic scattering of methyl radical with Ar and N{sub 2} is examined at collision energies of 330 ± 25 cm{sup −1} and 425 ± 50 cm{sup −1}, respectively. Differential cross sections (DCSs) were measured for different final n′ rotational levels (up to n′ = 5) of the methyl radicals, averaged over k′ sub-levels, using a crossed molecular beam machine with velocity map imaging. For Ar as a collision partner, we present a newly constructed ab initio potential energy surface and quantum mechanical scattering calculations of state-resolved DCSs. These computed DCSs agree well with the measurements. The DCSs formore » both Ar and N{sub 2} collision partners are strongly forward peaked for all spectroscopic lines measured. For scattering angles below 60°, the theoretical CD{sub 3}–Ar DCSs show diffraction oscillations that become less pronounced as n′ increases, but these oscillations are not resolved experimentally. Comparisons are drawn with our recently reported DCSs for scattering of methyl radicals with He atoms.« less

N-linked glycosylation of cortical N-methyl-D-aspartate and kainate receptor subunits in schizophrenia.

PubMed

Tucholski, Janusz; Simmons, Micah S; Pinner, Anita L; McMillan, Laurence D; Haroutunian, Vahram; Meador-Woodruff, James H

2013-08-21

Dysfunctional glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. Abnormal expressions in schizophrenia of ionotropic glutamate receptors (iGluRs) and the proteins that regulate their trafficking have been found to be region and subunit specific in brain, suggesting that abnormal trafficking of iGluRs may contribute toward altered glutamatergic neurotransmission. The post-translational modification N-glycosylation of iGluR subunits can be used as a proxy for their intracellular localization. Receptor complexes assemble in the lumen of the endoplasmic reticulum, where N-glycosylation begins with the addition of N-linked oligomannose glycans, and is subsequently trimmed and replaced by more elaborate glycans while trafficking through the Golgi apparatus. Previously, we found abnormalities in N-glycosylation of the GluR2 AMPA receptor subunit in schizophrenia. Here, we investigated N-glycosylation of N-methyl-D-aspartate and kainate (KA) receptor subunits in the dorsolateral prefrontal cortex from patients with schizophrenia and a comparison group. We used enzymatic deglycosylation with two glycosidases: endoglycosidase H (Endo H), which removes immature high mannose-containing sugars, and peptide-N-glycosidase F (PNGase F), which removes all N-linked sugars. The NR1, NR2A, NR2B, GluR6, and KA2 subunits were all sensitive to treatment with Endo H and PNGase F. The GluR6 KA receptor subunit was significantly more sensitive to Endo H-mediated deglycosylation in schizophrenia, suggesting a larger molecular mass of N-linked high mannose and/or hybrid sugars on GluR6. This finding, taken with our previous work, suggests that a cellular mechanism underlying abnormal glutamate neurotransmission in schizophrenia may involve abnormal trafficking of both AMPA and KA receptors.

Solubility and diffusivity of N{sub 2}O and CO{sub 2} in (monoethanolamine + N-methyldiethanolamine + water) and in (monoethanolamine + 2-amino-2-methyl-1-propanol + water)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, M.H.; Lai, M.D.

1995-03-01

Solutions of amines are frequently used in gas-treating processes to remove acid gases, such as CO{sub 2} and H{sub 2}S, from gas streams in the natural gas and synthetic ammonia industries and petroleum chemical plants. The solubility and diffusivity of N{sub 2}O in (monoethanolamine + N-methyldiethanolamine + water) and in (monoethanolamine + 2-amino-2-methyl-l-propanol + water) were measured at 30, 35, and 40 C and at atmospheric pressure. Six (monoethanolamine + N-methyldiethanolamine + water) and five (monoethanolamine + 2-amino-2-methyl-l-propanol + water) systems were studied. The total amine mass percent in all cases was 30. The solubilities were measured by a solubilitymore » apparatus similar to that of Haimour and Sandall (1984). A wetted wall column absorber was used to obtain the diffusivity of N{sub 2}O in amines. The N{sub 2}O solubilities in amine solutions have been correlated on the basis of the excess Henry constant correlation of Wang et al. (1992). The N{sub 2}O analogy was used to estimate the solubility and diffusivity of CO{sub 2} in (monoethanolamine + N-methyldiethanolamine + water) and in (monoethanolamine + 2-amino-2-methyl-l-propanol + water).« less

Poly(methyl vinyl ether-alt-maleic acid)-functionalized porous silicon nanoparticles for enhanced stability and cellular internalization.

PubMed

Shahbazi, Mohammad-Ali; Almeida, Patrick V; Mäkilä, Ermei; Correia, Alexandra; Ferreira, Mónica P A; Kaasalainen, Martti; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A

2014-03-01

Currently, developing a stable nanocarrier with high cellular internalization and low toxicity is a key bottleneck in nanomedicine. Here, we have developed a successful method to covalently conjugate poly(methyl vinyl ether-co-maleic acid) (PMVE-MA) copolymer on the surface of (3-aminopropyl)triethoxysilane-functionalized thermally carbonized porous silicon nanoparticles (APSTCPSi NPs), forming a surface negatively charged nanovehicle with unique properties. This polymer conjugated NPs could modify surface smoothness, charge, and hydrophilicity of the developed NPs, leading to considerable improvement in the colloidal and plasma stabilities via enhanced suspensibility and charge repulsion. Furthermore, despite the surface negative charge of the polymer-conjugated NPs, the cellular internalization was increased in both MDA-MB-231 and MCF-7 breast cancer cells. These results provide a proof-of-concept evidence that such polymer-based PSi nanocomposite can be extensively used as a promising candidate for intracellular drug delivery. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Preventive effect of rebamipide on N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats.

PubMed

Tsukamoto, Hironobu; Mizoshita, Tsutomu; Katano, Takahito; Hayashi, Noriyuki; Ozeki, Keiji; Ebi, Masahide; Shimura, Takaya; Mori, Yoshinori; Tanida, Satoshi; Kataoka, Hiromi; Tsukamoto, Tetsuya; Tatematsu, Masae; Joh, Takashi

2015-03-01

Chemoprevention strategies against gastric cancer (GC) need to be explored in light of the fact that stomach cancer still occurs in the absence of Helicobacter pylori (HP) infection and following HP eradication. We evaluated the effect of rebamipide on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced carcinogenesis in SD rats. Thirty-nine male rats were divided into four groups based on whether or not they were treated with rebamipide and/or MNNG: Control, Rebamipide, Control-M, and Rebamipide-M groups. From 8 weeks of age, rats in the Control-M and Rebamipide-M groups received MNNG in drinking water for 30 weeks. The Rebamipide and Rebamipide-M groups were administered 5mg/kg/day of rebamipide. At 50 weeks, cancerous lesions were not observed in either the Control or Rebamipide groups. Nine rats in the Control-M group had developed GC, while four rats in the Rebamipide-M group had developed GC. The incidence of cancer in the Rebamipide-M group was significantly less than in the Control-M group (p<0.05), with a trend toward a lower incidence of invasive carcinoma in the Rebamipide-M group. Carcinomatous invasion into the muscularis propria was not observed in the Rebamipide-M group. In conclusion, the present study demonstrates that rebamipide suppresses. MNNG-induced carcinogenesis and may also inhibit progression of cancer in rats. Copyright © 2015 Elsevier GmbH. All rights reserved.

N-methyl-N'-nitro-N-nitrosoguanidine interferes with the epidermal growth factor receptor-mediated signaling pathway.

PubMed

Gao, Zhihua; Yang, Jun; Huang, Yun; Yu, Yingnian

2005-03-01

Many environmental factors, such as ultraviolet (UV) and arsenic, can induce the clustering of cell surface receptors, including epidermal growth factor receptor (EGFR). This is accompanied by the phosphorylation of the receptors and the activation of ensuing cellular signal transduction pathways, which are implicated in the various cellular responses caused by the exposure to these factors. In this study, we have shown that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), an alkylating agent, also induced the clustering of EGFR in human amnion FL cells, which was similar in morphology to that of epidermal growth factor treatment. However, MNNG treatment did not activate Ras, the downstream mediator in EGFR signaling pathway, as compared to EGF treatment. The autophosphorylation of tyrosine residues Y1068 and Y1173 at the intracellular domain of EGFR, which is related to Ras activation under EGF treatment, was also not observed by MNNG exposure. Interestingly, although MNNG did not affect the binding of EGF to EGFR, MNNG can interfere with EGF function. For instance, pre-incubating FL cells with MNNG inhibited the autophosphorylation of EGFR by EGF treatment, as well as the activation of Ras. In addition, the phosphorylation of Y845 on EGFR by EGF, which is mediated through c-Src or related kinases but not autophosphorylation, was also affected by MNNG. Therefore, MNNG may influence the tyrosine kinase activity as well as the phosphorylation of EGFR through its interaction with EGFR.

Radiosynthesis of N-¹¹C-Methyl-Taurine-Conjugated Bile Acids and Biodistribution Studies in Pigs by PET/CT.

PubMed

Schacht, Anna Christina; Sørensen, Michael; Munk, Ole Lajord; Frisch, Kim

2016-04-01

During cholestasis, accumulation of conjugated bile acids may occur in the liver and lead to hepatocellular damage. Inspired by our recent development of N-(11)C-methyl-glycocholic acid-that is, (11)C-cholylsarcosine-a tracer for PET of the endogenous glycine conjugate of cholic acid, we report here a radiosynthesis of N-(11)C-methyl-taurine-conjugated bile acids and biodistribution studies in pigs by PET/CT. A radiosynthesis of N-(11)C-methyl-taurine-conjugated bile acids was developed and used to prepare N-(11)C-methyl-taurine conjugates derived from cholic, chenodeoxycholic, deoxycholic, ursodeoxycholic, and lithocholic acid. The lipophilicity of these new tracers was determined by reversed-phase thin-layer chromatography. The effect of lipophilicity and structure on the biodistribution was investigated in pigs by PET/CT using the tracers derived from cholic acid (3α-OH, 7α-OH, 12α-OH), ursodeoxycholic acid (3α-OH, 7β-OH), and lithocholic acid (3α-OH). The radiosyntheses of the N-(11)C-methyl-taurine-conjugated bile acids proceeded with radiochemical yields of 61% (decay-corrected) or greater and radiochemical purities greater than 99%. PET/CT in pigs revealed that the tracers were rapidly taken up by the liver and secreted into bile. There was no detectable radioactivity in urine. Significant reflux of N-(11)C-methyl-taurolithocholic acid into the stomach was observed. We have successfully developed a radiosynthesis of N-(11)C-methyl-taurine-conjugated bile acids. These tracers behave in a manner similar to endogenous taurine-conjugated bile acids in vivo and are thus promising for functional PET of patients with cholestatic diseases. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Synthesis and characterization of a thermo-sensitive poly( N-methyl acryloylglycine methyl ester) used as a drug release carrier

NASA Astrophysics Data System (ADS)

Deng, Kui-Lin; Zhong, Hai-Bin; Jiao, Yi-Suo; Fan, Ting; Qiao, Xiao; Zhang, Peng-Fei; Ren, Xiao-Bo

2010-06-01

In this article, poly( N-methyl acryloylglycine methyl ester) (PNMAME) was prepared as a novel thermosensitive material with a lower critical solution temperature (LCST) at around 49.5°C. The chemical structures of the monomer NMAME and PNMAME were characterized by 1H NMR and IR measurements. The LCST was investigated systematically as a function of PNMAME concentration, inorganic salt solution and pH value. The results indicated that LCST of PNMAME was obviously dependent on PNMAME concentration and pH. The LCST was increased with a decrease in pH value and PNMAME concentration. To obtain a thermo-sensitive hydrogel with the phase transition temperature close to human body temperature, the copolymerization was conducted between NMAME and N-acryloylglycine ethyl ester (NAGEE). The release behavior of caffeine was evaluated at different temperatures and contents of cross-linkers ( N, N-methylenebis(acrylamide) (NMBA)). The increase of cross-linker content led to a decrease in the release rate of caffeine due to higher crossing density in the hydrogel network. In addition, a faster release of caffeine from the hydrogel with 3% NMBA at 37°C was found in contrast to that at 18°C.

Attenuation by d-limonene of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

PubMed

Yano, H; Tatsuta, M; Iishi, H; Baba, M; Sakai, N; Uedo, N

1999-08-27

The effects of prolonged administration of d-limonene, a monocyclic monoterpene, on sodium chloride-enhanced induction of gastric carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine, the labeling and apoptotic indices, and ornithine decarboxylase (ODC) activity of gastric cancers were investigated in Wistar rats. After 25 weeks of carcinogen treatment, rats were given chow pellets containing 10% sodium chloride and 1% limonene ad libitum. In week 52, the incidence of gastric cancers, the labeling index and ODC activity were significantly higher and the apoptotic index was significantly lower in rats given sodium chlolide than in untreated control rats. However, in rats given both sodium chloride and d-limonene, the incidence of gastric cancers, the labeling index and ODC activity were significantly lower and the apoptotic index was significantly higher than in rats given sodium chloride alone. Our findings suggest that limonene attenuates the gastric carcinogenesis enhanced by sodium chloride via increased apoptosis and decreased ODC activity in gastric cancers. Copyright 1999 Wiley-Liss, Inc.

(E)-N′-(4-Meth­oxy­benzyl­idene)pyridine-3-carbohydrazide dihydrate

PubMed Central

Novina, J. Josephine; Vasuki, G.; Suresh, M.; Padusha, M. Syed Ali

2013-01-01

In the title compound, C14H13N3O2·2H2O, the hydrazone mol­ecule adopts an E conformation with respect to the C=N bond. The dihedral angle between the benzene and pyridine rings is 8.55 (10)°. The methyl­idene–hydrazide [–C(=O)–N–N=C–] fragment is essentially planar, with a maximum deviation of 0.0375 (13) Å. The mean planes of the benzene and pyridine rings make dihedral angles of 2.71 (14) and 11.25 (13)°, respectively, with mean plane of the methyl­idene-hydrazide fragment. In the crystal, the benzohydrazide and water mol­ecules are linked by N—H⋯O, O—H⋯O and O—H⋯N hydrogen bonds into a three-dimensional network. PMID:24046719

Antioxidant and Antimicrobial Activity of 5-methyl-2-(5-methyl-1,3-diphenyl-1H-pyrazole-4-carbonyl)-2,4-dihydro-pyrazol-3-one

PubMed Central

Umesha, K. B.; Rai, K. M. L.; Harish Nayaka, M. A.

2009-01-01

Cycloaddition of nitrile imines 4 generated in situ by the catalytic dehydrogenation of diphenyl hydrazones 3 using Chloramine-T (CAT) as oxidant in glacial acetic acid with enolic form of ethyl acetoacetate 5 afforded Ethyl 3-aryl-5-methyl-1-phenyl-1H-pyrazol-4-carboxylate 6 in 80% yield. The said pyrazoles 6 refluxed with 80% hydrazine hydrate using absolute alcohol as solvent for about 2–3 hours to produce the respective 5-methyl-1,3-diphenyl-1H-pyrazole-4-carboxylic acid hydrazide 7. The alcoholic solution of pyrazole acid hydrazides on heating with ethyl acetoacetate 5 to give the 5-methyl-2-(5-methyl-1,3-diphenyl-1H-pyrazole-4-carbonyl)-2,4-dihydro-pyrazol-3-one 8. The synthesized compounds were found to exhibit good antimicrobial and antioxidant activity as evaluated by 1,1-diphenyl-2-picryl Hydrazyl (DPPH) radical scavenging, reducing power and DNA protection assays. PMID:23675159

Steric control of the asymmetric synthesis of N-substituted 2-methyl-4-piperidones

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grishina, G.V.; Potapov, V.M.; Abdulganeeva, S.A.

Transmission of the iodomethylate of 1,2-dimethyl-4-piperidone by (S)-sec-butylamine gives 1-(S-sec-butyl)-2S-methyl-4-piperidone in 33% optical yield while transamination by (S)-1-methyl-2-phenylethylamine gives a 1:1 diastereomeric mixture of 1-(1-methyl-2-phenylethyl)-2-methyl-4-piperidone. The decrease in the optical yield is related to the facile opening of the piperidone ring at the C-N bond with subsequent recyclization. The /sup 13/C NMR data indicate that all the diastereomers of the 4-piperidones obtained are in the chain conformation with predominantly equatorial orientation of the methyl group at C/sub (2)/. The chiral optical properties were studied and the absolution configurations of the 4-piperidones obtained were established.

Preparation and characterization of poly(methyl methacrylate) and poly(maleic anhydride-co-diallyl phthalate) grafted carbon black through γ-ray irradiation

NASA Astrophysics Data System (ADS)

Bo, Yang; Cui, Jiayang; Cai, Yangben; Xu, Shiai

2016-02-01

In this study, the grafting polymerization of methyl methacrylate (MMA) monomer and maleic anhydride/diallyl phthalate (MAH/DAP) co-monomer onto the surface of carbon black (CB) were carried out at room temperature and normal pressure by γ-ray irradiation. The surface chemistry of grafted CBs were characterized by infrared spectroscopy (IR), thermo-gravimetric analysis (TGA) and X-ray photoelectron spectroscopy (XPS). The results show that there are some remanent polymers on the surface of modified CBs after extract for 48 h, indicating that poly(methyl methacrylate) (PMMA) and poly(MAH-co-DAP) have been successfully grafted onto the surface of CB without using initiator due to the high energy of γ-ray irradiation. Dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) reveal that the grafted CBs have smaller average aggregate size and better dispersibility than that of CB in absolute ethanol. In addition, it was found that the amount of oxygen groups and the irradiation doses/dose rates have little effect on the grafting degree of CB.

DNA methylation on N6-adenine in mammalian embryonic stem cells

PubMed Central

Wu, Tao P.; Wang, Tao; Seetin, Matthew G.; Lai, Yongquan; Zhu, Shijia; Lin, Kaixuan; Liu, Yifei; Byrum, Stephanie D.; Mackintosh, Samuel G.; Zhong, Mei; Tackett, Alan; Wang, Guilin; Hon, Lawrence S.; Fang, Gang; Swenberg, James A.; Xiao, Andrew Z.

2016-01-01

It has been widely accepted that 5-methylcytosine is the only form of DNA methylation in mammalian genomes. Here we identify N6-methyladenine as another form of DNA modification in mouse embryonic stem cells. Alkbh1 encodes a demethylase for N6-methyladenine. An increase of N6-methyladenine levels in Alkbh1-deficient cells leads to transcriptional silencing. N6-methyladenine deposition is inversely correlated with the evolutionary age of LINE-1 transposons; its deposition is strongly enriched at young (<1.5 million years old) but not old (>6 million years old) L1 elements. The deposition of N6-methyladenine correlates with epigenetic silencing of such LINE-1 transposons, together with their neighbouring enhancers and genes, thereby resisting the gene activation signals during embryonic stem cell differentiation. As young full-length LINE-1 transposons are strongly enriched on the X chromosome, genes located on the X chromosome are also silenced. Thus, N6-methyladenine developed a new role in epigenetic silencing in mammalian evolution distinct from its role in gene activation in other organisms. Our results demonstrate that N6-methyladenine constitutes a crucial component of the epigenetic regulation repertoire in mammalian genomes. PMID:27027282

Separator Membrane from Crosslinked Poly(Vinyl Alcohol) and Poly(Methyl Vinyl Ether-alt-Maleic Anhydride)

PubMed Central

Rohatgi, Charu Vashisth; Dutta, Naba K.; Choudhury, Namita Roy

2015-01-01

In this work, we report separator membranes from crosslinking of two polymers, such as poly vinyl alcohol (PVA) with an ionic polymer poly(methyl vinyl ether-alt-maleic anhydride) (PMVE-MA). Such interpolymer-networked systems were extensively used for biomedical and desalination applications but they were not examined for their potential use as membranes or separators for batteries. Therefore, the chemical interactions between these two polymers and the influence of such crosslinking on physicochemical properties of the membrane are systematically investigated through rheology and by critical gel point study. The hydrogen bonding and the chemical interaction between PMVE-MA and PVA resulted in highly cross-linked membranes. Effect of the molecular weight of PVA on the membrane properties was also examined. The developed membranes were extensively characterized by studying their physicochemical properties (water uptake, swelling ratio, and conductivity), thermal and electrochemical properties using differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), thermo-gravimetric analysis (TGA) and electrochemical impedance spectroscopy (EIS). The DSC study shows the presence of a single Tg in the membranes indicating compatibility of the two polymers in flexible and transparent films. The membranes show good stability and ion conductivity suitable for separator applications. PMID:28347019

Synthesis of ethylene maleic anhydride copolymer containing fungicides and evaluation of their effect for wood decay resistance

Treesearch

George C. Chen

2008-01-01

The aim of the present study was to combat wood decay based on the approach controlled-release biocides from polymers. The possibility of introducing polymer-bonded fungicides into the cell lumens was investigated. The synthesis of ethylene maleic anhydride copolymer containing pentachlorophenol (penta) and 8-hydroxy quinoline (8HQ) in N, N dimethyl formamide is...

Density and viscosity of aqueous blends of N-methyldiethanolamine and 2-amino-2-methyl-1-propanol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Welsh, L.M.; Davis, R.A.

Aqueous solutions of alkanolamines such as N-methyldiethanolamine (MDEA) and 2-amino-2-methyl-1-propanol (AMP) have application in acid gas treatment for the removal of acid gases such as carbon dioxide and hydrogen sulfide. The density and kinematic viscosity of aqueous blends of N-methyldiethanolamine and 2-amino-2-methyl-1-propanol were determined from experiments within the temperature range 10--60 C. The composition of the alkanolamines in water ranged from 5% to 50% by mass.

DHA-rich n-3 fatty acid supplementation decreases DNA methylation in blood leukocytes: the OmegAD study.

PubMed

Karimi, Mohsen; Vedin, Inger; Freund Levi, Yvonne; Basun, Hans; Faxén Irving, Gerd; Eriksdotter, Maria; Wahlund, Lars-Olof; Schultzberg, Marianne; Hjorth, Erik; Cederholm, Tommy; Palmblad, Jan

2017-10-01

Background: Dietary fish oils, rich in long-chain n-3 (ω-3) fatty acids (FAs) [e.g., docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3)], modulate inflammatory reactions through various mechanisms, including gene expression, which is measured as messenger RNA concentration. However, the effects of long-term treatment of humans with DHA and EPA on various epigenetic factors-such as DNA methylation, which controls messenger RNA generation-are poorly described. Objective: We wanted to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global DNA methylation of peripheral blood leukocytes (PBLs) and the relation to plasma EPA and DHA concentrations in Alzheimer disease (AD) patients. Design: In the present study, DNA methylation in four 5'-cytosine-phosphate-guanine-3' (CpG) sites of long interspersed nuclear element-1 repetitive sequences was assessed in a group of 63 patients (30 given the n-3 FA preparation and 33 given placebo) as an estimation of the global DNA methylation in blood cells. Patients originated from the randomized, double-blind, placebo-controlled OmegAD study, in which 174 AD patients received either 1.7 g DHA and 0.6 g EPA (the n-3 FA group) or placebo daily for 6 mo. Results: At 6 mo, the n-3 FA group displayed marked increases in DHA and EPA plasma concentrations (2.6- and 3.5-fold), as well as decreased methylation in 2 out of 4 CpG sites ( P < 0.05 for all), respectively. This hypomethylation in CpG2 and CpG4 sites showed a reverse correlation to changes in plasma EPA concentration ( r = -0.25, P = 0.045; and r = -0.26, P = 0.041, respectively), but not to changes in plasma DHA concentration, and were not related to apolipoprotein E-4 allele frequency. Conclusion: Supplementation with n-3 FA for 6 mo was associated with global DNA hypomethylation in PBLs. Our data may be of importance in measuring various effects of marine oils, including gene expression, in patients

A DOSE-RESPONSE STUDY OF THE TOXICITY OF A MIXTURE OF 7N-METHYL CARBAMATE PESTICIDES IN ADULT, MALE RATS.

EPA Science Inventory

There is scarce knowledge regarding the toxicity of pesticide mixtures, especially mixtures of the anticholinesterase N-methyl carbamates. A mixture study was conducted using 7 N-methyl carbamates (carbaryl, carbofuran, formetanate HCl, methiocarb, methomyl, oxamyl, and propoxur...

A pivotal role for reductive methylation in the de novo crystallization of a ternary complex composed of Yersinia pestis virulence factors YopN, SycN and YscB.

PubMed

Schubot, Florian D; Waugh, David S

2004-11-01

Structural studies of a ternary complex composed of the Yersina pestis virulence factors YopN, SycN and YscB were initially hampered by poor solubility of the individual proteins. Co-expression of all three proteins in Escherichia coli yielded a well behaved complex, but this sample proved to be recalcitrant to crystallization. As crystallization efforts remained fruitless, even after the proteolysis-guided engineering of a truncated YopN polypeptide, reductive methylation of lysine residues was employed to alter the surface properties of the complex. The methylated complex yielded crystals that diffracted X-rays to a maximal resolution of 1.8 A. The potential utility of reductive methylation as a remedial strategy for high-throughput structural biology was further underscored by the successful modification of a selenomethionine-substituted sample.

Effect of pressure on bilayer phase behavior of N-methylated di-O-hexadecylphosphatidylethanolamines: relevance of head-group modification on the bilayer interdigitation.

PubMed

Goto, Masaki; Aoki, Yuya; Tamai, Nobutake; Matsuki, Hitoshi

2017-12-01

The phase transitions of N-methylated di-O-hexadecylphosphatidylethanolamines (DHPE, DH-N-methyl-PE (DHMePE) and DH-N,N-dimethyl-PE (DHMe 2 PE)) were observed by differential scanning calorimetry (DSC) and fluorometry under atmospheric pressure and by light-transmittance measurements under high pressure. The DSC thermograms showed that the N-methylated DHPE bilayers underwent the phase transition from the gel phase to the liquid crystalline (L α ) phase under atmospheric pressure. The gel phase was identified by fluorometry as the lamellar gel (L β ) phase, and not interdigitated gel (L β I) phase. The gel/L α transition temperature increased with pressure while decreased stepwise with increasing polar head-group size. This stepwise depression of the transition temperature may be caused by the inverse-proportional hydrogen-bonding capabilities of the head-group to the head-group size. The thermodynamic quantities of the gel/L α transition were comparable for the N-methylated DHPE bilayers. The pressure-induced L β I phase was not found in these bilayers although the bilayer of di-O-hexadecylphosphatidylcholine (DHPC), which is a kind of N-methylated DHPEs, forms the L β I phase only by hydration under atmospheric pressure. Taking into account that the bilayers of diacyl-homologs of N-methylated DHPEs, N-methylated dipalmitoyl-PEs except for dipalmitoylphosphatidylcholine (DPPC), do not form the L β I phase in the whole pressure range investigated but the DPPC bilayer forms the L β I phase under high pressure, we can say that the interdigitation requires weaker interaction between large-sized head groups like the bulky choline group. Copyright © 2017 Elsevier B.V. All rights reserved.

Molecular recognition at methyl methacrylate/n-butyl acrylate (MMA/nBA) monomer unit boundaries of phospholipids at p-MMA/nBA copolymer surfaces.

PubMed

Yu, Min; Urban, Marek W; Sheng, Yinghong; Leszczynski, Jerzy

2008-09-16

Lipid structural features and their interactions with proteins provide a useful vehicle for further advances in membrane proteins research. To mimic one of potential lipid-protein interactions we synthesized poly(methyl methacrylate/ n-butyl acrylate) (p-MMA/nBA) colloidal particles that were stabilized by phospholipid (PLs). Upon the particle coalescence, PL stratification resulted in the formation of surface localized ionic clusters (SLICs). These entities are capable of recognizing MMA/nBA monomer interfaces along the p-MMA/nBA copolymer backbone and form crystalline SLICs at the monomer interface. By utilizing attenuated total reflectance Fourier transform infrared (ATR FT-IR) spectroscopy and selected area electron diffraction (SAD) combined with ab initio calculations, studies were conducted that identified the origin of SLICs as well as their structural features formed on the surface of p-MMA/nBA copolymer films stabilized by 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) PL. Specific entities responsible for SLIC formation are selective noncovalent bonds of anionic phosphate and cationic quaternary ammonium segments of DLPC that interact with two neighboring carbonyl groups of nBA and MMA monomers of the p-MMA/nBA polymer backbone. To the best of our knowledge this is the first example of molecular recognition facilitated by coalescence of copolymer colloidal particles and the ability of PLs to form SLICs at the boundaries of the neighboring MMA and nBA monomer units of the p-MMA/nBA chain. The dominating noncovalent bonds responsible for the molecular recognition is a combination of H-bonding and electrostatic interactions.

Ethanol Inhibition of Constitutively Open N-Methyl-d-Aspartate Receptors

PubMed Central

Xu, Minfu; Smothers, C. Thetford; Trudell, James

2012-01-01

N-Methyl-d-aspartate (NMDA) receptors gate a slow and calcium-rich component of the postsynaptic glutamate response. Like all ionotropic glutamate receptors, NMDA subunits contain a highly conserved motif (SYTANLAAF) in the transmembrane (TM) 3 domain that is critically involved in channel gating. Mutation of an alanine in this domain (A7; underlined above) results in constitutively open receptors that show reduced sensitivity to several allosteric modulators. In this study, we examined the effects of ethanol, a substance that inhibits NMDA currents via an unknown mechanism, on tonically active NMDA receptors expressed in human embryonic kidney 293 cells. Ethanol (100 mM) inhibited currents from GluN1(A7R)/GluN2A and GluN1(A7R)/GluN2B receptors by approximately 50%, whereas those from GluN1/GluN2B(A7R) receptors were reduced by less than 10%. In cysteine-substituted GluN1 and GluN2 A7 mutants, estimated ethanol IC50 values for agonist-gated currents were 101, 117, 103, and 69 mM for GluN1(A7C)/GluN2A, GluN1(A7C)/GluN2B, GluN1/GluN2A(A7C), and GluN1/GluN2B(A7C) receptors, respectively. After exposure to the thiol-modifying reagent 2-(trimethylammonium)ethyl methanethiosulfonate (MTSET), A7C mutants showed robust agonist-independent currents and reduced sensitivity to ethanol (IC50 values of 371, 256, 715, and 958 mM, respectively, as above). In contrast, cysteine modification of the ligand-binding domain resulted in constitutively open receptors that showed robust ethanol inhibition. Ethanol inhibition of MTSET-treated GluN1(A7C) receptors was further reduced by TM3/TM4 mutations previously shown to reduce ethanol sensitivity of agonist-gated receptors. Overall, these results show that ethanol affects NMDA receptor function at a site distal from agonist binding and appears to exert greater effects via perturbation of GluN2 subunits. PMID:22005043

SPE-GC/FTD determination of N-methyl-2-pyrrolidone and its metabolites in urine.

PubMed

Kubota, Ryuichi; Endo, Yoko; Takeuchi, Akito; Inoue, Yoshinori; Ogata, Hiroko; Ogawa, Masanori; Nakagawa, Tomoo; Onda, Nobuhiko; Endo, Ginji

2007-07-01

An analytical method using a combination of solid-phase extraction (SPE) and gas chromatography with a flame thermionic detector (GC/FTD) was developed for determination of N-methyl-2-pyrrolidone (NMP), N-methylsuccinimide (MSI), and 2-hydroxy-N-methylsuccinimide (2-HMSI) in human urine. The SPE cartridge of poly(divinylbenzene/hydroxymethacrylate) used was directly loaded with urine sample, followed by elution with methyl isobutyl ketone (MIBK) and subsequent centrifugation, and the supernatant was injected into the capillary GC using a DB1701. This method allowed efficient separation of NMP, MSI, and 2-HMSI, which were nearly free of interference by other GC peaks arising from urine. Recoveries of NMP, MSI, and 2-HMSI from the SPE cartridge were about 98, 101, and 67%, respectively, with limits of detection of 0.04, 0.02, and 0.06 mg/L, respectively, which met the regulatory requirements. The present method was used for assay in biological monitoring of workers exposed to NMP in their occupational environment.

40 CFR 180.296 - Dimethyl phosphate of 3-hydroxy-N-methyl-cis-crotonamide; tolerances for residues.

Code of Federal Regulations, 2010 CFR

2010-07-01

...-methyl-cis-crotonamide; tolerances for residues. 180.296 Section 180.296 Protection of Environment... RESIDUES IN FOOD Specific Tolerances § 180.296 Dimethyl phosphate of 3-hydroxy-N-methyl-cis-crotonamide; tolerances for residues. (a) General. Tolerances are established for residues of the insecticide Dimethyl...

MeDIP-seq and nCpG analyses illuminate sexually dimorphic methylation of gonadal development genes with high historic methylation in turtle hatchlings with temperature-dependent sex determination.

PubMed

Radhakrishnan, Srihari; Literman, Robert; Mizoguchi, Beatriz; Valenzuela, Nicole

2017-01-01

DNA methylation alters gene expression but not DNA sequence and mediates some cases of phenotypic plasticity. Temperature-dependent sex determination (TSD) epitomizes phenotypic plasticity where environmental temperature drives embryonic sexual fate, as occurs commonly in turtles. Importantly, the temperature-specific transcription of two genes underlying gonadal differentiation is known to be induced by differential methylation in TSD fish, turtle and alligator. Yet, how extensive is the link between DNA methylation and TSD remains unclear. Here we test for broad differences in genome-wide DNA methylation between male and female hatchling gonads of the TSD painted turtle Chrysemys picta using methyl DNA immunoprecipitation sequencing, to identify differentially methylated candidates for future study. We also examine the genome-wide nCpG distribution (which affects DNA methylation) in painted turtles and test for historic methylation in genes regulating vertebrate gonadogenesis. Turtle global methylation was consistent with other vertebrates (57% of the genome, 78% of all CpG dinucleotides). Numerous genes predicted to regulate turtle gonadogenesis exhibited sex-specific methylation and were proximal to methylated repeats. nCpG distribution predicted actual turtle DNA methylation and was bimodal in gene promoters (as other vertebrates) and introns (unlike other vertebrates). Differentially methylated genes, including regulators of sexual development, had lower nCpG content indicative of higher historic methylation. Ours is the first evidence suggesting that sexually dimorphic DNA methylation is pervasive in turtle gonads (perhaps mediated by repeat methylation) and that it targets numerous regulators of gonadal development, consistent with the hypothesis that it may regulate thermosensitive transcription in TSD vertebrates. However, further research during embryogenesis will help test this hypothesis and the alternative that instead, most differential methylation

Fatty acid methyl ester from Neurospora intermedia N-1 isolated from Indonesian red peanut cake (oncom merah).

PubMed

Priatni, S; Hartati, S; Dewi, P; Kardono, L B S; Singgih, M; Gusdinar, T

2010-08-01

The objective of this study was to identify the Fatty Acid Methyl Ester (FAME) from Neurospora intermedia N-1 that isolated from Indonesian red peanut cake (oncom). FAME profiles have been used as biochemical characters to study many different groups of organisms, such as bacteria and yeasts. FAME from N. intermedia N-1 was obtained by some stages of extraction the orange spores and fractination using a chromatotron. The pure compound (1) was characterized by 500 mHz NMR (1H and 13C), FTIR and LC-MS. Summarized data's of 1H and 13C NMR spectra of compound 1 contained 19 Carbon, 34 Hydrogen and 2 Oxygen (C19H34O2). The position of the double bonds at carbon number 8 and 12 were indicated in the HMBC spectrum (2D-NMR). LC-MS spectrum indicates molecular weight of the compound 1 as 294 which is visible by the presence of protonated molecular ion [M+H] at m/z 295. Methyl esters of long chain fatty acids was presented by a 3 band pattern of IR spectrum with bands near 1249, 1199 and 1172 cm(-1). We suggested that the structure of the pure compound 1 is methyl octadeca-8,12-dienoate. The presence methyl octadeca-8,12-dienoate in N. intermedia is the first report.

TIME-COURSE OF ACUTE NEUROTOXICITY PRODUCED BY N-METHYL CARBAMATES IN PREWEANLING RATS.

EPA Science Inventory

N-methyl carbamate insecticides are reversible inhibitors of central and peripheral acetylcholinesterease (ChE). Despite their widespread and long-term use, we could find no studies of a systematic comparison of neurotoxicity in young animals across this group of chemicals. To ...

Data-derived uncertainty factor approach in the revised N-methyl carbamate risk assessment.

EPA Science Inventory

EPA completed its Revised Cumulative Risk Assessment (CRA) of the N-methyl Carbamate (NMC) Pesticides in 2007. This assessment evaluated the joint risk to 10 pesticides from food, water, and residential exposure. NMCs share the ability to inhibit acetylcholinesterase (AChE) via c...

Improving oral bioavailability of cyclic peptides by N-methylation.

PubMed

Räder, Andreas F B; Reichart, Florian; Weinmüller, Michael; Kessler, Horst

2018-06-01

The renaissance of peptides in pharmaceutical industry results from their importance in many biological functions. However, low metabolic stability and the lack of oral availability of most peptides is a certain limitation. Whereas metabolic instability may be often overcome by development of small cyclic peptides containing d-amino acids, the very low oral availability of most peptides is a serious limitation for some medicinal applications. The situation is complicated because a twofold optimization - biological activity and oral availability - is required to overcome this problem. Moreover, most simple "rules" for achieving oral availability are not general and are applicable only to limited cases. Many structural modifications for increasing biological activities and metabolic stabilities of cyclic peptides have been described, of which N-alkylation is probably the most common. This mini-review focuses on the effects of N-methylation of cyclic peptides in strategies to optimize bioavailabilities. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Study of antileishmanial activity of 2-aminobenzoyl amino acid hydrazides and their quinazoline derivatives.

PubMed

Khattab, Sherine Nabil; Haiba, Nesreen Saied; Asal, Ahmed Mosaad; Bekhit, Adnan A; Guemei, Aida A; Amer, Adel; El-Faham, Ayman

2017-02-15

A new small library of 2-aminobenzoyl amino acid hydrazide derivatives and quinazolinones derivatives was synthesized and fully characterized by IR, NMR, and elemental analysis. The activity of the prepared compounds on the growth of Leishmania aethiopica promastigotes was evaluated. 2-Benzoyl amino acid hydrazide showed higher inhibitory effect than the quinazoline counterpart. The in vitro antipromastigote activity demonstrated that compounds 2a, 2b, 2f and 4a had IC 50 better than standard drug miltefosine and comparable activity to amphotericin B deoxycholate, which indicates their high antileishmanial activity against Leishmania. aethiopica. Among the prepared compounds; 2-amino-N-(6-hydrazinyl-6-oxohexyl)benzamide 2f (IC 50 =0.051μM) has the best activity, 154 folds more active than reference standard drug miltefosine (IC 50 =7.832μM), and half fold the activity of amphotericin B (IC 50 =0.035μM). In addition, this compound was safe and well tolerated by experimental animals orally up to 250mg/kg and parenterally up to 100mg/kg. Copyright © 2017 Elsevier Ltd. All rights reserved.

A new in vitro method for testing plant metabolism in mutagenicity studies.

PubMed

Benigni, R; Bignami, M; Camoni, I; Carere, A; Conti, G; Iachetta, R; Morpurgo, G; Ortali, V A

1979-09-01

A rapid method was proposed to detect whether a harmless agricultural chemical can be converted into a mutagenic one by plant metabolism. The method is based on the use of Nicotiana alata cell cultures. Results obtained with five pesticides (atrazine, dichlorvos, tetrachlorvinphos, Kelevan, and maleic hydrazide) suggest that the proposed method simulates the metabolism of the whole plant. This procedure was also successfully applied to the genetic system of Aspergillus nidulans. One pesticide, atrazine, induced mutations and somatic segregation only after metabolism during cocultivation with N. alata cells.

Identical acyl transfer reactions between pyridine N-oxides and their N-acylonium salts

NASA Astrophysics Data System (ADS)

Rybachenko, V. I.; Shroeder, G.; Chotii, K. Yu.; Kovalenko, V. V.; Red'Ko, A. N.; Gierzyk, B.

2007-10-01

28 identical acyl exchange reactions R-CO-Nu+, X- + Nu between pyridine N-oxides in acetonitrile were studied. Here, X- = BPh{4/-} and R = methyl, N,N-dimethylamino, N,N-diethylamino, 4-morpholino, 1-piperidino, N-methyl, N-phenylamino, or N,N-diphenylamino group. The IR and NMR spectroscopic characteristics of acyloxypyridinium salts were determined, and the quantum-chemical parameters of all reagents calculated. The results were subjected to correlation analysis. It was found that the rate of identical acyl transfer reactions was controlled by the interaction of frontier orbitals in the transition state.

Crystal structures of N-(3-fluoro-benzo-yl)benzene-sulfonamide and N-(3-fluoro-benzo-yl)-4-methyl-benzene-sulfonamide.

PubMed

Suchetan, P A; Naveen, S; Lokanath, N K; Lakshmikantha, H N; Srivishnu, K S; Supriya, G M

2016-04-01

The crystal structures of two N-(aryl-sulfon-yl)aryl-amides, namely N-(3-fluoro-benzo-yl)benzene-sulfonamide, C13H10FNO3S, (I), and N-(3-fluoro-benzo-yl)-4-methyl-benzene-sulfonamide, C14H12FNO3S, (II), are described and compared with related structures. The dihedral angle between the benzene rings is 82.73 (10)° in (I) compared to 72.60 (12)° in (II). In the crystal of (I), the mol-ecules are linked by C-H⋯O and C-H⋯π inter-actions, resulting in a three-dimensional grid-like architecture, while C-H⋯O inter-actions lead to one-dimensional ribbons in (II). The crystals of both (I) and (II) feature strong but non-structure-directing N-H⋯O hydrogen bonds with R 2 (2)(8) ring motifs. The structure of (I) also features π-π stacking inter-actions.

76 FR 72311 - Hazardous Waste Management System; Identification and Listing of Hazardous Waste; Final Exclusion

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-23

... waste in any State with delisting authorization, Eastman Chemical must obtain delisting authorization... benzene, ethyl ether, methyl isobutyl ketone, n-butyl alcohol, cyclohexane, methanol. F005 Toluene, methyl... Isobutyl alcohol. U147 Maleic anhydride. U154 Methanol. U159 Methyl ethyl ketone. U161 Methyl isobutyl...

Proline derivatives in fruits of bergamot (Citrus bergamia Risso et Poit): presence of N-methyl-L-proline and 4-hydroxy-L-prolinebetaine.

PubMed

Servillo, Luigi; Giovane, Alfonso; Balestrieri, Maria Luisa; Cautela, Domenico; Castaldo, Domenico

2011-01-12

The content of proline and various compounds deriving from its metabolism (4-hydroxy-L-proline, N-methyl-L-proline, N,N-dimethylproline, and 4-hydroxy-L-prolinebetaine) was determined in fruits and seeds of Bergamot (Citrus bergamia Risso et Poit), growing in the Calabria region (South Italy). A HPLC-ESI-tandem mass spectrometry method, which allowed rapid determination of L-proline, 4-hydroxy-L-proline, N-methyl-L-proline, N,N-dimethylproline, and 4-hydroxy-L-prolinebetaine in juice and extracts of bergamot fruit with minimum sample preparation and short analysis time (about 10 min), is presented. Proline and 4-hydroxy-L-proline levels in the samples were also determined by HPLC analysis with fluorescence detection and the results compared to those obtained with HPLC-ESI-tandem mass spectrometry. For the first time, the presence of N-methyl-L-proline and 4-hydroxy-L-prolinebetaine in the fruits of a plant of the Citrus genus is reported.

[Cancer chemotherapy with special reference to pharmacokinetics of nitrosoureas].

PubMed

Wakui, A

1982-08-01

This paper provides an overview of cancer chemotherapy with special reference to the pharmacokinetics of the nitrosoureas. At physiological PH, the chloroethylnitrosoureas can be decomposed into an isocyanate and 2-chloroethyl diazene hydroxide. Therefore, it is clear that they have both alkylation and carbamoylation actions. In addition to the spontaneous chemical dissociation, the nitrosoureas can be metabolized by liver microsomal enzymes to more polar hydroxylated products, and certain nitrosoureas can be denitrosated by these enzymes to the parent urea. Since the lipid-soluble nitrosoureas and some of the water-soluble nitrosoureas such as ACNU and MCNU demonstrated to cross the blood-brain barrier, they have been used in the treatment of primary brain tumors and tumors and tumors of metastatic origin. It has been demonstrated from the results of our study and other reports that the alkylation of DNA by ACNU progresses more slowly as compared with that of other alkylating agents. This is an important finding in relation to the appearance of delayed myelosuppression of the nitrosoureas and in the design of dose schedules of these agents. The major clinical emphasis has been directed towards the more active chloroethylnitrosoureas with reduced myelosuppression, and attempts are now made for this purpose. Unfortunately, the results of phase I and II trials of the newly developed nitrosoureas suggest that these agents produce delayed and cumulative bone marrow toxicity. Antitumor activity of the nitrosoureas is frequestly observed in chronic myelocytic leukemia, malignant lymphoma, brain tumors and small cell carcinoma of the lung, and less frequently in gastrointestinal carcinoma, multiple myeloma and malignant melanoma. In order to enhance clinical effects of the nitrosoureas, further investigation of the design in therapeutic schedules on the basis of their pharmacokinetic characteristics will be needed.

[Chemotherapeutic characterization of new nitrosourea compounds].

PubMed

Zeller, W J; Berger, M R; Eisenbrand, G; Petru, E

1988-01-01

The development of new nitrosoureas is described using selected examples. Results obtained with water-soluble analogs and with compounds linked to biomolecules as for instance amino acids, oligopeptides and steroids, are presented. The pronounced antineoplastic effect of some water-soluble analogs is paralleled by an increased rate of DNA-interstrand cross-links and by an increased suppression of hematopoietic stem cells. The suppression of bone marrow stem cells is followed by their rapid regeneration. Water-soluble nitrosoureas induce significant less inhibition of glutathione reductase as compared with established compounds. With regard to long-term toxicity and carcinogenicity water-soluble are superior to established compounds as for instance BCNU. Linking of the nitrosourea moiety to amino acids and oligopeptides led to some analogs with outstanding therapeutic ratio. Out of a group of steroid-linked nitrosoureas, CNC-L-alanine-estradiol-17-ester (CNC-ala-17-E2) is chosen to demonstrate the possibility of reducing bone marrow toxicity despite unchanged or increased therapeutic activity by attachment of the nitrosourea moiety to a steroid. Results of a comparative interspecies in vitro evaluation of CNC-ala-17-E2 in transplanted MXT mammary carcinoma of the mouse, MNU-induced autochthonous rat mammary carcinoma and primary human mammary carcinomas are presented and the question is discussed to what extent in vitro activity of such receptor agents using the tumor stem cell assay reflects their in vivo activity.

Time-course, dose-response, and age comparative sensitivity of N-methyl carbamates in rats

EPA Science Inventory

N-Methyl carbamate insecticides are reversible inhibitors of central and peripheral acetylcholinesterease (ChE). Despite their widespread use, there are few studies of neurotoxicity in young animals. To study potential age-related differences, we evaluated seven carbamates (carba...

Probes for narcotic receptor mediated phenomena. 42. Synthesis and in vitro pharmacological characterization of the N-methyl and N-phenethyl analogues of the racemic ortho-c and para-c oxide-bridged phenylmorphans

PubMed Central

Kim, Jin-Hee; Deschamps, Jeffrey R.; Rothman, Richard B.; Dersch, Christina M.; Folk, John E.; Cheng, Kejun; Jacobson, Arthur E.; Rice, Kenner C.

2011-01-01

A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmorphans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacological properties of these compounds were determined. The N-phenethyl substituted ortho-c oxide-bridged phenylmorphan (rac-(3R,6aS,11aS)-2-phenethyl-2,3,4,5,6,11a-hexahydro-1H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (12)) was found to have the highest μ-opioid receptor affinity (Ki = 1.1 nM) of all of the a- through f-oxide-bridged phenylmorphans. Functional data ([35S]GTP-γ-S) showed that the racemate 12 was more than three times more potent than naloxone as an μ-opioid antagonist. PMID:21570305

Attenuation by genistein of sodium-chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

PubMed

Tatsuta, M; Iishi, H; Baba, M; Yano, H; Uehara, H; Nakaizumi, A

1999-01-29

The effects of prolonged administration of genistein, a tyrosine-kinase inhibitor, on sodium-chloride-enhanced induction of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labeling and apoptotic indices and vessel counts in the gastric mucosa and gastric cancers, were investigated in Wistar rats. After 25 weeks of the carcinogen treatment, rats were fed chow pellets containing 10% sodium chloride and were given s.c. injections of genistein at dosages of 15 mg/kg or 30 mg/kg body weight every other day. In week 52, the incidence of gastric cancers was significantly greater in rats fed sodium chloride than in untreated control rats. Prolonged administration of genistein at a dosage of 30 mg/kg, but not 15 mg/kg, body weight significantly reduced the incidence of gastric cancers, which was increased by oral treatment with sodium chloride. Genistein at the higher dose significantly decreased the labeling index and vessel counts of the antral mucosa and the gastric cancers (which were increased by treatment with sodium chloride) and significantly increased the apoptotic index of the antral mucosa and the cancers (which was lowered by the treatment with sodium chloride). These findings suggest that genistein attenuates gastric carcinogenesis promoted by sodium chloride, by inducing increased apoptosis and lower cell proliferation and angiogenesis of antral mucosa and gastric cancers.

Low-protein diet promotes sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

PubMed

Iishi, H; Tatsuta, M; Baba, M; Hirasawa, R; Sakai, N; Yano, H; Uehara, H; Nakaizumi, A

1999-07-01

Sodium chloride (NaCl) initiates and promotes experimental carcinogenesis in rats. We recently found that a high-protein diet attenuates NaCl-enhanced gastric carcinogenesis in Wistar rats. To investigate the effect of a purified low-protein diet on NaCl-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Wistar rats, rats were fed a purified diet with an equalized caloric content containing 1% or 2% NaCl and 25% casein (normal-protein diet) or 10% casein (low-protein diet) after oral treatment with MNNG for 25 weeks. In week 52, neither 1% nor 2% NaCl had a significant effect on gastric carcinogenesis in rats fed a normal-protein diet. However, oral administration of 2%, but not 1%, NaCl significantly increased the incidence of gastric cancers in rats fed a low-protein diet. Oral administration of 2% NaCl also significantly increased the bromodeoxyuridine (BrdU)-labeling index and the ornithine decarboxylase (ODC) activity and decreased apoptosis of gastric cancers in rats fed a low-protein diet. However, 2% NaCl had no significant effect on these three parameters in rats fed a normal-protein diet. These findings indicate that a low-protein diet enhances the effect of NaCl in gastric carcinogenesis and that this enhancement may be mediated by increased cell proliferation and reduced apoptosis of gastric cancers.

Poly[[tetra-μ-cyanido-κ8 C:N-dodeca-cyanido-κ12 C-tris­(N,N-di­methyl­formamide-κO)tris­(methanol-κO)tris­(3,4,7,8-tetra­methyl-1,10-phenanthroline-κ2 N,N′)trimanganese(II)ditungstate(V)] dihydrate

PubMed Central

Yang, Fei-Lin; Yang, Dan

2014-01-01

The asymmetric unit of the title compound, {[Mn3{W(CN)8}2(C16H16N2)3(C3H7NO)3(CH3OH)3]·2H2O}n, consists of three [Mn(N,N-di­methyl­formamide)(methanol)(3,4,7,8-tetra­methyl-1,10-phenanthroline)]2+ cations, two [W(CN)8]3− anions and two water mol­ecules. Each water mol­ecule is disordered over three sets of sites, with a refined occupancy ratio of 0.310 (9):0.275 (9):0.415 (9) for one mol­ecule and 0.335 (9):0.288 (9):0.377 (9) for the other mol­ecule. The MnII atoms exhibit a distorted octa­hedral geometry, while the WV atoms adopt a distorted square-anti­prismatic geometry. The MnII and WV atoms are linked alternatively through cyanide groups, forming a tetra­nuclear 12-atom rhombic metallacycle. Adjacent metallacycles are further connected by μ2-bridging cyanide anions, generating a 3,2-chain structure running parallel to [101]. Inter­chain π–π inter­actions are observed [centroid–centroid distances = 3.763 (3) and 3.620 (2) Å]. PMID:24860305

Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands.

PubMed

Deekonda, Srinivas; Wugalter, Lauren; Kulkarni, Vinod; Rankin, David; Largent-Milnes, Tally M; Davis, Peg; Bassirirad, Neemah M; Lai, Josephine; Vanderah, Todd W; Porreca, Frank; Hruby, Victor J

2015-09-15

A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-(piperidin-4-yl)propionamide derivatives to study the biological effects of these substituents on μ and δ opioid receptor interactions. Recently our group reported novel 4-anilidopiperidine analogues, in which several aromatic ring-contained amino acids were conjugated with N-phenyl-N-(piperidin-4-yl)propionamide and examined their biological activities at the μ and δ opioid receptors. In continuation of our efforts in these novel 4-anilidopiperidine analogues, we took a peptidomimetic approach in the present design, in which we substituted aromatic amino acids with tetrahydronaphthalen-2yl methyl moiety with amino, amide and hydroxyl substitutions at the 5th position. In in vitro assays these ligands, showed very good binding affinity and highly selective toward the μ opioid receptor. Among these, the lead ligand 20 showed excellent binding affinity (2 nM) and 5000 fold selectivity toward the μ opioid receptor, as well as functional selectivity in GPI assays (55.20 ± 4.30 nM) and weak or no agonist activities in MVD assays. Based on the in vitro bioassay results the lead compound 20 was chosen for in vivo assessment for efficacy in naïve rats after intrathecal administration. Compound 20 was not significantly effective in alleviating acute pain. This discrepancy between high in vitro binding affinity, moderate in vitro activity, and low in vivo activity may reflect differences in pharmacodynamics (i.e., engaging signaling pathways) or pharmacokinetics (i.e., metabolic stability). In sum, our data suggest that further optimization of this compound 20 is required to enhance in vivo activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Biotransformation and pharmacokinetics of the nitrate trans-2-amino-2-methyl-N-(4-nitroxycyclohexyl)-propionamide in dogs.

PubMed

Pressmar, F; Neidlein, R; Strein, K

1992-11-01

The biotransformation and the pharmacokinetic behavior of the organic nitrate trans-2-Amino-2-methyl-N-(4-nitroxycyclohexyl)-propionamide (BM 12.1179, CAS 129795-96-6) were examined in dogs. BM 12.1179 was predominantly eliminated by urinary excretion, and the unchanged molecule prevailed in urine as well as in plasma. By means of various mass spectroscopic methods, the chemical structures of the metabolites were elucidated. As metabolites trans-2-amino-2-methyl-N-(4-hydroxycyclohexyl)-propionamide and trans-2-amino-2-methyl-N-(4-oxocyclohexyl)-propionamide were formed. Urine levels of the main metabolite were determined by high-pressure liquid chromatography; plasma and urine levels of BM 12.1179 were determined by capillary gas chromatography. The absolute bioavailability of BM 12.1179 was 80-100%. The plasma protein binding was about 34% which is high in comparison to other organic nitrates. BM 12.1179 represents a long-acting organic nitrate in that it shows a slow reductive denitration, and a long elimination half-life of about 10 h.

DFT investigations of phosphotriesters hydrolysis in aqueous solution: a model for DNA single strand scission induced by N-nitrosoureas.

PubMed

Liu, Tingting; Zhao, Lijiao; Zhong, Rugang

2013-02-01

DNA phosphotriester adducts are common alkylation products of DNA phosphodiester moiety induced by N-nitrosoureas. The 2-hydroxyethyl phosphotriester was reported to hydrolyze more rapidly than other alkyl phosphotriesters both in neutral and in alkaline conditions, which can cause DNA single strand scission. In this work, DFT calculations have been employed to map out the four lowest activation free-energy profiles for neutral and alkaline hydrolysis of triethyl phosphate (TEP) and diethyl 2-hydroxyethyl phosphate (DEHEP). All the hydrolysis pathways were illuminated to be stepwise involving an acyclic or cyclic phosphorane intermediate for TEP or DEHEP, respectively. The rate-limiting step for all the hydrolysis reactions was found to be the formation of phosphorane intermediate, with the exception of DEHEP hydrolysis in alkaline conditions that the decomposition process turned out to be the rate-limiting step, owing to the extraordinary low formation barrier of cyclic phosphorane intermediate catalyzed by hydroxide. The rate-limiting barriers obtained for the four reactions are all consistent with the available experimental information concerning the corresponding hydrolysis reactions of phosphotriesters. Our calculations performed on the phosphate triesters hydrolysis predict that the lower formation barriers of cyclic phosphorane intermediates compared to its acyclic counter-part should be the dominant factor governing the hydrolysis rate enhancement of DEHEP relative to TEP both in neutral and in alkaline conditions.

Increased levels of N(ε)- Carboxy methyl lysine (N(ε)-CML) are associated with topographic alterations in retinal pigment epithelium: A preliminary study.

PubMed

Mishra, Nibha; Saxena, Sandeep; Ruia, Surabhi; Prasad, Senthamizh; Singh, Vinita; Khanna, Vinay; Staffa, Robert; Gaspar, Ludovit; Kruzliak, Peter

2016-07-01

To evaluate the association of serum levels of N(ε)- Carboxy methyl lysine (N(ε)-CML), an advanced glycation end product with topographic alterations in retinal pigment epithelium (RPE) in diabetic retinopathy on spectral domain optical coherence tomography (SD-OCT). Consecutive cases of type 2 diabetes mellitus with no retinopathy (n=20); non-proliferative diabetic retinopathy (n=20); proliferative diabetic retinopathy (n=20) and healthy controls (n=20) between the ages of 40 and 65years were included. RPE alterations were graded on segmentation map of SD-OCT: grade 0, No RPE alterations; grade 1, RPE alterations in up to two quadrants and grade 2, RPE alterations in more than two quadrants. Serum level of N(ε)-CML and glycated hemoglobin (HbA1c) was analyzed using the standard protocol. Statistical analysis was done. Significant increase in N(ε)-CML was observed with increased severity of diabetic retinopathy (F=34.1; p<0.0001). Fisher exact test revealed significant increase in grades of RPE alterations with increased severity of diabetic retinopathy (p<0.001). Univariate ordinal regression analysis was done to calculate the risk of progression in grades of RPE alteration with individual changes in variables like duration of diabetes (odds ratio=1.37; p=0.001), HbA1c (odds ratio=1.37; p=0.002) and Nε-CML (odds ratio=1.37; p<0.0001). Multivariate ordinal regression analysis for predicting progression in grades of RPE alteration revealed Nε-CML to be an independent predictor of increase in grades of RPE alteration (adjusted odds ratio=1.07; p<0.01) when duration of diabetes and HbA1c were held constant. Increase in serum levels of N(ε)- Carboxy methyl lysine is significantly associated with topographic alterations in RPE. Grades of RPE alteration increase significantly with increased severity of diabetic retinopathy. Copyright © 2016 Elsevier Inc. All rights reserved.

Crystal structure of catena-poly[N,N,N′,N′-tetra­methyl­guanidinium [(chlorido­cadmate)-di-μ-chlorido

PubMed Central

Ndiaye, Mamadou; Samb, Abdoulaye; Diop, Libasse; Maris, Thierry

2016-01-01

In the structure of the title salt, {(C5H14N3)[CdCl3]}n, the CdII atom of the complex anion is five-coordinated by one terminal and four bridging Cl atoms. The corresponding coordination polyhedron is a distorted trigonal bipyramid, with Cd—Cl distances in the range 2.4829 (4)–2.6402 (4) Å. The bipyramids are condensed into a polyanionic zigzag chain extending parallel to [101]. The tetra­methyl­guanidinium cations are situated between the polyanionic chains and are linked to them through N—H⋯Cl hydrogen bonds, forming a layered network parallel to (010). PMID:26870572

Distribution and elimination of the glycosidase inhibitors 1-deoxymannojirimycin and N-methyl-1-deoxynojirimycin in the rat in vivo.

PubMed

Faber, E D; Oosting, R; Neefjes, J J; Ploegh, H L; Meijer, D K

1992-11-01

We studied the pharmacokinetics of two synthetic derivatives of 1-deoxynojirimycin in the rat after intravenous administration. The mannosidase IA/B inhibitor 1-deoxymannojirimycin and the glucosidase inhibitor N-methyl-1-deoxynojirimycin exhibited minimal plasma protein binding and showed a rapid biphasic plasma disappearance, with an initial t1/2 of 3.0 and 4.5 min, respectively, and a terminal t1/2 of 51 and 32 min, respectively. For both compounds renal excretion is the major route of elimination. After 120 min, 52% of the dose of 1-deoxymannojirimycin and 80% of the dose of N-methyl-1-deoxymannojirimycin was recovered unchanged from the urine, whereas only 4.9 and 0.2%, respectively, of the dose was excreted in bile. Urinary clearance of 1-deoxymannojirimycin was similar to the glomerular filtration rate. In contrast, urinary clearance of N-methyl-1-deoxynojirimycin was two to three times higher than the glomerular filtration rate, indicating active tubular secretion. Ligation of the renal vessels decreased the total-body clearance of 1-deoxymannojirimycin and N-methyl-1-deoxynojirimycin 18- and 24-fold, respectively. Neither alkalinization of the urine by infusion of bicarbonate solutions nor forced diuresis altered the renal excretion rate of these compounds, implying the absence of tubular reabsorption. At 120 min, the amounts of 1-deoxymannojirimycin in liver and kidney were 2.1 and 1.1% of the dose, respectively, while small intestine, stomach, and heart contained only 0.9, 0.6 and 0.1%. Less than 1% of the dose of N-methyl-1-deoxynojirimycin was found in the collected organs 2 hr after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Mice with an N-Ethyl-N-Nitrosourea (ENU) Induced Tyr209Asn Mutation in Natriuretic Peptide Receptor 3 (NPR3) Provide a Model for Kyphosis Associated with Activation of the MAPK Signaling Pathway.

PubMed

Esapa, Christopher T; Piret, Sian E; Nesbit, M Andrew; Loh, Nellie Y; Thomas, Gethin; Croucher, Peter I; Brown, Matthew A; Brown, Steve D M; Cox, Roger D; Thakker, Rajesh V

2016-01-01

Non-syndromic kyphosis is a common disorder that is associated with significant morbidity and has a strong genetic involvement; however, the causative genes remain to be identified, as such studies are hampered by genetic heterogeneity, small families and various modes of inheritance. To overcome these limitations, we investigated 12 week old progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessments including dysmorphology, radiography, and dual-energy X-ray absorptiometry. This identified a mouse with autosomal recessive kyphosis (KYLB). KYLB mice, when compared to unaffected littermates, had: thoraco-lumbar kyphosis, larger vertebrae, and increased body length and increased bone area. In addition, female KYLB mice had increases in bone mineral content and plasma alkaline phosphatase activity. Recombination mapping localized the Kylb locus to a 5.5Mb region on chromosome 15A1, which contained 51 genes, including the natriuretic peptide receptor 3 (Npr3) gene. DNA sequence analysis of Npr3 identified a missense mutation, Tyr209Asn, which introduced an N-linked glycosylation consensus sequence. Expression of wild-type NPR3 and the KYLB-associated Tyr209Asn NPR3 mutant in COS-7 cells demonstrated the mutant to be associated with abnormal N-linked glycosylation and retention in the endoplasmic reticulum that resulted in its absence from the plasma membrane. NPR3 is a decoy receptor for C-type natriuretic peptide (CNP), which also binds to NPR2 and stimulates mitogen-activated protein kinase (MAPK) signaling, thereby increasing the number and size of hypertrophic chondrocytes. Histomorphometric analysis of KYLB vertebrae and tibiae showed delayed endochondral ossification and expansion of the hypertrophic zones of the growth plates, and immunohistochemistry revealed increased p38 MAPK phosphorylation throughout the growth plates of KYLB vertebrae. Thus, we established a model of kyphosis due to a novel NPR3 mutation, in

Mice with an N-Ethyl-N-Nitrosourea (ENU) Induced Tyr209Asn Mutation in Natriuretic Peptide Receptor 3 (NPR3) Provide a Model for Kyphosis Associated with Activation of the MAPK Signaling Pathway

PubMed Central

Nesbit, M. Andrew; Loh, Nellie Y.; Thomas, Gethin; Croucher, Peter I.; Brown, Matthew A.; Brown, Steve D. M.; Cox, Roger D.; Thakker, Rajesh V.

2016-01-01

Non-syndromic kyphosis is a common disorder that is associated with significant morbidity and has a strong genetic involvement; however, the causative genes remain to be identified, as such studies are hampered by genetic heterogeneity, small families and various modes of inheritance. To overcome these limitations, we investigated 12 week old progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessments including dysmorphology, radiography, and dual-energy X-ray absorptiometry. This identified a mouse with autosomal recessive kyphosis (KYLB). KYLB mice, when compared to unaffected littermates, had: thoraco-lumbar kyphosis, larger vertebrae, and increased body length and increased bone area. In addition, female KYLB mice had increases in bone mineral content and plasma alkaline phosphatase activity. Recombination mapping localized the Kylb locus to a 5.5Mb region on chromosome 15A1, which contained 51 genes, including the natriuretic peptide receptor 3 (Npr3) gene. DNA sequence analysis of Npr3 identified a missense mutation, Tyr209Asn, which introduced an N-linked glycosylation consensus sequence. Expression of wild-type NPR3 and the KYLB-associated Tyr209Asn NPR3 mutant in COS-7 cells demonstrated the mutant to be associated with abnormal N-linked glycosylation and retention in the endoplasmic reticulum that resulted in its absence from the plasma membrane. NPR3 is a decoy receptor for C-type natriuretic peptide (CNP), which also binds to NPR2 and stimulates mitogen-activated protein kinase (MAPK) signaling, thereby increasing the number and size of hypertrophic chondrocytes. Histomorphometric analysis of KYLB vertebrae and tibiae showed delayed endochondral ossification and expansion of the hypertrophic zones of the growth plates, and immunohistochemistry revealed increased p38 MAPK phosphorylation throughout the growth plates of KYLB vertebrae. Thus, we established a model of kyphosis due to a novel NPR3 mutation, in

Designing and exploring active N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against three Trypanosoma cruzi strains more prevalent in Chagas disease patients.

PubMed

Palace-Berl, Fanny; Pasqualoto, Kerly Fernanda Mesquita; Jorge, Salomão Dória; Zingales, Bianca; Zorzi, Rodrigo Rocha; Silva, Marcelo Nunes; Ferreira, Adilson Kleber; de Azevedo, Ricardo Alexandre; Teixeira, Sarah Fernandes; Tavares, Leoberto Costa

2015-01-01

Chagas disease affects around 8 million people worldwide and its treatment depends on only two nitroheterocyclic drugs, benznidazole (BZD) and nifurtimox (NFX). Both drugs have limited curative power in chronic phase of disease. Nifuroxazide (NF), a nitroheterocyclic drug, was used as lead to design a set of twenty one compounds in order to improve the anti-Trypanosoma cruzi activity. Lipinski's rules were considered in order to support drug-likeness designing. The set of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides was assayed against three T. cruzi strains, which represent the discrete typing units more prevalent in human patients: Y (TcII), Silvio X10 cl1 (TcI), and Bug 2149 cl10 (TcV). All the derivatives, except one, showed enhanced trypanocidal activity against the three strains as compared to BZD. In the Y strain 62% of the compounds were more active than NFX. The most active compound was N'-((5-nitrofuran-2-yl) methylene)biphenyl-4-carbohydrazide (C20), which showed IC50 values of 1.17 ± 0.12 μM; 3.17 ± 0.32 μM; and 1.81 ± 0.18 μM for Y, Silvio X10 cl1, and Bug 2149 cl10 strains, respectively. Cytotoxicity assays with human fibroblast cells have demonstrated high selectivity indices for several compounds. Exploratory data analysis indicated that primarily topological, steric/geometric, and electronic properties have contributed to the discrimination of the set of investigated compounds. The findings can be helpful to drive the designing, and subsequently, the synthesis of additional promising drugs against Chagas disease. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

N-(Diphenyl­carbamo­yl)-N,N′,N′,N′′,N′′-penta­methyl­guanidinium tetra­phenyl­borate

PubMed Central

Tiritiris, Ioannis

2013-01-01

In the title salt, C19H25N4O+·C24H20B−, the C=N and C—N bond lengths in the CN3 unit are 1.3327 (8)/1.3364 (9) and 1.3802 (9) Å, indicating double- and single-bond character, respectively. The N—C—N angles are 118.77 (6), 120.29 (6) and 120.81 (6)°, showing only a small deviation of the CN3 plane from an ideal trigonal-planar geometry. The bonds between the N atoms and the terminal methyl C atoms all have values close to a typical single bond [1.4636 (9)–1.4772 (9) Å]. The crystal packing is caused by electrostatic inter­actions between cations and anions. PMID:23476477

Structure and conformation of N-(2-methyl-5-chlorophenyl)salicylaldimine

NASA Astrophysics Data System (ADS)

Elmali, A.; Elerman, Y.

1998-02-01

N-(2-methyl-5-chlorophenyl)salicylaldimine (C 14H 12ClNO) has been studied by X-ray analysis and AM1 molecular orbital methods. It crystallises in the orthorhombic space group P2 12 12 1 with a = 7.474(1) Å, b = 12.155(1) Å, c = 13.378(1) Å, V = 1215.3(2) Å3, Z = 4, Dc = 1.343 g cm -3 and μ(Mo Kα) = 0.296 mm -1. The structure was solved by direct methods and refined to R = 0.0374 for 1689 reflections [ I > 2 σ( I)]. The title compound is photochromic and the molecule is not planar. There is a strong intramolecular hydrogen bond of distance 2.604(3) Å between the hydroxyl oxygen atom and imine nitrogen atom, the hydrogen atom essentially being bonded to the oxygen atom. Minimum energy conformations from AM1 were calculated as a function of the three torsion angles θ1(C8N1C7C6), θ2(C9C8N1C7) and θ3(N1C7C6C5), varied every 10°. The optimised geometry of the crystal structure corresponding to a non-planar conformation is the most stable conformation in all calculations.

Cysteine Substitution of Transmembrane Domain Amino Acids Alters the Ethanol Inhibition of GluN1/GluN2A N-Methyl-d-Aspartate Receptors

PubMed Central

Xu, Minfu; Smothers, C. Thetford

2015-01-01

N-Methyl-d-aspartate receptors (NMDARs) are inhibited by behaviorally relevant concentrations of ethanol, and residues within transmembrane (TM) domains of NMDARs, including TM3 GluN1 phenylalanine 639 (F639), regulate this sensitivity. In the present study, we used cysteine (C) mutagenesis to determine whether there are additional residues within nearby TM domains that regulate ethanol inhibition on NMDARs. GluN1(F639C)/GluN2A receptors were less inhibited by ethanol than wild-type receptors, and inhibition was restored to wild-type levels following treatment with ethanol-like methanethiosulfonate reagents. Molecular modeling identified six residues in the GluN1 TM1 domain (valine V566; serine S569) and the GluN2A TM4 domain (methionine, M817; V820, F821, and leucine, L824) that were in close vicinity to the TM3 F639 residue, and these were individually mutated to cysteine and tested for ethanol inhibition and receptor function. The F639C-induced decrease in ethanol inhibition was blunted by coexpression of GluN1 TM1 mutants V566C and S569C, and statistically significant interactions were observed for ethanol inhibition among V566C, F639C, and GluN2A TM4 mutants V820C and F821C and S569C, F639C, and GluN2A TM4 mutants F821C and L824C. Ethanol inhibition was also reduced when either GluN1 TM1 mutant V566C or S569C was combined with GluN2A V820C, suggesting a novel TM1:TM4 intrasubunit site of action for ethanol. Cysteines substituted at TM3 and TM4 sites previously suggested to interact with ethanol had less dramatic effects on ethanol inhibition. Overall, the results from these studies suggest that interactions among TM1, TM3, and TM4 amino acids in NMDARs are important determinants of ethanol action at these receptors. PMID:25635140

Investigation on Adsorption and the Corrosion Inhibition Effect of Some Novel Hydrazide Derivatives for Mild Steel in HCl Solution

NASA Astrophysics Data System (ADS)

Singh, Dharmendra Kumar; Behera, Debasis; Singh, Mantu Kumar; Udayabhanu, G.; John, Rohith P.

2017-10-01

Two hydrazide derivatives, namely, N'-(thiophene-2-ylmethylene)nicotinic hydrazone (TNH) and N'-(pyrrol-2-ylmethylene)nicotinic hydrazone (PNH), have been synthesized and investigated as corrosion inhibitors for mild steel in 1 M HCl solution by electrochemical, weight loss, field emission-scanning electron microscope (FE-SEM), atomic force microscope (AFM), and quantum chemical calculation methods. The experimental results show that both the compounds are good inhibitors for mild steel in 1 M HCl. They act as mixed type inhibitors with predominating cathodic character. The adsorption of inhibitors obeys the Langmuir adsorption isotherm. Correlation between quantum chemical parameters and experimental results is discussed.

Comparison of new nitrosoureas esters with modified steroidal nucleus for cytogenetic and antineoplastic activity.

PubMed

Hussein, A; Mioglou-Kalouptsi, E; Papageorgiou, A; Karapidaki, I; Iakovidou-Kritsi, Z; Lialiaris, T; Xrysogelou, E; Camoutsis, C; Mourelatos, D

2007-01-01

Nitrosourea is decomposed under physiological conditions to react with biological macromolecules by two mechanisms: alkylation (with proteins and nucleic acids) and carbamoylation (with proteins but not nucleic acids). It has been suggested that the alkylating action is responsible for the therapeutic effects of nitrosoureas, and that the carbamoylation activity leads to toxicity effects. In order to reduce systemic toxicity and improve specificity and distribution for cancer therapy, 2-haloethyl nitrosourea has been esterified with modified steroids, which are used as biological platforms for transporting the alkylating agent to the tumor site in a specific manner. The cytogenetic and antineoplastic effect were studied of seven newly synthesized esters of N,N-bis(2-chloroethyl)alanyl carboxyl derivatives with a modified steroidal nucleus (compounds 1-7). As a very sensitive indicator of genotoxicity the Sister Chromatid Exchange (SCE) assay was used and as a valuable marker of cytostatic activity the cell Proliferation Rate Index (PRI) in cultures of normal human lymphocytes was used. The order of magnitude of the cytogenetic activity on a molar basis (15, 30, 120 microM) of the compounds was 7>6>3>5>2>4>1. The most active compound 7 has an enlarged (seven carbon atoms) A ring modified with a lactam group (-NHCO-) with the nitrosourea moiety esterified at position 17 In the group of seven substances a correlation was observed between the magnitude of SCE response and the depression in PRI (r=-O, 65, p<0.001). According to the criterion of activity of National Cancer Institute (NCI), the order of antineoplastic activity of compounds on lymphoid L1210 leukemia is 7>6>2>5>4>3>1 and on lympocytic P388 leukemia cells is 7>2>6>5>4>3>1. The present results are in agreement with previous suggestions that the effectiveness in cytogenetic activity may well be correlated with antitumor effects [T/C: 248% for the compound 7 in 250 mg/kg b.w.; T/C: mean survival time of drug

Mechanism of uptake of nitrosoureas by L5178Y lymphoblasts in vitro.

PubMed

Begleiter, A; Lam, H P; Goldenberg, G J

1977-04-01

The mechanism of uptake of nitrosoureas by L5178Y cells in vitro was investigated. A time course of the uptake of radioactivity on incubation of L5178Y lymphoblast with [14C]-1,3-bis(2-chloroethyl)-1-nitrosourea was linear for 30 min and then entered a plateau phase; it was markedly temperature dependent. A similar time course for cells incubated with [14C]ethylene-labeled 1-(2-chlorethyl)-3-cyclohexyl-1-nitrosourea reached equilibrium rapidly, was temperature independent, and resulted in a relatively low level of uptake of radioactivity. However, cells treated with 3-[cyclohexyl-14C]-1-(2-chlorethyl)-1-nitrosourea had a time course that was linear for 30 min, resulted in much higher levels of uptake of radioactivity, and was strongly temperature dependent. These findings, at least for 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, suggest that some drug decomposition precedes uptake. The percentage of radioactivity found in the cell sap fraction was at least 85% of total cell activity when cells were incubated with any of the three 14C-labeled nitrosoureas. Furthermore, thin-layer chromatography of the cell sap fraction revealed the presence of free intact drug. These findings indicate that intracellular uptake of intact nitrosoureas occurred. A time course of uptake of intact 1,3-bis(2-chloroethyl)-1-nitrosourea reached equilibrium rapidly with cell/medium distribution ratios of 0.2 to 0.6 and was temperature independent. The addition of excess unlabeled 1,3-bis(2-chlorethyl)-1-nitrosourea or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea had no effect on uptake of [14C]-1,3-bis(2-chloroethyl)-1-nitrosourea, These findings suggest that uptake of intact 1,3-bis(2-chloroethyl)-1-nitrosourea was by passive diffusion. A time course of the uptake of intact 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with either [14C]ethylene- or ring-labeled drug rapidly reached equilibrium, was temperature independent, and attained a cell/medium ratio greater than unity. Uptake of 1

Fire and heat resistant laminating resins based on maleimido and citraconimido substituted 1-(diorgano oxyphosphonyl) methyl -2,4- and -2,6- diaminobenzenes

NASA Technical Reports Server (NTRS)

Mikroyannidis, John A. (Inventor); Kourtides, Demetrius A. (Inventor)

1987-01-01

A class of fire and heat resistant bisimide resins prepared by thermal polymerization of maleimido or citraconimido substituted 1-((dialkoxyphosphonyl) methyl)-2-4 and -2,6-diaminobenzenes are described. The polymer precursors are prepared by reacting 1-((diorganooxyphosphonyl) methyl)-2-4 and -2,6-diaminobenzenes with maleic anhydride or citraconic anhydride in a mole ratio 1:2. Chain extension of the monomers is achieved by reacting the mono-N-maleimido derivatives of 1-((diorganooxyphosphonyl) methyl)-2,4 and -2,6-diaminobenzenes with aryl tetracarboxylic dianhydrides, such as benzophenone tetracarbocylic dianhydride, or aryl diisocyanates, such as methylenebis (4-phenylisocyanate), in a mole ratio 2:1. The polymerization of the monomers is studied by differential scanning calorimetry (DSC) and the thermal stability of the polymers is ascertained by thermogravimetric analysis (TGA).

COMPARISON OF ACUTE NEUROBEHAVIORAL AND CHOLINESTERASE INHIBITORY EFFECTS OF N-METHYL CARBAMATES IN RAT

EPA Science Inventory

There are few studies evaluating direct functional and biochemical consequences of exposure. In the present study of the acute toxicity of seven N-methyl carbamate pesticides, we evaluated the dose-response profiles of cholinesterase (ChE) inhibition in brain and erythrocytes (R...

Study of the n-methyl-d-aspartate antagonistic properties of anticholinergic drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

McDonough, J.H.; Shih, T.M.

1995-12-31

A study of the N-methyl-D-aspartate antagonistic properties of anticholinergic drugs. PHARMACOL BIOCHEM BEHAV. 51(2/3) 249-253, 1995. Drugs that act at the N-methyl-D-aspartate (NMDA) receptor complex have the ability to terminate nerve agent-induced seizures and modulate the neuropathologic consequences of agent exposure. Drugs with mixed anticholinergic and anti-NMDA properties potentially provide an ideal class of compounds for development as anticonvulsant treatments for nerve agent casualties. The present experiment evaluated the potential NMDA antagonist activity of 11 anticholinergic drugs by determining whether pretreatment with the compound was capable of protecting mice from the lethal effects of NMDA. The following anticholinergic drugs antagonizedmore » NMDA lethality and are ranked according to their potency: mecamylamine > procyclidine = benactyzine > biperiden > tribexyphenidyl. The anticholinergics atropine, aprophen, azaprophen, benztropine, 3-quinudidinyl benzilate (QNB), and scopolamine failed to show NMDA antagonist properties. In addition, and unexpectedly, diazepam, ethanol, and pentobarbital were also shown to be capable of antagonizing NMDA lethality over a certain range of doses. The advantages and limitations of using antagonism of NMDA lethality in mice as a bioassay for determining the NMDA antagonist properties of drugs are also discussed.« less

Propofol effectively inhibits lithium-pilocarpine- induced status epilepticus in rats via downregulation of N-methyl-D-aspartate receptor 2B subunit expression

PubMed Central

Wang, Henglin; Wang, Zhuoqiang; Mi, Weidong; Zhao, Cong; Liu, Yanqin; Wang, Yongan; Sun, Haipeng

2012-01-01

Status epilepticus was induced via intraperitoneal injection of lithium-pilocarpine. The inhibitory effects of propofol on status epilepticus in rats were judged based on observation of behavior, electroencephalography and 24-hour survival rate. Propofol (12.5–100 mg/kg) improved status epilepticus in a dose-dependent manner, and significantly reduced the number of deaths within 24 hours of lithium-pilocarpine injection. Western blot results showed that, 24 hours after induction of status epilepticus, the levels of N-methyl-D-aspartate receptor 2A and 2B subunits were significantly increased in rat cerebral cortex and hippocampus. Propofol at 50 mg/kg significantly suppressed the increase in N-methyl-D-aspartate receptor 2B subunit levels, but not the increase in N-methyl-D-aspartate receptor 2A subunit levels. The results suggest that propofol can effectively inhibit status epilepticus induced by lithium-pilocarpine. This effect may be associated with downregulation of N-methyl-D-aspartate receptor 2B subunit expression after seizures. PMID:25737709

Progesterone up-regulates vasodilator effects of calcitonin gene-related peptide in N(G)-nitro-L-arginine methyl ester-induced hypertension.

PubMed

Gangula, P R; Wimalawansa, S J; Yallampalli, C

1997-04-01

We recently reported that calcitonin gene-related peptide can reverse the hypertension produced by N(G)-nitro-L-arginine methyl ester in pregnant rats. In the current study we investigated whether these vasodilator effects of calcitonin gene-related peptide were progesterone dependent. Calcitonin gene-related peptide or N(G)-nitro-L-arginine methyl ester was infused through osmotic minipumps, either separately or in combination, to groups of five pregnant rats from day 17 of gestation until day 8 post partum or to nonpregnant ovariectomized rats for 8 days. Progesterone was injected during days 1 to 6 post partum and for 6 days after ovariectomy. Systolic blood pressure was measured daily. Animals receiving N(G)-nitro-L-arginine methyl ester exhibited significant elevations of blood pressure during pregnancy and post partum. Coadministration of calcitonin gene-related peptide to these rats reversed the hypertension during pregnancy but not during the postpartum period. At the dose used in this study calcitonin gene-related peptide administered alone was without significant effects on blood pressure. However, it reduced both the mortality and growth restriction of the fetus associated with N(G)-nitro-L-arginine methyl ester in these animals. Calcitonin gene-related peptide reversed the hypertension in N(G)-nitro-L-arginine methyl ester-infused postpartum rats during the periods of progesterone treatment only, and these effects were lost when progesterone treatment was stopped. Neither progesterone nor calcitonin gene-related peptide alone were effective. To further confirm these observations, progesterone effects were tested in ovariectomized adult rats. Similar to the findings in postpartum rats, calcitonin gene-related peptide completely reversed the elevation in blood pressure in N(G)-nitro-L-arginine methyl ester-treated rats receiving progesterone injections. The effects of calcitonin gene-related peptide were apparent only during the progesterone treatment

Photophysical and Photochemical Properties of Naturally Occurring normelinonine F and Melinonine F Alkaloids and Structurally Related N(2)- and/or N(9)-methyl-β-carboline Derivatives.

PubMed

Rasse-Suriani, Federico A O; García-Einschlag, Fernando S; Rafti, Matías; Schmidt De León, Tobías; David Gara, Pedro M; Erra-Balsells, Rosa; Cabrerizo, Franco M

2018-01-01

In the present work, we have synthesized and fully characterized the photophysical and photochemical properties of a selected group of N-methyl-β-carboline derivatives (9-methyl-β-carbolines and iodine salts of 2-methyl- and 2,9-dimethyl-β-carbolinium) in aqueous solutions, in the pH range 4.0-14.5. Moreover, despite the quite extensive studies reported in the literature regarding the overall photophysical behavior of N-unsubstituted βCs, this work constitutes the first full and unambiguous characterization of anionic species of N-unsubstituted βCs (norharmane, harmane and harmine), present in aqueous solution under highly alkaline conditions (pH > 13.0). Acid dissociation constants (K a ), thermal stabilities, room temperature UV-visible absorption and fluorescence emission and excitation spectra, fluorescence quantum yields (Ф F ) and fluorescence lifetimes (τ F ), as well as quantum yields of singlet oxygen production (Ф Δ ) have been measured for all the studied compounds. Furthermore, for the first time to our knowledge, chemometric techniques (MCR-ALS and PARAFAC) were applied on these systems, providing relevant information about the equilibria and species involved. The impact of all the foregoing observations on the biological role, as well as the potential biotechnological applications of these compounds, is discussed. © 2017 The American Society of Photobiology.

Attenuation by all-trans-retinoic acid of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

PubMed

Tatsuta, M; Iishi, H; Baba, M; Hirasawa, R; Yano, H; Sakai, N; Nakaizumi, A

1999-02-01

The effect of prolonged administration of all-trans-retinoic acid (RA) on sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labelling and apoptotic indices and immunoreactivity of transforming growth factor (TGF) alpha in the gastric cancers was investigated in Wistar rats. After 25 weeks of carcinogen treatment, the rats were given chow pellets containing 10% sodium chloride and subcutaneous injections of RA at doses of 0.75 or 1.5 mg kg(-1) body weight every other day. In week 52, oral supplementation with sodium chloride significantly increased the incidence of gastric cancers compared with the untreated controls. Long-term administration of RA at both doses significantly reduced the incidence of gastric cancers, which was enhanced by oral administration of sodium chloride. RA at both doses significantly decreased the labelling index and TGF-alpha immunoreactivity of gastric cancers, which were enhanced by administration of sodium chloride, and significantly increased the apoptotic index of cancers, which was lowered by administration of sodium chloride. These findings suggest that RA attenuates gastric carcinogenesis, enhanced by sodium chloride, by increasing apoptosis, decreasing DNA synthesis, and reducing TGF-alpha expression in gastric cancers.

(2-{[2-(1H-Benzimidazol-2-yl-κN 3)phen­yl]imino­methyl-κN}-5-methyl­phenolato-κO)chloridozinc(II)

PubMed Central

Eltayeb, Naser Eltaher; Teoh, Siang Guan; Chantrapromma, Suchada; Fun, Hoong-Kun

2011-01-01

In the title mononuclear complex, [Zn(C21H16N3O)Cl], the ZnII ion is coordinated in a distorted tetra­hedral geometry by two benzimidazole N atoms and one phenolate O atom from the tridentate Schiff base ligand and a chloride ligand. The benzimidazole ring system forms dihedral angles of 26.68 (9) and 56.16 (9)° with the adjacent benzene ring and the methyl­phenolate group benzene ring, respectively. In the crystal, mol­ecules are linked by N—H⋯Cl hydrogen bonds into chains along [100]. Furthermore, weak C—H⋯O and C—H⋯π inter­actions, in addition to π–π inter­actions with centroid–centroid distances in the range 3.5826 (13)–3.9681 (13) Å, are also observed. PMID:22065469

Novel Cobalt(II) complexes containing N,N-di(2-picolyl)amine based ligands; Synthesis, characterization and application towards methyl methacrylate polymerisation

NASA Astrophysics Data System (ADS)

Ahn, Seoung Hyun; Choi, Sang-Il; Jung, Maeng Joon; Nayab, Saira; Lee, Hyosun

2016-06-01

The reaction of [CoCl2·6H2O] with N‧-substituted N,N-di(2-picolyl)amine ligands such as 1-cyclohexyl-N,N-bis(pyridin-2-ylmethyl)methanamine (LA), 2-methoxy-N,N-bis(pyridin-2-ylmethyl)ethan-1-amine (LB), and 3-methoxy-N,N-bis(pyridin-2-ylmethyl)propan-1-amine (LC), yielded [LnCoCl2] (Ln = LA, LB and LC), respectively. The Co(II) centre in [LnCoCl2] (Ln = LA, and LC) adopted distorted bipyramidal geometries through coordination of nitrogen atoms of di(2-picolyl)amine moiety to the Co(II) centre along with two chloro ligands. The 6-coordinated [LBCoCl2] showed a distorted octahedral geometry, achieved through coordination of the two pyridyl units, two chloro units, and bidentate coordination of nitrogen and oxygen in the N‧-methoxyethylamine to the Co(II) centre. [LCCoCl2] (6.70 × 104 gPMMA/molCo h) exhibited higher catalytic activity for the polymerisation of methyl methacrylate (MMA) in the presence of modified methylaluminoxane (MMAO) compared to rest of Co(II) complexes. The catalytic activity was considered as a function of steric properties of ligand architecture and increased steric bulk around the metal centre resulted in the decrease catalytic activity. All Co(II) initiators yielded syndiotactic poly(methylmethacrylate) (PMMA).

Amplification of bovine papillomavirus DNA by N-methyl-N'-nitro-N-nitrosoguanidine, ultraviolet irradiation, or infection with herpes simplex virus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schmitt, J.; Schlehofer, J.R.; Mergener, K.

1989-09-01

Treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or irradiation with ultraviolet light (uv254 nm) induces amplification of integrated as well as episomal sequences of bovine papillomavirus (BPV) type 1 DNA in BPV-1-transformed mouse C127 cells (i.e., ID13 cells). This is shown by filter in situ hybridization and Southern blot analysis of cellular DNA. Similarly, infection of ID13 cells with herpes simplex virus (HSV) type 1 which has been shown to be mutagenic for host cell DNA leads to amplification of BPV DNA sequences. In contrast to this induction of DNA amplification by initiators, treatment of ID13 cells with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)more » does not result in increased synthesis of BPV DNA nor does TPA treatment modulate the initiator-induced DNA amplification. Similar to other cell systems infection with adeno-associated virus (AAV) type 2 inhibits BPV-1 DNA amplification irrespective of the inducing agent. In contrast to initiator-induced DNA amplification, treatment with carcinogen (MNNG) or tumor promoters or combination of MNNG and promoter of C127 cells prior to transformation by BPV-1 does not lead to an increase in the number of transformed foci. The induction of amplification of papillomavirus DNA by initiating agents possibly represents one of the mechanisms by which the observed synergism between papillomavirus infection and initiators in tumorigenesis might occur.« less

(BOSC) DOSE-RESPONSE MODELING FOR THE ASSESSMENT OF CUMULATIVE RISK DUE TO EXPOSURE TO N-METHYL CARBAMATE PRESTICIDES

EPA Science Inventory

THE US EPA'S N-METHYL CARBAMATE CUMULATIVE RISK ASSESSMENT (NMCRA) ASSESSES THE EFFECT ON ACETYLCHOLINE ESTERASE (AChE) ACTIVITY OF EXPOSURE TO 10 N-METHLY CARBAMATE (NMC)PESTICIDES THROUGH DIETARY, DRINKING WATER, AND RESIDENTIAL EXPOSURES. THESE DATA THUS INFORM, BUT DO NOT COM...

[N-methyl-D-aspartate receptor antibody encephalitis: value of immunomodulatory therapy].

PubMed

Le Moigno, L; Ternant, D; Paintaud, G; Thibault, G; Cloarec, S; Tardieu, M; Lagrue, E; Castelnau, P

2014-06-01

Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is little known to pediatricians and likely underdiagnosed. The child's vital and cognitive prognosis is at stake. The use of immunomodulatory drugs, such as rituximab has led to spectacular results, but many questions remain about its mode of action in this type of pathology. We report the case of a 6-year-old girl with no medical history, admitted for status epilepticus preceded by behavior symptoms and sleep disorders. Gradually, the child became bedridden, mute, and animated by predominantly orofacial dyskinesia. Examinations were normal (cerebrospinal fluid [CSF] analysis, brain MRI). The diagnosis was established by the presence of NMDA-R antibodies in the CSF. After exclusion of a tumor-associated syndrome, treatment was started initially by intravenous immunoglobulins, then by plasma exchange, and finally rituximab. The patient was cured with rituximab despite an unusually early recovery of the B-cell pool. Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is a severe but potentially reversible neurologic disorder only recently described, even in childhood. It may be reversible without sequelae if diagnosed and treated early. The use of immunomodulatory therapy, such as rituximab seemingly improves the outcome. Immunological monitoring is needed to better understand its mechanism of action in autoimmune diseases of the nervous system in childhood. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Failure of dietary alpha-difluoromethylornithine to inhibit gastric carcinogenesis in rats after 8 weeks of treatment with N-methyl-N'-nitro-N-nitrosoguanidine and sodium chloride.

PubMed

Tanakamaru, Z; Nishikawa, A; Furukawa, F; Imazawa, T; Lee, I S; Kasahara, K; Tanaka, T; Takahashi, M

1997-11-25

The modifying effects of alpha-difluoromethylomithine (DFMO) on glandular stomach carcinogenesis after initiation with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and sodium chloride were investigated in male outbred Wistar rats. Animals were simultaneously given MNNG solution (100 ppm) as their drinking water and diet supplemented with 10% sodium chloride for 8 weeks, and administered DFMO (dietary levels of 2000 ppm or 500 ppm) and tap water for the following 70 weeks. The DFMO treatment did not show any tendency to inhibit the development of gastric adenocarcinomas. The incidences and multiplicities of atypical hyperplasias in the glandular stomachs were also comparable in all groups of rats given MNNG/sodium chloride. Neither gastric carcinomas nor atypical hyperplasias were observed without the carcinogen treatment. Thus, DFMO did not exert any inhibitory effects when given during the post-initiation phase of two-stage glandular stomach carcinogenesis in rats initiated with MNNG and sodium chloride for 8 weeks.

Physicochemical and electrochemical properties of N-methyl-N-methoxymethylpyrrolidinium bis(fluorosulfonyl)amide and its lithium salt composites

NASA Astrophysics Data System (ADS)

Horiuchi, Shunsuke; Yoshizawa-Fujita, Masahiro; Takeoka, Yuko; Rikukawa, Masahiro

2016-09-01

The ionic liquid (IL) N-Methyl-N-methoxymethylpyrrolidinium bis(fluorosulfonyl)amide ([Pyr1,1O1][FSA]) was synthesized, and its physicochemical and electrochemical properties were investigated with respect to its application as an electrolyte in lithium-ion secondary batteries operating over a wide temperature range. [Pyr1,1O1][FSA]/Li salt (0.34 mol kg-1) composites were prepared by adding lithium bis(trifluoromethylsulfonyl)amide (LiTFSA) into the IL. [Pyr1,1O1][FSA] and [Pyr1,1O1][FSA]/LiTFSA exhibited melting temperatures (Tm) below -30 °C. [Pyr1,1O1][FSA] exhibited a higher ionic conductivity value as compared with that of the corresponding IL with only alkyl substituents. The electrochemical window for both [Pyr1,1O1][FSA] and [Pyr1,1O1][FSA]/LiTFSA was 5.1 V. Stable lithium deposition and dissolution occurred on a Ni electrode at 25 °C.

Cellular Biochemistry and Cytogenetics in a Rat Lung Tumor Model

DTIC Science & Technology

1984-10-01

lung tumor system the specific aims are: 1. To conduct studies of the effect of 3-methylchlanthrene (MCA) on DNA synthesis and cell proliferation in...alkylation of nucleic acids of the rat by N-methyl-N- nitrosourea , dimethylnitrosamine, dimethylsulfate, and methylmethanesulfonate. Biochem. J. 110:39-47

The preference of tryptophan for membrane interfaces: insights from N-methylation of tryptophans in gramicidin channels.

PubMed

Sun, Haiyan; Greathouse, Denise V; Andersen, Olaf S; Koeppe, Roger E

2008-08-08

To better understand the structural and functional roles of tryptophan at the membrane/water interface in membrane proteins, we examined the structural and functional consequences of Trp --> 1-methyl-tryptophan substitutions in membrane-spanning gramicidin A channels. Gramicidin A channels are miniproteins that are anchored to the interface by four Trps near the C terminus of each subunit in a membrane-spanning dimer. We masked the hydrogen bonding ability of individual or multiple Trps by 1-methylation of the indole ring and examined the structural and functional changes using circular dichroism spectroscopy, size exclusion chromatography, solid state (2)H NMR spectroscopy, and single channel analysis. N-Methylation causes distinct changes in the subunit conformational preference, channel-forming propensity, single channel conductance and lifetime, and average indole ring orientations within the membrane-spanning channels. The extent of the local ring dynamic wobble does not increase, and may decrease slightly, when the indole NH is replaced by the non-hydrogen-bonding and more bulky and hydrophobic N-CH(3) group. The changes in conformational preference, which are associated with a shift in the distribution of the aromatic residues across the bilayer, are similar to those observed previously with Trp --> Phe substitutions. We conclude that indole N-H hydrogen bonding is of major importance for the folding of gramicidin channels. The changes in ion permeability, however, are quite different for Trp --> Phe and Trp --> 1-methyl-tryptophan substitutions, indicating that the indole dipole moment and perhaps also ring size and are important for ion permeation through these channels.

N-(1-Allyl-1H-indazol-5-yl)-4-methyl­benzene­sulfonamide

PubMed Central

Chicha, Hakima; Rakib, El Mostapha; Abderrafia, Hafid; Saadi, Mohamed; El Ammari, Lahcen

2013-01-01

The asymmetric unit of the title compound, C17H17N3O2S, contains two independent mol­ecules linked by an N—H⋯O hydrogen bond. The mol­ecules show different conformations. In the first mol­ecule, the fused five- and six-membered ring system is almost perpendicular to the plane through the atoms forming the allyl group, as indicated by the dihedral angle of 85.1 (4)°. The dihedral angle with the methyl­benzene­sulfonamide group is 78.8 (1)°. On the other hand, in the second mol­ecule, the dihedral angles between the indazole plane and the allyl and methyl­benzene­sulfonamide groups are 80.3 (3) and 41.5 (1)°, respectively. In the crystal, mol­ecules are further linked by N—H⋯N and C—H⋯O hydrogen bonds, forming a three-dimensional network. PMID:24454264

Synthesis of N-oleyl O-sulfate chitosan from methyl oleate with O-sulfate chitosan as edible film material

NASA Astrophysics Data System (ADS)

Daniel; Sihaloho, O.; Saleh, C.; Magdaleni, A. R.

2018-04-01

The research on the synthesis of N-oleyl O-sulfate chitosan through sulfonation reaction on chitosan with ammonium sulfate and followed by amidation reaction using methyl oleate has been done. In this study, chitosan was chemically modified into N-oleyl O-sulfatechitosan as an edible film making material. N-oleyl O-sulfate chitosan was synthesized by reaction between methyl oleate and O-sulfate chitosan. Wherein the depleted chitosan of O-sulfate chitosan into O-sulfate chitosan was obtained by reaction of sulfonation between ammonium sulfate and chitosan aldimine. While chitosan aldimine was obtained through reaction between chitosan with acetaldehyde. The structure of N-oleyl O-sulfate chitosan was characterized by FT-IR analysis which showed vibration uptake of C-H sp3 group, S=O group, and carbonyl group C=O of the ester. The resulting of N-oleyl O-sulfate chitosan yielded a percentage of 93.52%. Hydrophilic-Lipophilic Balance (HLB) test results gave a value of 6.68. In the toxicity test results of N-oleyl O-sulfate chitosan obtained LC50 value of 3738.4732 ppm. In WVTR (Water Vapor Transmission Rate) test results for chitosan film was 407.625 gram/m2/24 hours and N-oleylO-sulfate chitosan film was 201.125 gram/m2/24 hours.

Maleic anhydride

Integrated Risk Information System (IRIS)

Maleic anhydride ; CASRN 108 - 31 - 6 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic

Palladium-catalyzed substitution of (coumarinyl)methyl acetates with C-, N-, and S-nucleophiles

PubMed Central

Chattopadhyay, Kalicharan; Fenster, Erik; Grenning, Alexander J

2012-01-01

Summary The palladium-catalyzed nucleophilic substitution of (coumarinyl)methyl acetates is described. The reaction proceeds though a palladium π-benzyl-like complex and allows for many different types of C-, N-, and S-nucleophiles to be regioselectively added to the biologically active coumarin motif. This new method was utilized to prepare a 128-membered library of aminated coumarins for biological screening. PMID:23019448

Effect of maleic anhydride pretreatment on tensile bond strength of a silicone soft liner to a denture base polymer.

PubMed

Demir, Hakan; Soygun, Koray; Dogan, Arife; Keskin, Selda; Dogan, Orhan Murat; Bolayir, Giray

2011-10-01

To determine the effect of resin surface treatment with dissolved maleic anhydride in butanone added into primer on the tensile bond strength between an acrylic denture base resin and a silicone soft liner. To test tensile bond strength, standard dumbbell-shaped acrylic specimens were prepared. Five experimental groups, including the control, were tested (n = 5). Maleic anhydride solutions prepared in butanone at concentrations of 1%, 5%, 10% or 20% were then mixed with 1 ml of Primo adhesive and the mixtures were applied onto the resin bonding surfaces. Silicone liner material was applied to resin surfaces in the conventional manner. Tensile bond strength of the specimens was measured in a universal testing machine. Fractured surfaces were observed under the scanning electron microscope, and resulting chemical changes with the solutions used were analyzed spectroscopically. The highest bond strength value was obtained for the group treated with 5% maleic anhydride (2.53 ± 0.48 MPa); the lowest value was for the group treated with 20% maleic anhydride (1.59 ± 0.29 MPa). Mixed failure was the dominant type seen in the experimental groups. Spectroscopic analysis showed the interaction of the anhydride carbonyl groups with the Primo primer. The treatment of resin surfaces with maleic anhydride added to Primo adhesive effectively increased bond strength between silicone soft liner and denture base resin.

m6A RNA Degradation Products are Catabolized by an Evolutionarily Conserved N6-methyl-AMP Deaminase in Plant and Mammalian Cells.

PubMed

Chen, Mingjia; Urs, Mounashree J; Sánchez-González, Ismael; Olayioye, Monilola A; Herde, Marco; Witte, Claus-Peter

2018-06-08

N6-methylated adenine (m6A) is the most frequent posttranscriptional modification in eukaryotic mRNA. Turnover of RNA generates N6-methylated AMP (N6-mAMP), which has an unclear metabolic fate. We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate (IMP) in vivo by hydrolytically removing the aminomethyl group. A phylogenetic, structural, and biochemical analysis revealed that many fungi partially or fully lack MAPDA, which coincides with a minor role of N6A-RNA methylation in these organisms. MAPDA likely protects RNA from m6A mis-incorporation. This is required because eukaryotic RNA polymerase can use N6-mATP as a substrate. Upon abrogation of MAPDA, root growth is slightly reduced, and the N6-methyladenosine, N6-mAMP, and N6-mATP concentrations are increased in Arabidopsis. Although this will potentially lead to m6A mis-incorporation into RNA, we show that the frequency is too low to be reliably detected in vivo. Since N6-mAMP was several fold more abundant than N6-mATP in MAPDA mutants, we speculate that additional molecular filters suppress the generation of N6-mATP. Enzyme kinetic data indicate that adenylate kinases represent such filters being highly selective for AMP versus N6-mAMP phosphorylation. We conclude that a multilayer molecular protection system is in place preventing N6-mAMP accumulation and salvage. © 2018 American Society of Plant Biologists. All rights reserved.

Quantification of four major metabolites of embryotoxic N-methyl- and N-ethyl-2-pyrrolidone in human urine by cooled-injection gas chromatography and isotope dilution mass spectrometry.

PubMed

Schindler, Birgit K; Koslitz, Stephan; Meier, Swetlana; Belov, Vladimir N; Koch, Holger M; Weiss, Tobias; Brüning, Thomas; Käfferlein, Heiko U

2012-04-17

N-Methyl- and N-ethyl-2-pyrollidone (NMP and NEP) are frequently used industrial solvents and were shown to be embryotoxic in animal experiments. We developed a sensitive, specific, and robust analytical method based on cooled-injection (CIS) gas chromatography and isotope dilution mass spectrometry to analyze 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI), two newly identified presumed metabolites of NEP, and their corresponding methyl counterparts (5-HNMP, 2-HMSI) in human urine. The urine was spiked with deuterium-labeled analogues of these metabolites. The analytes were separated from urinary matrix by solid-phase extraction and silylated prior to quantification. Validation of this method was carried out by using both, spiked pooled urine samples and urine samples from 56 individuals of the general population with no known occupational exposure to NMP and NEP. Interday and intraday imprecision was better than 8% for all metabolites, while the limits of detection were between 5 and 20 μg/L depending on the analyte. The high sensitivity of the method enables us to quantify NMP and NEP metabolites at current environmental exposures by human biomonitoring.

Effect of thiopental sodium on N-methyl-D-aspartate-gated currents.

PubMed

Liu, Hongliang; Dai, Tijun; Yao, Shanglong

2006-05-01

N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC) are closely related with the excitability of pyramidal neurons and PFC function. As the effect of thiopental sodium on the central nervous system may partly result from the inhibition of PFC NMDA receptors, we investigated the effect of thiopental sodium with different concentrations on NMDA-gated currents in acutely dissociated rat PFC pyramidal neurons. We sought to determine whether thiopental sodium inhibits NMDA receptor function. Three to four week old male Sprague-Dawley rats were sacrificed and the PFC was dissected. Pyramidal neurons from the PFC were prepared and standard whole-cell patch clamp recordings were performed. Escalating concentrations from 3-1000 microM NMDA were applied 100 microm from the pyramidal cells, and the concentration in the effect compartment related to 50% effect (EC50) of NMDA was determined for the ensuing experiments. One hundred microM NMDA alone (control) or NMDA with different concentrations (10-1000 microM) of thiopental sodium were applied. After the inhibitory concentration, in 50% of NMDA effect (IC50) of thiopental sodium was established this IC50 and NMDA 3-1000 microM were applied 100 microm from the pyramidal cells. The EC50 value of NMDA under the effect of IC50 thiopental sodium was determined. N-methyl-D-aspartate induced inward currents in a concentration-dependent manner, which were completely antagonized by 50 microM AP5. The maximal amplitude of NMDA-induced current was 1.15 +/- 0.27 nA. The EC50 of NMDA was 53.6 +/- 12.4 microM. The NMDA (100 microM)-gated current was inhibited by thiopental sodium in a concentration-dependent manner, and the IC50 of thiopental sodium was 33.6 +/- 6.1 microM. Under the effect of 33.6 microM thiopental sodium, the maximal amplitude of NMDA-induced current was 0.87 +/- 0.17 nA. The concentration-response curve of NMDA was shifted rightwards. The EC50 of NMDA was 128 +/- 15 microM, which was greater than that

Methyl-N-methylanthranilate, a pungent compound from Citrus reticulata Blanco leaves.

PubMed

Correa, Edwin; Quiñones, Winston; Echeverri, Fernando

2016-01-01

More analgesic compounds are needed in medicine against pain since the available drugs displayed secondary effects. Natural products are a source of molecules to develop new analgesics, using the information of plants, applied against pain, with effects such as pungency, tingling, and needle, due to their possible role in the central nervous system (NCS). Citrus reticulata Blanco (Rutaceae) leaves are usually bitten to flavor the mouth and possess this type effect in lips and tongues; due to this fact the structure of the bioctive compound could be the source of other types of analgesics. The objective of this study is to determine the causal agent of the pungent effect in mandarin essential oil. Mandarin essential oil was obtained and then purified by column chromatography. Each fraction was tested and pungency was detected only in the first fraction which was pure. The compound responsible for the pungency in the essential oils of leaves from Citrus reticulata (mandarin) was purified and the structure was assigned as methyl-N-methylanthranilate, on the basis of NMR 1D and 2D and MS. This substance corresponds to another type of molecule involving an antinociceptive effect. Terpenes are compounds found in essential oils. The compound responsible for the pungency of mandarin and other citrus leaves was isolated, and surprisingly it was identified as a methyl-N-methylanthranilate. This kind of molecules with this activity could be used to discover new analgesics in human therapy against pain.

Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit.

PubMed

Tozzi, Alessandro; de Iure, Antonio; Bagetta, Vincenza; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Costa, Cinzia; Di Filippo, Massimiliano; Ghiglieri, Veronica; Latagliata, Emanuele Claudio; Wegrzynowicz, Michal; Decressac, Mickael; Giampà, Carmela; Dalley, Jeffrey W; Xia, Jing; Gardoni, Fabrizio; Mellone, Manuela; El-Agnaf, Omar Mukhtar; Ardah, Mustafa Taleb; Puglisi-Allegra, Stefano; Björklund, Anders; Spillantini, Maria Grazia; Picconi, Barbara; Calabresi, Paolo

2016-03-01

Advanced Parkinson's disease (PD) is characterized by massive degeneration of nigral dopaminergic neurons, dramatic motor and cognitive alterations, and presence of nigral Lewy bodies, whose main constituent is α-synuclein (α-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overexpression of nigral α-syn are still a matter of debate. We performed behavioral, molecular, and immunohistochemical analyses in two transgenic models of PD, mice transgenic for truncated human α-synuclein 1-120 and rats injected with the adeno-associated viral vector carrying wild-type human α-synuclein. We also investigated striatal synaptic plasticity by electrophysiological recordings from spiny projection neurons and cholinergic interneurons. We found that overexpression of truncated or wild-type human α-syn causes partial reduction of striatal dopamine levels and selectively blocks the induction of long-term potentiation in striatal cholinergic interneurons, producing early memory and motor alterations. These effects were dependent on α-syn modulation of the GluN2D-expressing N-methyl-D-aspartate receptors in cholinergic interneurons. Acute in vitro application of human α-syn oligomers mimicked the synaptic effects observed ex vivo in PD models. We suggest that striatal cholinergic dysfunction, induced by a direct interaction between α-syn and GluN2D-expressing N-methyl-D-aspartate receptors, represents a precocious biological marker of the disease. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Analytical characterization of seventeen ring-substituted N,N-diallyltryptamines

PubMed Central

Brandt, Simon D.; Kavanagh, Pierce V.; Dowling, Geraldine; Talbot, Brian; Westphal, Folker; Meyer, Markus R.; Maurer, Hans H.; Halberstadt, Adam L.

2017-01-01

Many N,N-dialkylated tryptamines show psychoactive properties in humans and the number of derivatives involved in multidisciplinary areas of research has grown over the last few decades. Whereas some derivatives form the basis of a range of medicinal products, others are predominantly encountered as recreational drugs, and in some cases, the areas of therapeutic and recreational use can overlap. In recent years, 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) has appeared as a new psychoactive substance (NPS) and ‘research chemical’ whereas 4-acetoxy-DALT and the ring-unsubstituted DALT have only been detected very recently. Strategies pursued in the authors’ laboratories included the preparation and biological evaluation of previously unreported N,N-diallyltryptamines (DALTs). This report describes the analytical characterization of seventeen DALTs. Fifteen DALTs were prepared by a microwave-accelerated Speeter and Anthony procedure following established procedures developed previously in the authors’ laboratories. In addition to DALT, the substances included in this study were 2-phenyl-, 4-acetoxy-, 4-hydroxy-, 4,5-ethylenedioxy-, 5-methyl-, 5-methoxy-, 5-methoxy-2-methyl-, 5-ethoxy-, 5-fluoro-, 5-fluoro-2-methyl-, 5-chloro-, 5-bromo-, 5,6-methylenedioxy-, 6-fluoro-, 7-methyl, and 7-ethyl-DALT, respectively. The DALTs were characterized by nuclear magnetic resonance spectroscopy (NMR), gas chromatography (GC) quadrupole and ion trap (EI/CI) mass spectrometry (MS), low and high mass accuracy MS/MS, ultraviolet diode array detection and GC solid-state infrared analysis, respectively. A comprehensive collection of spectral data was obtained that are provided to research communities who face the challenge of encountering newly emerging substances where analytical data are not available. These data are also relevant to researchers who might wish to explore the clinical and non-clinical uses of these substances. PMID:27100373

Biomonitoring of exposure to N-methyl-2-pyrrolidone in workers of the automobile industry.

PubMed

Meier, Swetlana; Schindler, Birgit K; Koslitz, Stephan; Koch, Holger M; Weiss, Tobias; Käfferlein, Heiko U; Brüning, Thomas

2013-07-01

N-methyl-2-pyrrolidone (NMP) is an important organic solvent for varnishes in industry. NMP has been previously shown to be a developmental toxicant in rodents. This study reports current exposures to NMP in the spraying department of an automobile plant using biological monitoring. Two specific metabolites, 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methyl-succinimide (2-HMSI), were analyzed in 69 urine samples of 14 workers exposed to NMP and 9 nonexposed controls. Three different working tasks ('loading' and 'cleaning' of the sprayer system and 'wiping/packing' of the sprayed materials) and three sampling times (preshift, postshift, and preshift of the following day) were studied in exposed workers. Median exposures of 5-HNMP and 2-HMSI in postshift urine of exposed workers were 0.91 and 0.52mg g(-1) creatinine, respectively, whereas median levels in controls were below the limit of detection. Decreased levels of 5-HNMP were observed in preshift urine samples on the following day (0.39mg g(-1) creatinine) in exposed workers, while the concentration of 2-HMSI did not change (0.49mg g(-1) creatinine). Highest exposures occurred during sprayer cleaning with a maximum level of 8.31mg g(-1) creatinine of 5-HNMP in postshift urine. In contrast to 'wipers/packers', no decrease in 5-HNMP could be observed in preshift urine samples on day 2 of the 'loaders' and 'cleaners'. Overall, exposure in terms of 5-HNMP postshift and 2-HMSI preshift of the following day were well below the current biological limit values of the European Union (70 and 20mg g(-1) creatinine). Our results provide initial data on NMP exposure in the automobile industry and suggest that the analysis of 5-HNMP in preshift samples also provides essential information, particularly in situations involving direct handling of liquid NMP-containing formulations.

Clinically significant response to zolpidem in disorders of consciousness secondary to anti-N-methyl-D-aspartate receptor encephalitis in a teenager: a case report.

PubMed

Appu, Merveen; Noetzel, Michael

2014-03-01

Anti-N-methyl-d-aspartate receptor encephalitis has been associated with a prolonged neuropsychiatric phase that may last for months to years. We report the case of a 16-year-old girl who was diagnosed with anti-N-methyl-d-aspartate receptor encephalitis resulting from left ovarian mature teratoma 2 weeks after presentation with psychosis. Following tumor removal and immunotherapy, recovery from a minimally conscious state was accelerated significantly by zolpidem that was used for her sleep disturbance. Our patient was discharged home 8 weeks after admission with marked improvement in her neurological function. Zolpidem has been reported to improve arousal in disorders of consciousness but there are no previous reports of its benefit among patients with anti-N-methyl-d-aspartate receptor encephalitis. Zolpidem would be a reasonable consideration as an adjunctive treatment in anti-N-methyl-d-aspartate receptor encephalitis after tumor removal and immunotherapy to accelerate recovery and rehabilitation. Copyright © 2014 Elsevier Inc. All rights reserved.

N-methyl-D-aspartate receptors and large conductance calcium-sensitive potassium channels inhibit the release of opioid peptides that induce mu-opioid receptor internalization in the rat spinal cord.

PubMed

Song, B; Marvizón, J C G

2005-01-01

Endogenous opioids in the spinal cord play an important role in nociception, but the mechanisms that control their release are poorly understood. To simultaneously detect all opioids able to activate the mu-opioid receptor, we measured mu-opioid receptor internalization in rat spinal cord slices stimulated electrically or chemically to evoke opioid release. Electrical stimulation of the dorsal horn in the presence of peptidase inhibitors produced mu-opioid receptor internalization in half of the mu-opioid receptor neurons. This internalization was rapidly abolished by N-methyl-D-aspartate (IC50=2 microM), and N-methyl-D-aspartate antagonists prevented this effect. mu-Opioid receptor internalization evoked by high K+ or veratridine was also inhibited by N-methyl-D-aspartate receptor activation. N-methyl-D-aspartate did not affect mu-opioid receptor internalization induced by exogenous endomorphins, confirming that the effect of N-methyl-D-aspartate was on opioid release. We hypothesized that this inhibition was mediated by large conductance Ca2+-sensitive K+ channels BK(Ca2+). Indeed, inhibition by N-methyl-D-aspartate was prevented by tetraethylammonium and by the selective BK(Ca2+) blockers paxilline, penitrem A and verruculogen. Paxilline did not increase mu-opioid receptor internalization in the absence of N-methyl-D-aspartate, indicating that it does not produce an increase in opioid release unrelated to the inhibition by N-methyl-d-aspartate. The BK(Ca2+) involved appears to be a subtype with slow association kinetics for iberiotoxin, which was effective only with long incubations. The BK(Ca2+) opener NS-1619 also inhibited the evoked mu-opioid receptor internalization, and iberiotoxin prevented this effect. We concluded that Ca2+ influx through N-methyl-D-aspartate receptors causes the opening of BK(Ca2+) and hyperpolarization in opioid-containing dorsal horn neurons, resulting in the inhibition of opioid release. Since mu-opioid receptors in the dorsal horn

N-METHYL-d-ASPARTATE RECEPTORS AND LARGE CONDUCTANCE CALCIUM-SENSITIVE POTASSIUM CHANNELS INHIBIT THE RELEASE OF OPIOID PEPTIDES THAT INDUCE μ-OPIOID RECEPTOR INTERNALIZATION IN THE RAT SPINAL CORD

PubMed Central

SONG, B.; MARVIZÓN, J. C. G.

2006-01-01

Endogenous opioids in the spinal cord play an important role in nociception, but the mechanisms that control their release are poorly understood. To simultaneously detect all opioids able to activate the μ-opioid receptor, we measured μ-opioid receptor internalization in rat spinal cord slices stimulated electrically or chemically to evoke opioid release. Electrical stimulation of the dorsal horn in the presence of peptidase inhibitors produced μ-opioid receptor internalization in half of the μ-opioid receptor neurons. This internalization was rapidly abolished by N-methyl-d-aspartate (IC50=2 μM), and N-methyl-d-aspartate antagonists prevented this effect. μ-Opioid receptor internalization evoked by high K+ or veratridine was also inhibited by N-methyl-d-aspartate receptor activation. N-methyl-d-aspartate did not affect μ-opioid receptor internalization induced by exogenous endomorphins, confirming that the effect of N-methyl-d-aspartate was on opioid release. We hypothesized that this inhibition was mediated by large conductance Ca2+-sensitive K+ channels BK(Ca2+). Indeed, inhibition by N-methyl-d-aspartate was prevented by tetraethylammonium and by the selective BK(Ca2+) blockers paxilline, penitrem A and verruculogen. Paxilline did not increase μ-opioid receptor internalization in the absence of N-methyl-d-aspartate, indicating that it does not produce an increase in opioid release unrelated to the inhibition by N-methyl-d-aspartate. The BK(Ca2+) involved appears to be a subtype with slow association kinetics for iberiotoxin, which was effective only with long incubations. The BK(Ca2+) opener NS-1619 also inhibited the evoked μ-opioid receptor internalization, and iberiotoxin prevented this effect. We concluded that Ca2+ influx through N-methyl-d-aspartate receptors causes the opening of BK(Ca2+) and hyperpolarization in opioid-containing dorsal horn neurons, resulting in the inhibition of opioid release. Since μ-opioid receptors in the dorsal horn

A hit to lead discovery of novel N-methylated imidazolo-, pyrrolo-, and pyrazolo-pyrimidines as potent and selective mTOR inhibitors.

PubMed

Lee, Wendy; Ortwine, Daniel F; Bergeron, Philippe; Lau, Kevin; Lin, Lichuan; Malek, Shiva; Nonomiya, Jim; Pei, Zhonghua; Robarge, Kirk D; Schmidt, Stephen; Sideris, Steve; Lyssikatos, Joseph P

2013-09-15

A series of N-7-methyl-imidazolopyrimidine inhibitors of the mTOR kinase have been designed and prepared, based on the hypothesis that the N-7-methyl substituent on imidazolopyrimidine would impart selectivity for mTOR over the related PI3Kα and δ kinases. The corresponding N-Me substituted pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines also show potent mTOR inhibition with selectivity toward both PI3α and δ kinases. The most potent compound synthesized is pyrazolo[4,3-d]pyrimidine 21c. Compound 21c shows a Ki of 2 nM against mTOR inhibition, remarkable selectivity (>2900×) over PI3 kinases, and excellent potency in cell-based assays. Copyright © 2013 Elsevier Ltd. All rights reserved.

N-demethylation of N-methyl-4-aminoantipyrine, the main metabolite of metamizole.

PubMed

Bachmann, Fabio; Duthaler, Urs; Rudin, Deborah; Krähenbühl, Stephan; Haschke, Manuel

2018-05-08

Metamizole is an old analgesic used frequently in some countries. Active metabolites of metamizole are the non-enzymatically generated N-methyl-4-aminoantipyrine (4-MAA) and its demethylation product 4-aminoantipyrine (4-AA). Previous studies suggested that 4-MAA demethylation can be performed by hepatic cytochrome P450 (CYP) 3A4, but the possible contribution of other CYPs remains unclear. Using human liver microsomes (HLM), liver homogenate and HepaRG cells, we could confirm 4-MAA demethylation by CYPs. Based on CYP induction (HepaRG cells) and CYP inhibition (HLM) we could identify CYP2B6, 2C8, 2C9 and 3A4 as major contributors to 4-MAA demethylation. The 4-MAA demethylation rate by HLM was 280 pmol/mg protein/h, too low to account for in vivo 4-MAA demethylation in humans. Since peroxidases can perform N-demethylation, we investigated horseradish peroxidase and human myeloperoxidase (MPO). Horse radish peroxidase efficiently demethylated 4-MAA, depending on the hydrogen peroxide concentration. This was also true for MPO; this reaction was saturable with a K m of 22.5 μM and a maximal velocity of 14 nmol/min/mg protein. Calculation of the entire body MPO capacity revealed that the demethylation capacity by granulocyte/granulocyte precursors was approximately 600 times higher than the liver capacity and could account for 4-MAA demethylation in humans. 4-MAA demethylation could also be demonstrated in MPO-expressing granulocyte precursor cells (HL-60). In conclusion, 4-MAA can be demethylated in the liver by several CYPs, but hepatic metabolism cannot fully explain 4-MAA demethylation in humans. The current study suggests that the major part of 4-MAA is demethylated by circulating granulocytes and granulocyte precursors in bone marrow. Copyright © 2018 Elsevier B.V. All rights reserved.

21 CFR 177.1820 - Styrene-maleic anhydride copolymers.

Code of Federal Regulations, 2010 CFR

2010-04-01

... maleic anhydride monomer content shall be determined by a gas chromatographic method titled “Determination of Residual Maleic Anhydride in Polymers by Gas Chromatography,” which is incorporated by...

21 CFR 177.1820 - Styrene-maleic anhydride copolymers.

Code of Federal Regulations, 2011 CFR

2011-04-01

... maleic anhydride monomer content shall be determined by a gas chromatographic method titled “Determination of Residual Maleic Anhydride in Polymers by Gas Chromatography,” which is incorporated by...

mRNA N6-methyladenosine methylation of postnatal liver development in pig.

PubMed

He, Shen; Wang, Hong; Liu, Rui; He, Mengnan; Che, Tiandong; Jin, Long; Deng, Lamei; Tian, Shilin; Li, Yan; Lu, Hongfeng; Li, Xuewei; Jiang, Zhi; Li, Diyan; Li, Mingzhou

2017-01-01

N6-methyladenosine (m6A) is a ubiquitous reversible epigenetic RNA modification that plays an important role in the regulation of post-transcriptional protein coding gene expression. Liver is a vital organ and plays a major role in metabolism with numerous functions. Information concerning the dynamic patterns of mRNA m6A methylation during postnatal development of liver has been long overdue and elucidation of this information will benefit for further deciphering a multitude of functional outcomes of mRNA m6A methylation. Here, we profile transcriptome-wide m6A in porcine liver at three developmental stages: newborn (0 day), suckling (21 days) and adult (2 years). About 33% of transcribed genes were modified by m6A, with 1.33 to 1.42 m6A peaks per modified gene. m6A was distributed predominantly around stop codons. The consensus motif sequence RRm6ACH was observed in 78.90% of m6A peaks. A negative correlation (average Pearson's r = -0.45, P < 10-16) was found between levels of m6A methylation and gene expression. Functional enrichment analysis of genes consistently modified by m6A methylation at all three stages showed genes relevant to important functions, including regulation of growth and development, regulation of metabolic processes and protein catabolic processes. Genes with higher m6A methylation and lower expression levels at any particular stage were associated with the biological processes required for or unique to that stage. We suggest that differential m6A methylation may be important for the regulation of nutrient metabolism in porcine liver.

Altered Levels of Zinc and N-methyl-D-aspartic Acid Receptor Underlying Multiple Organ Dysfunctions After Severe Trauma

PubMed Central

Wang, Guanghuan; Yu, Xiaojun; Wang, Dian; Xu, Xiaohu; Chen, Guang; Jiang, Xuewu

2015-01-01

Background Severe trauma can cause secondary multiple organ dysfunction syndrome (MODS) and death. Oxidative stress and/or excitatory neurotoxicity are considered as the final common pathway in nerve cell injuries. Zinc is the cofactor of the redox enzyme, and the effect of the excitatory neurotoxicity is related to N-methyl-D-aspartic acid receptor (NMDAR). Material/Methods We investigated the levels of zinc and brainstem NMDAR in a rabbit model of severe trauma. Zinc and serum biochemical profiles were determined. Immunohistochemistry was used to detect brainstem N-methyl-D-aspartic acid receptor 1 (NR1), N-methyl-D-aspartic acid receptor 2A (NR2A), and N-methyl-D-aspartic acid receptor 2B (NR2B) expression. Results Brain and brainstem Zn levels increased at 12 h, but serum Zn decreased dramatically after the trauma. NR1 in the brainstem dorsal regions increased at 6 h after injury and then decreased. NR2A in the dorsal regions decreased to a plateau at 12 h after trauma. The levels of NR2B were lowest in the death group in the brainstem. Serum zinc was positively correlated with NR2A and 2B and negatively correlated with zinc in the brain. Correlations were also found between the brainstem NR2A and that of the dorsal brainstem, as well as between brainstem NR2A and changes in NR2B. There was a negative correlation between zinc and NR2A. Conclusions Severe trauma led to an acute reduction of zinc enhancing oxidative stress and the changes of NMDAR causing the neurotoxicity of the nerve cells. This may be a mechanism for the occurrence of MODS or death after trauma. PMID:26335029

Mechanism of action of (2-haloethyl)nitrosoureas on DNA. Isolation and reactions of postulated 2-(alkylimino)-3-nitrosooxazolidine intermediates in the decomposition of 1,3-bis(2-chloroethyl)-, 1-(2-chloroethyl)-3-cyclohexyl-, and 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)-1-nitrosourea.

PubMed

Lown, J W; Chauhan, S M

1981-03-01

Three examples of the postulated but hitherto unisolated 2-(alkylimino)-3-nitrosooxazolidines (2) have been prepared containing cyclohexyl, trans-4-methylcyclohexyl, and 2-chloroethyl groups at the 2 position, respectively. These compounds correspond to intermediates previously postulated to be formed in the aqueous decomposition of the antitumor agents 1-(2-chloroethyl)-3-cyclohexyl- (CCNU), 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)- (MeCCNU), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), respectively, Compounds 2 decompose under physiological conditions to give a range of products similar to those formed from the corresponding (2-chloroethyl)nitrosoureas, including the hitherto unrecognized 2-hydroxyethl N-alkylcarbamates (9). Compounds 2a and 2b are converted with hydrochloric acid into CCNU and MeCCNU, respectively, suggesting that 2a and 2b may be reaction intermediates of decomposition. The corresponding 3-alkyl-1-nitroso-1-(2-hydroxyethyl)ureas (4) were characterized and, since they also decompose to give the same products as 2, may arise from the ring opening of 2. The intermediacy of compounds 4 can explain the formation of hydroxyethylated nucleosides isolated by other workers from the reaction of (2-chloroethyl)nitrosoureas on polynucleotides.

Prolonged Hypocalcemic Effect by Pulmonary Delivery of Calcitonin Loaded Poly(Methyl Vinyl Ether Maleic Acid) Bioadhesive Nanoparticles

PubMed Central

Varshosaz, J.; Minaiyan, M.; Forghanian, M.

2014-01-01

The purpose of the present study was to design a pulmonary controlled release system of salmon calcitonin (sCT). Therefore, poly(methyl vinyl ether maleic acid) [P(MVEMA)] nanoparticles were prepared by ionic cross-linking method using Fe2+ and Zn2+ ions. Physicochemical properties of nanoparticles were studied in vitro. The stability of sCT in the optimized nanoparticles was studied by electrophoretic gel method. Plasma calcium levels until 48 h were determined in rats as pulmonary-free sCT solution or nanoparticles (25 μg·kg−1), iv solution of sCT (5 μg·kg−1), and pulmonary blank nanoparticles. The drug remained stable during fabrication and tests on nanoparticles. The optimized nanoparticles showed proper physicochemical properties. Normalized reduction of plasma calcium levels was at least 2.76 times higher in pulmonary sCT nanoparticles compared to free solution. The duration of hypocalcemic effect of pulmonary sCT nanoparticles was 24 h, while it was just 1 h for the iv solution. There was not any significant difference between normalized blood calcium levels reduction in pulmonary drug solution and iv injection. Pharmacological activity of nanoparticles after pulmonary delivery was 65% of the iv route. Pulmonary delivery of P(MVEMA) nanoparticles of sCT enhanced and prolonged the hypocalcemic effect of the drug significantly. PMID:24701588

Spin-labeled 1-alkyl-1-nitrosourea synergists of antitumor antibiotics.

PubMed

Gadjeva, V; Koldamova, R

2001-01-01

A new method for synthesis of four spin-labeled structural analogues of the antitumor drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), using ethyl nitrite for nitrosation of the intermediate spin-labeled ureas has been described. In vitro synergistic effects of 1-ethyl-3-[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)]-1-nitrosourea (3b) on the cytotoxicity of bleomycin and farmorubicin were found in human lymphoid leukemia tumor cells. We measured the tissue distribution of 3b in organ homogenates of C57BL mice by an electron paramagnetic resonance method. The spin-labeled nitrosourea was mainly localized in the lungs. Our results strongly support the development and validation of a new approach for synthesis of less toxic nitrosourea derivatives as potential synergists of antitumor drugs.

Modification of N6-methyladenosine RNA methylation on heat shock protein expression.

PubMed

Yu, Jiayao; Li, Yi; Wang, Tian; Zhong, Xiang

2018-01-01

This study was conducted to investigate effect of N6-methyladenosine (m6A) RNA methylation on Heat shock proteins (HSPs) and dissect the profile of HSP RNA methylation. The results showed that m6A methyltransferases METTL3 mRNA was decreased in responses to heat shock stress in HepG2 cells, but m6A-specific binding protein YTHDF2 mRNA was upregulated in a manner similar to HSP70 induction. Immunofluorescence staining showed that the majority of YTHDF2 was present in the cytosol, however, nearly all YTHDF2 translocated from the cytosol into the nucleus after heat shock. METTL3 knockdown significantly changed HSP70, HSP60, and HSP27 mRNA expression in HepG2 cells using siRNA, however, mRNA lifetime was not impacted. Silence of YTHDF2 using siRNA did not change expression of HSP70, but significantly increased HSP90, HSP60, and HSPB1 mRNA expression. In addition, m6A-seq revealed that HSP m6A methylation peaks are mainly enriched on exons and around stop codons, and shows a unique distribution profile in the 5'UTR and 3'UTR. Knockdown of METTL3 changed the methylation patterns of HSPs transcript. In conclusion, m6A RNA methylation regulates HSP gene expression. Differential expression of HSPs modulated by m6A may depend on the m6A site and abundance of the target gene. This finding provides insights into new regulatory mechanisms of HSPs in normal and stress situations.

Development and characterization of methacrylate-based hydrazide monoliths for oriented immobilization of antibodies.

PubMed

Brne, P; Lim, Y-P; Podgornik, A; Barut, M; Pihlar, B; Strancar, A

2009-03-27

Convective interaction media (CIM; BIA Separations) monoliths are attractive stationary phases for use in affinity chromatography because they enable fast affinity binding, which is a consequence of convectively enhanced mass transport. This work focuses on the development of novel CIM hydrazide (HZ) monoliths for the oriented immobilization of antibodies. Adipic acid dihydrazide (AADH) was covalently bound to CIM epoxy monoliths to gain hydrazide groups on the monolith surface. Two different antibodies were afterwards immobilized to hydrazide functionalized monolithic columns and prepared columns were tested for their selectivity. One column was further tested for the dynamic binding capacity.

Effects of weaning by surrogate mothers (ACI) on tumor development in SD rats treated with methylnitrosourea (MNU) and/or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).

PubMed

Shiraki, Katsuhisa; Lu, Huimei; Ishimura, Yoshimasa; Kashiwabara, Shoji; Uesaka, Toshihiro; Katoh, Osamu; Watanabe, Hiromitsu

2002-09-01

In this experiment, methylnitrosourea (MNU) was administered, followed by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), to assess effects of surrogate mothering on tumor. One or two day old male SD pups were treated with or without 30 mg/kg body weight of MNU and nursed by SD or ACI surrogate mothers for 5 weeks. When 6-weeks-old they were then treated with 100 ppm MNNG or tap water for 16 weeks. The tumor incidence in the MNNG alone group was significantly lower than with MNU alone or MNU+MNNG (p < 0.01). Kidney or nerve tumors mainly developed in the MNU group, gastric tumors in the MNNG group, and the two combined in the MNU+MNNG group. The incidence and mean number of tumors did not significantly differ between the two weaning groups. However, mean survival time with the ACI surrogate mothers after treatment with MNU was increased as compared with the SD mother group. Cumulative development of tumors in the ACI surrogate mother group was also delayed (p < 0.05). Similar results were obtained with MNU+MNNG and MNNG alone. The present experiment suggested that tumor induction might be effected by components of the mother's milk.

The Effects of Internal Rotation and 14N Quadrupole Coupling in N-Methyldiacetamide

NASA Astrophysics Data System (ADS)

Kannengießer, Raphaela; Eibl, Konrad; Nguyen, Ha Vinh Lam; Stahl, Wolfgang

2015-06-01

Acetyl- and nitrogen containing substances play an important role in chemical, physical, and especially biological systems. This applies in particular for acetamides, which are structurally related to peptide bonds. In this work, N-methyldiacetamide, CH_3N(COCH_3)_2, was investigated by a combination of molecular beam Fourier transform microwave spectroscopy and quantum chemical calculations. In N-methyldiacetamide, at least three large amplitude motions are possible: (1) the internal rotation of the methyl group attached to the nitrogen atom and (2, 3) the internal rotations of both acetyl methyl groups. This leads to a rather complicated torsional fine structure of all rotational transitions with additional quadrupole hyperfine splittings caused by the 14N nucleus. Quantum chemical calculations were carried out at the MP2/6-311++G(d,p) level of theory to support the spectral assignment. Conformational analysis was performed by calculating a full potential energy surface depending on the orientation of the two acetyl groups. This yielded three stable conformers with a maximum energy difference of 35.2 kJ/mol. The spectrum of the lowest energy conformer was identified in the molecular beam. The quadrupole hyperfine structure as well as the internal rotation of two methyl groups could be assigned. For the N-methyl group and for one of the two acetyl methyl groups, barriers to internal rotation of 147 cm-1 and of 680 cm-1, respectively, were determined. The barrier of the last methyl group seems to be so high that no additional splittings could be resolved. Using the XIAM program, a global fit with a standard deviation on the order of our experimental accuracy could be achieved.

Gas-phase reactions of glycine, alanine, valine and their N-methyl derivatives with the nitrosonium ion, NO+.

PubMed

Freitas, M A; O'Hair, R A; Schmidt, J A; Tichy, S E; Plashko, B E; Williams, T D

1996-10-01

The gas-phase reactions of the nitrosonium ion, NO+ with the amino acids glycine, alanine and valine and their N-methyl derivatives were investigated under chemical ionization mass spectrometric (CIMS) conditions. Two products were observed in all cases: the formation of the iminium ion and the formation of an [M-H]+ ion. The latter product is consistent with a reaction channel involving hydride abstraction by NO+, and was confirmed by (i) examining the Ar+CI mass spectra of the same amino acids under similar source conditions and (ii) examining the unimolecular fragmentation reactions of the [M + H]+ ions of the N-nitroso-N-methyl derivatives of each of the amino acids in a tandem mass spectrometer. Further insights into the reaction of glycine with NO+ were obtained by performing ab initio calculations (at the MP2/6-31G* parallel HF/6-31G* level). These results indicate that four reactions are thermodynamically viable for glycine: (i) hydride abstraction; (ii) iminium ion formation (with concomitant loss of HONO and CO); (iii) diazonium ion formation; and (iv) diazonium ion formation followed by loss of N2. Possible reasons why reactions (iii) and (iv) are not observed are discussed, and comparisons with solution reactivity and the gas-phase reactivity of NO+ are also made.

Crystal structures of 4-meth-oxy-N-(4-methyl-phenyl)benzene-sulfonamide and N-(4-fluoro-phenyl)-4-meth-oxy-benzene-sulfonamide.

PubMed

Rodrigues, Vinola Z; Preema, C P; Naveen, S; Lokanath, N K; Suchetan, P A

2015-11-01

Crystal structures of two N-(ar-yl)aryl-sulfonamides, namely, 4-meth-oxy-N-(4-methyl-phen-yl)benzene-sulfonamide, C14H15NO3S, (I), and N-(4-fluoro-phen-yl)-4-meth-oxy-benzene-sulfonamide, C13H12FNO3S, (II), were determined and analyzed. In (I), the benzene-sulfonamide ring is disordered over two orientations, in a 0.516 (7):0.484 (7) ratio, which are inclined to each other at 28.0 (1)°. In (I), the major component of the sulfonyl benzene ring and the aniline ring form a dihedral angle of 63.36 (19)°, while in (II), the planes of the two benzene rings form a dihedral angle of 44.26 (13)°. In the crystal structure of (I), N-H⋯O hydrogen bonds form infinite C(4) chains extended in [010], and inter-molecular C-H⋯πar-yl inter-actions link these chains into layers parallel to the ab plane. The crystal structure of (II) features N-H⋯O hydrogen bonds forming infinite one dimensional C(4) chains along [001]. Further, a pair of C-H⋯O inter-molecular inter-actions consolidate the crystal packing of (II) into a three-dimensional supra-molecular architecture.

Synthesis of water-soluble polyamine derivatives effective as N-methyl-D-aspartate receptor antagonists.

PubMed

Masuko, Takashi; Yoshida, Shuhei; Metori, Koichi; Kizawa, Yasuo; Kusama, Tadashi; Miyake, Muneharu

2010-06-01

The novel water-soluble N-methyl-D-aspartate (NMDA) receptor antagonists, N-{4-[4-(4-Guanidinobutylamino)butylamino]butyl}-p-toluenesulfonamide trihydrochloride (1a, TsHSPMG), N-{4-[4-(4-Guanidinobutylamino)butylamino]butyl}butane-1-sulfonamide trihydrochloride (1b, BsHSPMG), N-{3-[4-(3-Guanidinopropylamino)butylamino]propyl}-p-toluenesulfonamide trihydrochroride (2a, TsSPMG) and N-{3-[4-(3-Guanidinopropylamino)butylamino]propyl}butane-1-sulfonamide trihydrochroride (2b, BsSPMG), were synthesized, and the effects of these polyamine derivatives on NMDA receptors were studied using voltage-clamp recordings of recombinant NMDA receptors expressed in Xenopus oocytes. Although spermine potentiates 153% and 310% of NMDA (NR1A/NR2B) receptors in the presence of saturated and unsaturated glycine, respectively, all the novel polyamine derivatives, TsHSPMG (1a), BsHSPMG (1b), TsSPMG (2a) and BsSPMG (2b), significantly inhibited NR1A/NR2B receptors in both conditions. The degree of NMDA receptor inhibition by TsHSPMG (1a) and BsHSPMG (1b) was stronger than that by TsSPMG (2a) and BsSPMG (2b).

Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE2 production: Synthesis, biological activity, and molecular docking study.

PubMed

Kim, Minju; Lee, Sunhoe; Park, Eun Beul; Kim, Kwang Jong; Lee, Hwi Ho; Shin, Ji-Sun; Fischer, Katrin; Koeberle, Andreas; Werz, Oliver; Lee, Kyung-Tae; Lee, Jae Yeol

2016-01-01

Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound 1 (IC50=5700nM against PGE2 production), for a potent suppressor of PGE2 production is described. Subsequent optimization led to the identification of the potent lead compound 8n with IC50 values of 4.5 and 6.9nM, respectively, against LPS-induced PGE2 production and NO production in RAW 264.7 macrophage cells. In addition, 8n was about 30- and >150-fold more potent against mPGES-1 enzyme in a cell-free assay (IC50=70nM) than MK-886 and hit compound 1, respectively. Molecular docking suggests that compound 8n could inhibit PGE2 production by blocking the PGH2 binding site of human mPGES-1 enzyme. Copyright © 2015 Elsevier Ltd. All rights reserved.

Benchmark Dose Analysis from Multiple Datasets: The Cumulative Risk Assessment for the N-Methyl Carbamate Pesticides

EPA Science Inventory

The US EPA’s N-Methyl Carbamate (NMC) Cumulative Risk assessment was based on the effect on acetylcholine esterase (AChE) activity of exposure to 10 NMC pesticides through dietary, drinking water, and residential exposures, assuming the effects of joint exposure to NMCs is dose-...

Solution-phase synthesis of a hindered N-methylated tetrapeptide using Bts-protected amino acid chlorides: efficient coupling and methylation steps allow purification by extraction.

PubMed

Vedejs, E; Kongkittingam, C

2000-04-21

N-Benzothiazole-2-sulfonyl (Bts)-protected amino acid chlorides were used to prepare the hindered cyclosporin 8-11 tetrapeptide subunit 1. The synthesis was performed via 3a and the deprotected amines 5a, 13, and 19, including three repeated cycles involving N-methylation using iodomethane/potassium carbonate, deprotection of the Bts group, and N-acylation with a N-Bts-amino acid chloride such as 9b or 9c. Among three Bts cleavage methods compared (H3PO2/THF; NaBH4/EtOH; PhSH/K2CO3), the third gave somewhat higher overall yields. N-Acylation of 5a with the Bts-protected N-methylamino acid chloride 10b followed by deprotection was also highly efficient and could be used as an alternative route to 11. Each of the deprotected amines was isolated without chromatography using simple extraction methods to remove neutral byproducts. The tetrapeptide 1 was obtained in analytically pure form as the monohydrate.

Environmental Exposures, Genetic Polymorphisms and p53 Mutational Spectra in a Case-Control Study of Breast Cancer.

DTIC Science & Technology

1997-01-01

frequently reported in premenopausal rather than postmenopausal women. It is currently unknown what might be the carcinogenic agents in alcoholic... agents in human main-that they could affect heterogeneity of Breast cancer and cigarette smoking. N Engl J mary epithelial cells. CancerRes. 1992;52:5617...trosamines, polycyclic aromatic hydrocarbons, aryl aro- Abbreviations: NMU, N-methyl-N- nitrosourea ; CYP2E1, cytochrome matic amines, and heterocyclic

Neuroprotection against traumatic brain injury by xenon, but not argon, is mediated by inhibition at the N-methyl-D-aspartate receptor glycine site.

PubMed

Harris, Katie; Armstrong, Scott P; Campos-Pires, Rita; Kiru, Louise; Franks, Nicholas P; Dickinson, Robert

2013-11-01

Xenon, the inert anesthetic gas, is neuroprotective in models of brain injury. The authors investigate the neuroprotective mechanisms of the inert gases such as xenon, argon, krypton, neon, and helium in an in vitro model of traumatic brain injury. The authors use an in vitro model using mouse organotypic hippocampal brain slices, subjected to a focal mechanical trauma, with injury quantified by propidium iodide fluorescence. Patch clamp electrophysiology is used to investigate the effect of the inert gases on N-methyl-D-aspartate receptors and TREK-1 channels, two molecular targets likely to play a role in neuroprotection. Xenon (50%) and, to a lesser extent, argon (50%) are neuroprotective against traumatic injury when applied after injury (xenon 43±1% protection at 72 h after injury [N=104]; argon 30±6% protection [N=44]; mean±SEM). Helium, neon, and krypton are devoid of neuroprotective effect. Xenon (50%) prevents development of secondary injury up to 48 h after trauma. Argon (50%) attenuates secondary injury, but is less effective than xenon (xenon 50±5% reduction in secondary injury at 72 h after injury [N=104]; argon 34±8% reduction [N=44]; mean±SEM). Glycine reverses the neuroprotective effect of xenon, but not argon, consistent with competitive inhibition at the N-methyl-D-aspartate receptor glycine site mediating xenon neuroprotection against traumatic brain injury. Xenon inhibits N-methyl-D-aspartate receptors and activates TREK-1 channels, whereas argon, krypton, neon, and helium have no effect on these ion channels. Xenon neuroprotection against traumatic brain injury can be reversed by increasing the glycine concentration, consistent with inhibition at the N-methyl-D-aspartate receptor glycine site playing a significant role in xenon neuroprotection. Argon and xenon do not act via the same mechanism.

Self-healing pH-sensitive poly[(methyl vinyl ether)-alt-(maleic acid)]-based supramolecular hydrogels formed by inclusion complexation between cyclodextrin and adamantane.

PubMed

Ma, Xiaoe; Zhou, Naizhen; Zhang, Tianzhu; Hu, Wanjun; Gu, Ning

2017-04-01

Self-healing materials are of interest for drug delivery, cell and gene therapy, tissue engineering, and other biomedical applications. In this work, on the base of biocompatible polymer poly(methyl vinyl ether-alt-maleic acid) (P(MVE-alt-MA)), host polymer β-cyclodextrin-grafted P(MVE-alt-MA) (P(MVE-alt-MA)-g-β-CD) and guest polymer adamantane-grafted P(MVE-alt-MA) (P(MVE-alt-MA)-g-Ad) were first prepared. Then through taking advantage of the traditional host-guest interaction of β-cyclodextrin and adamantane, a novel self-healing pH-sensitive physical P(MVE-alt-MA)-g-β-CD/P(MVE-alt-MA)-g-Ad supramolecular hydrogels were obtained after simply mixing the aqueous solution of host polymer and guest polymer. This kind of supramolecular hydrogels not only possess pH-sensitivity, but also possess the ability to repair themselves after being damaged. Copyright © 2016 Elsevier B.V. All rights reserved.

Microwave assisted IMDAF# reaction: microwave irradiation applied with success to cycloaddition reaction of N-propargyl-N-p-tolyl-N-2-furfurylamines.

PubMed

Mance, Ana Dunja; Jakopcić, Kresimir

2005-01-01

The new tertiary furfurylamine with triple bond as a dienophylic part i.e. N-(5-methyl-2-furfuryl)-N-prop-2-ynyl-p-toluidine (1) was prepared and the intramolecular Diels-Alder reaction of the amine (1) was performed under microwave irradiation conditions and by heating a benzene solution of the amine under nitrogen. Comparing the results of the usual thermal and the MAOS reaction, we confirmed our expectations that MAOS could promote the outcome of IMDA reaction of the suitably N-substituted tertiary 2-furfuryl-amines. In the present example, N-p-tolyl-5-methyl-5,7a-dihydro-5,7a-epoxyisoindoline was obtained in much better yield and of higher purity.

Effects of n-alkanols and a methyl ester on a transient potassium (IA) current in identified neurones from Helix aspersa.

PubMed Central

Winpenny, J P; Elliott, J R; Harper, A A

1992-01-01

1. A two-microelectrode voltage clamp was used to determine the effects of n-butanol, n-hexanol, n-octanol, n-decanol and methyl hexanoate on a transient potassium (IA) current in identified Helix aspersa neurones. Experiments were carried out at a temperature of 10-12 degrees C. 2. Each n-alkanol reversibly reduced the amplitude of the IA current. Logarithmic dose-response curves for the current reduction by each homologue were sigmoidal and had slope factors of around four. The concentrations required to reduce the peak (with time) current at -30 mV by 50% (ED50 +/- fitted standard error) were: 57 +/- 5 mM (n-butanol); 2.0 +/- 0.1 mM (n-hexanol); 0.28 +/- 0.02 mM (n-octanol) and 0.016 +/- 0.001 mM (n-decanol). Methyl hexanoate also reduced the current amplitude, with an ED50 of 1-2 mM. The Helix IA current thus showed a similar sensitivity to n-alkanols to that of squid and rat sodium currents but was rather more sensitive than the squid delayed rectifier potassium current. 3. The n-alkanol ED50 concentrations were used to calculate a standard free energy per methylene group for adsorption to a site of action in the cell of -3.1 +/- 0.2 kJ/mol. This suggested a hydrophobic site or sites of action. The regularity of the change in free energy with chain length was maintained up to, and including, n-decanol. This implied that the site(s) could accommodate a ten-carbon chain as readily as an eight-carbon chain. 4. The voltage dependencies of IA current activation and steady-state inactivation were not consistently altered by treatment with n-alkanols at concentrations around or above their current suppression ED50 concentrations. 5. The kinetics of current activation and inactivation were affected, particularly by lower chain length compounds. At 60 mM n-butanol reduced the time constant for development of inactivation of open channels (tau b) by 56%, while 0.016 mM n-decanol produced only a 13% reduction. n-Butanol (60 mM) also caused a substantial (76%) reduction

Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methyl metabolism.

PubMed

Obeid, Rima; Awwad, Hussain M; Rabagny, Yannick; Graeber, Stefan; Herrmann, Wolfgang; Geisel, Juergen

2016-03-01

Elevated plasma concentrations of the gut bacteria choline metabolite trimethylamine N-oxide (TMAO) are associated with atherosclerosis. However, the determinants of TMAO in humans require additional assessment. We examined cardiometabolic risk factors and pathways associated with TMAO concentrations in humans. A total of 283 individuals (mean ± SD age: 66.7 ± 9.0 y) were included in this observational study. Plasma concentrations of trimethylamine, TMAO, choline, lipids, phospholipids, and methyl metabolites were measured. Study participants were divided into 4 groups by median concentrations of TMAO and choline (4.36 and 9.7 μmol/L, respectively). Compared with the group with TMAO and choline concentrations that were less than the median (n = 82), the group with TMAO and choline concentrations that were at least the median (n = 83) was older and had lower high-density lipoprotein (HDL) cholesterol, phospholipids, and methylation potential, higher creatinine, betaine, S-adenosylhomocysteine (SAH), and S-adenosylmethionine (SAM), and higher percentages of men and subjects with diabetes. The difference in plasma TMAO concentrations between men and women (7.3 ± 10.0 compared with 5.4 ± 5.6 μmol/L, respectively) was NS after adjustment for age and creatinine (P = 0.455). The TMAO:trimethylamine ratio was higher in men (P < 0.001). Diabetes was associated with significantly higher plasma TMAO concentration (8.6 ± 12.2 compared with 5.4 ± 5.2 μmol/L) even after adjustments. Sex and diabetes showed an interactive effect on trimethylamine concentrations (P = 0.010) but not on TMAO concentrations (P = 0.950). Positive determinants of TMAO in a stepwise regression model that applied to the whole group were SAH, trimethylamine, choline, and female sex, whereas plasma phosphatidylcholine was a negative determinant. High TMAO and choline concentrations are associated with an advanced cardiometabolic risk profile. Diabetes is related to higher plasma TMAO

Enhancement of nitrosourea cytotoxicity by misonidazole in vitro: correlation with carbamoylating potential.

PubMed Central

Mulcahy, R. T.; Dembs, N. L.; Ublacker, G. A.

1984-01-01

We have investigated the relationships between nitrosourea structure and physicochemical properties and the ability of misonidazole (MISO) to potentiate nitrosourea cytotoxicity in an in vitro model system. EMT-6/Ro tumour cells were exposed in suspension to each of 9 different nitrosourea anti-tumour drugs under hypoxic and aerobic culture conditions. Additional cultures were similarly treated with nitrosoureas in the presence of 1.0 mM MISO. Seven of the 9 nitrosoureas did not demonstrate any selective toxicity toward aerobic or hypoxic cells. In contrast, chlorozotocin (CHLZ) was slightly more toxic toward hypoxic cells while Bis-OH CyNU more effectively killed aerobic cells. The addition of MISO to the drug treatment enhanced the effectiveness of all the nitrosoureas under hypoxic conditions, with the exception of CHLZ which was uninfluenced by MISO. The magnitude of the MISO dose enhancement factor (DEF, defined as the ratio of drug doses required to reduce cell survival to S = 10(-3) in 4 hours in the absence and presence of 1.0 mM MISO) for each combination was examined as a function of the relative carbamoylating or alkylating activity of the nitrosourea included in that combination. Such an analysis revealed a significant (P less than 0.05) positive correlation between relative carbamoylating potency and DEF. No significant (P greater than 0.20) relationship could be established for DEF and alkylating activity. PMID:6704305

A 2:1 co-crystal of 2-methyl-benzoic acid and N,N'-bis-(pyridin-4-ylmeth-yl)ethanedi-amide: crystal structure and Hirshfeld surface analysis.

PubMed

Syed, Sabrina; Jotani, Mukesh M; Halim, Siti Nadiah Abdul; Tiekink, Edward R T

2016-03-01

The asymmetric unit of the title 2:1 co-crystal, 2C8H8O2·C14H14N4O2, comprises an acid mol-ecule in a general position and half a di-amide mol-ecule, the latter being located about a centre of inversion. In the acid, the carb-oxy-lic acid group is twisted out of the plane of the benzene ring to which it is attached [dihedral angle = 28.51 (8)°] and the carbonyl O atom and methyl group lie approximately to the same side of the mol-ecule [hy-droxy-O-C-C-C(H) torsion angle = -27.92 (17)°]. In the di-amide, the central C4N2O2 core is almost planar (r.m.s. deviation = 0.031 Å), and the pyridyl rings are perpendicular, lying to either side of the central plane [central residue/pyridyl dihedral angle = 88.60 (5)°]. In the mol-ecular packing, three-mol-ecule aggregates are formed via hy-droxy-O-H⋯N(pyrid-yl) hydrogen bonds. These are connected into a supra-molecular layer parallel to (12[Formula: see text]) via amide-N-H⋯O(carbon-yl) hydrogen bonds, as well as methyl-ene-C-H⋯O(amide) inter-actions. Significant π-π inter-actions occur between benzene/benzene, pyrid-yl/benzene and pyrid-yl/pyridyl rings within and between layers to consolidate the three-dimensional packing.

Abundant Lysine Methylation and N-Terminal Acetylation in Sulfolobus islandicus Revealed by Bottom-Up and Top-Down Proteomics*

PubMed Central

Vorontsov, Egor A.; Rensen, Elena; Prangishvili, David; Krupovic, Mart; Chamot-Rooke, Julia

2016-01-01

Protein post-translational methylation has been reported to occur in archaea, including members of the genus Sulfolobus, but has never been characterized on a proteome-wide scale. Among important Sulfolobus proteins carrying such modification are the chromatin proteins that have been described to be methylated on lysine side chains, resembling eukaryotic histones in that aspect. To get more insight into the extent of this modification and its dynamics during the different growth steps of the thermoacidophylic archaeon S. islandicus LAL14/1, we performed a global and deep proteomic analysis using a combination of high-throughput bottom-up and top-down approaches on a single high-resolution mass spectrometer. 1,931 methylation sites on 751 proteins were found by the bottom-up analysis, with methylation sites on 526 proteins monitored throughout three cell culture growth stages: early-exponential, mid-exponential, and stationary. The top-down analysis revealed 3,978 proteoforms arising from 681 proteins, including 292 methylated proteoforms, 85 of which were comprehensively characterized. Methylated proteoforms of the five chromatin proteins (Alba1, Alba2, Cren7, Sul7d1, Sul7d2) were fully characterized by a combination of bottom-up and top-down data. The top-down analysis also revealed an increase of methylation during cell growth for two chromatin proteins, which had not been evidenced by bottom-up. These results shed new light on the ubiquitous lysine methylation throughout the S. islandicus proteome. Furthermore, we found that S. islandicus proteins are frequently acetylated at the N terminus, following the removal of the N-terminal methionine. This study highlights the great value of combining bottom-up and top-down proteomics for obtaining an unprecedented level of accuracy in detecting differentially modified intact proteoforms. The data have been deposited to the ProteomeXchange with identifiers PXD003074 and PXD004179. PMID:27555370

EPR study of gamma-irradiated N-methyl-L-alanine, DL-2-methyl glutamic acid hemihydrate and Di-leucine hydrochloride in solid state

NASA Astrophysics Data System (ADS)

Sütçü, Kerem; Osmanoğlu, Y. Emre

2017-12-01

In this study, it was aimed to investigate ɣ-irradiated powders of N-methyl-L-alanine (NMLA), DL-2-methyl glutamic acid hemihydrate (DL2MGAH), and Di-leucine hydrochloride (DLHCl) at room temperature by electron paramagnetic resonance spectroscopy. After the γ-irradiation the samples indicated the existence of the CH3ĊNHCH3COOH, HOOCCH3NH2CĊHCH2COOH·1/2H2O and (CH3)2ĊCH2CH NHCOOHCOCH (NH2HCl) CH2CH (CH3)2 radicals, respectively. The spectral parameters of the radicals were determined. The results were compared with the earlier studies and discussed accordingly.

Endogenous 5-methylcytosine protects neighboring guanines from N7 and O6-methylation and O6-pyridyloxobutylation by the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

PubMed

Ziegel, Rebecca; Shallop, Anthony; Upadhyaya, Pramod; Jones, Roger; Tretyakova, Natalia

2004-01-20

All CG dinucleotides along exons 5-8 of the p53 tumor suppressor gene contain endogenous 5-methylcytosine (MeC). These same sites (e.g., codons 157, 158, 245, 248, and 273) are mutational hot spots in smoking-induced lung cancer. Several groups used the UvrABC endonuclease incision assay to demonstrate that methylated CG dinucleotides of the p53 gene are the preferred binding sites for the diol epoxides of bay region polycyclic aromatic hydrocarbons (PAH). In contrast, effects of endogenous cytosine methylation on the distribution of DNA lesions induced by tobacco-specific nitrosamines, e.g., 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have not been elucidated. In the work presented here, a stable isotope labeling HPLC-ESI-MS/MS approach was employed to analyze the reactivity of the N7 and O6 positions of guanines within hemimethylated and fully methylated CG dinucleotides toward NNK-derived methylating and pyridyloxobutylating species. 15N3-labeled guanine bases were placed within synthetic DNA sequences representing endogenously methylated p53 codons 154, 157, and 248, followed by treatment with acetylated precursors to NNK diazohydroxides. HPLC-ESI-MS/MS analysis was used to determine the relative yields of N7- and O6-guanine adducts at the 15N3-labeled position. In all cases, the presence of MeC inhibited the formation of N7-methylguanine, O6-methylguanine, and O6-pyridyloxobutylguanine at a neighboring G, with the greatest decrease observed in fully methylated dinucleotides and at guanines preceded by MeC. Furthermore, the O6-Me-dG/N7-Me-G molar ratios were decreased in the presence of the 5'-neighboring MeC, suggesting that the observed decline in O6-alkylguanine adduct yields is, at least partially, a result of an altered reactivity pattern in methylated CG dinucleotides. These results indicate that, unlike N2-guanine adducts of PAH diol epoxides, NNK-induced N7- and O6-alkylguanine adducts are not preferentially formed at the endogenously

N-methyl-D-aspartate neurotoxicity in hippocampal slices: protection by aniracetam.

PubMed

Pizzi, M; Consolandi, O; Memo, M; Spano, P

1995-03-14

Aniracetam, a drug known to elicit cognition enhancing properties in both animals and humans, was found to counteract the neurotoxicity induced by excitatory amino acids in primary cultures of cerebellar neurons. We report here that aniracetam prevents the neurotoxic effect induced by N-methyl-D-aspartate (NMDA) in rat hippocampal slices. Time-course experiments showed that the aniracetam-induced neuroprotection does not require preincubation of the slices with the drug. Maximal effective concentration of aniracetam was 10 microM. Since the NMDA-mediated cell death in hippocampal slices is considered a valuable experimental model of ischemia, these results suggest a possible novel therapeutic application for aniracetam.

Nitrosoureas in the Management of Malignant Gliomas.

PubMed

Brandes, Alba A; Bartolotti, Marco; Tosoni, Alicia; Franceschi, Enrico

2016-02-01

Nitrosoureas represent one of the most active classes of agents in the treatment of high-grade gliomas and glioblastoma. In clinical practice, the most commonly used compounds are lomustine (either alone or in combination with procarbazine and vincristine), carmustine, and fotemustine. Given their toxicity profile and subsequent to the introduction of temozolomide in clinical practice, most of these agents were moved to the recurrent setting. This review focuses on the role of the nitrosoureas currently used in clinical practice for the treatment of malignant gliomas.

Developmental regulation of N-methyl-D-aspartate- and kainate-type glutamate receptor expression in the rat spinal cord

NASA Technical Reports Server (NTRS)

Stegenga, S. L.; Kalb, R. G.

2001-01-01

Spinal motor neurons undergo experience-dependent development during a critical period in early postnatal life. It has been suggested that the repertoire of glutamate receptor subunits differs between young and mature motor neurons and contributes to this activity-dependent development. In the present study we examined the expression patterns of N-methyl-D-aspartate- and kainate-type glutamate receptor subunits during the postnatal maturation of the spinal cord. Young motor neurons express much higher levels of the N-methyl-D-aspartate receptor subunit NR1 than do adult motor neurons. Although there are eight potential splice variants of NR1, only a subgroup is expressed by motor neurons. With respect to NR2 receptor subunits, young motor neurons express NR2A and C, while adult motor neurons express only NR2A. Young motor neurons express kainate receptor subunits GluR5, 6 and KA2 but we are unable to detect these or any other kainate receptor subunits in the adult spinal cord. Other spinal cord regions display a distinct pattern of developmental regulation of N-methyl-D-aspartate and kainate receptor subunit expression in comparison to motor neurons. Our findings indicate a precise spatio-temporal regulation of individual subunit expression in the developing spinal cord. Specific combinations of subunits in developing neurons influence their excitable properties and could participate in the emergence of adult neuronal form and function.

Toxicity, Mutagenicity, and Mutational Spectra of Vinyl Chloride, 2- Chloroethylene Oxide, and Chloracetaldehyde in a Human Lymphoblastoid Line Expressing Cytochrome P450IIE1.

DTIC Science & Technology

1992-01-01

concluded that CEO was the alkylating agent involved in conversion of adenosine to l,N 6 -ethenoadenosine. 1,N6 - Ethenoadenosine was not produced by CEO...guanines as nearest neighbors upon the alkylation of a guanine residue in DNA. N-methyl-N- nitrosourea (MNU) was reacted with a synthetic polynucleotide...the alkylating agent MNNG or the intercalating agent ICR-191. In the study they determined that mutants comprising at least one percent of the total

Design and in vitro activities of N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, novel small molecule Hypoxia Inducible Factor-1 (HIF-1) pathway inhibitors and anti-cancer agents

PubMed Central

Mun, Jiyoung; Jabbar, Adnan Abdul; Devi, Narra Sarojini; Yin, Shaoman; Wang, Yingzhe; Tan, Chalet; Culver, Deborah; Snyder, James P.; Van Meir, Erwin G.; Goodman, Mark M.

2013-01-01

The Hypoxia Inducible Factor (HIF) pathway is an attractive target for cancer as it controls tumor adaptation to growth under hypoxia and mediates chemo- and radiation resistance. We previously discovered 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, as a novel small molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 μM in water; logP7.4: 3.7). Here we describe the synthesis of twelve N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental logP7.4 values of 8 of the 12 new analogs ranged from 1.2 ∼ 3.1. Aqueous solubilities of 3 analogs were measured, among which the most soluble N-[(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide had an aqueous solubility of 80 μM, e.g. a solubility improvement of ∼9,000-fold. The pharmacological optimization had minimal impact on drug efficacy as the compounds retained IC50 values at or below 5 μM in our HIF-dependent reporter assay. PMID:22746274

Novel bifunctional anthracycline and nitrosourea chemotherapy for human bladder cancer: analysis in a preclinical survival model.

PubMed

Glaves, D; Murray, M K; Raghavan, D

1996-08-01

A hybrid drug [N-2-chloroethylnitrosoureidodaunorubicin (AD312)] that combines structural and functional features of both anthracyclines and nitrosoureas was evaluated in a preclinical survival model of human bladder cancer. To measure the therapeutic activity of AD312, UCRU-BL13 transitional cell carcinoma cells were grown as xenografts in nude mice, and tumor growth rates were compared after i.v. administration of the drug at three dose levels. AD312 treatment at 45 and 60 mg/kg achieved 7-10-fold inhibition of tumor growth and increased host survival by 156 and 249%, respectively. Doses of 60 mg/kg showed optimal therapeutic efficacy, with sustained tumor growth inhibition, an over 2-fold increase in life span, and 40% of mice tumor free ("cured") at 120 days. Tumors were unresponsive to maximum tolerated doses of doxorubicin, a standard anthracycline used as a single agent and in combination therapies for bladder cancer. 1,3-Bis-[2-chloroethyl]-1-nitrosourea was used as a control for the apparently enhanced response of human tumors in murine hosts to nitrosoureas. 1, 3-Bis-[2-chloroethyl]-1-nitrosourea administered in three injections of 20 mg/kg did not cure mice but temporarily inhibited tumor growth by 70% and prolonged survival by 55%; its activity in this model suggests that it may be included in the repertoire of alkylating agents currently used for treatment of bladder cancers. AD312 showed increased antitumor activity with less toxicity than doxorubicin, and its bifunctional properties provide the opportunity for simultaneous treatment of individual cancer cells with two cytotoxic modalities as well as treatment of heterogeneous populations typical of bladder cancers. This novel cytotoxic drug cured doxorubicin-refractory disease and should be investigated for the clinical management of bladder cancer.

Determination of 5-hydroxy-N-methyl-2-pyrrolidone and 2-hydroxy-N-methylsuccinimide in human plasma and urine using liquid chromatography-electrospray tandem mass spectrometry.

PubMed

Carnerup, M A; Akesson, B; Jönsson, B A

2001-09-15

A method for simultaneous determination of 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) was developed. These compounds are metabolites from N-methyl-2-pyrrolidone (NMP), a powerful and widely used organic solvent. 5-HNMP and 2-HMSI were purified from plasma and urine by solid-phase extraction using Isolute ENV+ columns, and analysed by liquid chromatography coupled to a mass spectrometer fitted with an atmospheric pressure turbo ion spray ionisation interface in the positive ion mode. The method was validated for plasma and urine concentrations from 0.12 to 25 microg/ml. The recoveries for 5-HNMP and 2-HMSI in plasma were 99 and 98%, respectively, and in urine 111 and 106%, respectively. For 5-HNMP and 2-HMSI, the within-day precision in plasma was 1-4 and 3-6%, respectively, and in urine 2-12 and 3-10%, respectively. The corresponding data for the between-day precision was 5 and 3-6%, respectively, and 4-6 and 7-8%, respectively. The detection limit for 5-HNMP was 4 ng/ml in plasma and 120 ng/ml in urine. For 2-HMSI, it was 5 ng/ml in plasma and 85 ng/ml in urine. The method is applicable for analysis of plasma and urine samples from workers exposed to NMP.

An experimental study of the combined effects of n-hexane and methyl ethyl ketone.

PubMed Central

Takeuchi, Y; Ono, Y; Hisanaga, N; Iwata, M; Aoyama, M; Kitoh, J; Sugiura, Y

1983-01-01

This study was intended to determine whether or not methyl ethyl ketone (MEK) enhances the neurotoxicity of n-hexane at low concentration and after long term exposure. Separate groups of eight rats were exposed to 100 ppm n-hexane, 200 ppm MEK, 100 ppm n-hexane plus 200 ppm MEK, or fresh air in an exposure chamber for 12 hours a day for 24 weeks. The body weight, motor nerve conduction velocity (MCV), distal motor latency (DL), and mixed nerve conduction velocities (MNCVs) were measured before exposure and after four, eight, 12, 16, 20, and 24 weeks' exposure. One rat of each group was histopathologically examined after 24 weeks' exposure. Exposure of 100 ppm n-hexane did not significantly decrease the functions of the peripheral nerve throughout the experiment. Exposure to 200 ppm MEK significantly increased MCV and MNCVs and decreased DL after four weeks' exposure, but at this later stage no significant changes were found throughout the experiment by comparison with the controls. Mixed exposure to 100 ppm n-hexane plus 200 ppm MEK significantly decreased by comparison with the controls. On histopathological examination of the tail nerve, however, no changes were found in any of the exposed groups or the controls. These results suggest that MEK might enhance the neurotoxicity of n-hexane at a low concentration, and mixed exposures to n-hexane and MEK should be avoided. PMID:6830718

Geissoschizine methyl ether N-oxide, a new alkaloid with antiacetylcholinesterase activity from Uncaria rhynchophylla.

PubMed

Jiang, Wei-Wei; Su, Jia; Wu, Xing-De; He, Juan; Peng, Li-Yan; Cheng, Xiao; Zhao, Qin-Shi

2015-01-01

Geissoschizine methyl ether N-oxide, a new oxindole alkaloid, along with 14 known alkaloids, was isolated from the aerial part of Uncaria rhynchophylla. Their structures were identified by comprehensive spectral methods, including 2D NMR experiments, and confirmed by comparing with the literature data. In vitro acetylcholinesterase (AChE) inhibitory activity assay showed that the new compound exhibited anti-AChE activity with IC₅₀ value of 23.4 μM.

The toxicity of N-methyl-alpha-methyldopamine to freshly isolated rat hepatocytes is prevented by ascorbic acid and N-acetylcysteine.

PubMed

Carvalho, Márcia; Remião, Fernando; Milhazes, Nuno; Borges, Fernanda; Fernandes, Eduarda; Carvalho, Félix; Bastos, Maria Lourdes

2004-08-05

In the past decade, clinical evidence has increasingly shown that the liver is a target organ for 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") toxicity. The aims of the present in vitro study were: (1) to evaluate and compare the hepatotoxic effects of MDMA and one of its main metabolites, N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and (2) to investigate the ability of antioxidants, namely ascorbic acid and N-acetyl-L-cysteine (NAC), to prevent N-Me-alpha-MeDA-induced toxic injury, using freshly isolated rat hepatocytes. Cell suspensions were incubated with MDMA or N-Me-alpha-MeDA in the final concentrations of 0.1, 0.2, 0.4, 0.8, and 1.6 mM for 3 h. To evaluate the potential protective effects of antioxidants, cells were preincubated with ascorbic acid in the final concentrations of 0.1 and 0.5 mM, or NAC in the final concentrations of 0.1 and 1 mM for 15 min before treatment with 1.6 mM N-Me-alpha-MeDA for 3 h (throughout this incubation period the cells were exposed to both compounds). The toxic effects were evaluated by measuring the cell viability, glutathione (GSH) and glutathione disulfide (GSSG), ATP, and the cellular activities of GSH peroxidase (GPX), GSSG reductase (GR), and GSH S-transferase (GST). MDMA induced a concentration- and time-dependent GSH depletion, but had a negligible effect on cell viability, ATP levels, or on the activities of GR, GPX, and GST. In contrast, N-Me-alpha-MeDA was shown to induce not only a concentration- and time-dependent depletion of GSH, but also a depletion of ATP levels accompanied by a loss in cell viability, and decreases in the antioxidant enzyme activities. For both compounds, GSH depletion was not accompanied by increases in GSSG levels, which seems to indicate GSH depletion by adduct formation. Importantly, the presence of ascorbic acid (0.5 mM) or NAC (1 mM) prevented cell death and GSH depletion induced by N-Me-alpha-MeDA. The results provide evidence that MDMA and its metabolite N

Cometabolism of Methyl tertiary Butyl Ether and Gaseous n-Alkanes by Pseudomonas mendocina KR-1 Grown on C5 to C8 n-Alkanes

PubMed Central

Smith, Christy A.; O'Reilly, Kirk T.; Hyman, Michael R.

2003-01-01

Pseudomonas mendocina KR-1 grew well on toluene, n-alkanes (C5 to C8), and 1° alcohols (C2 to C8) but not on other aromatics, gaseous n-alkanes (C1 to C4), isoalkanes (C4 to C6), 2° alcohols (C3 to C8), methyl tertiary butyl ether (MTBE), or tertiary butyl alcohol (TBA). Cells grown under carbon-limited conditions on n-alkanes in the presence of MTBE (42 μmol) oxidized up to 94% of the added MTBE to TBA. Less than 3% of the added MTBE was oxidized to TBA when cells were grown on either 1° alcohols, toluene, or dextrose in the presence of MTBE. Concentrated n-pentane-grown cells oxidized MTBE to TBA without a lag phase and without generating tertiary butyl formate (TBF) as an intermediate. Neither TBF nor TBA was consumed by n-pentane-grown cells, while formaldehyde, the expected C1 product of MTBE dealkylation, was rapidly consumed. Similar Ks values for MTBE were observed for cells grown on C5 to C8 n-alkanes (12.95 ± 2.04 mM), suggesting that the same enzyme oxidizes MTBE in cells grown on each n-alkane. All growth-supporting n-alkanes (C5 to C8) inhibited MTBE oxidation by resting n-pentane-grown cells. Propane (Ki = 53 μM) and n-butane (Ki = 16 μM) also inhibited MTBE oxidation, and both gases were also consumed by cells during growth on n-pentane. Cultures grown on C5 to C8 n-alkanes also exhibited up to twofold-higher levels of growth in the presence of propane or n-butane, whereas no growth stimulation was observed with methane, ethane, MTBE, TBA, or formaldehyde. The results are discussed in terms of their impacts on our understanding of MTBE biodegradation and cometabolism. PMID:14660389

Direct binding of Toll-like receptor 4 to ionotropic glutamate receptor N-methyl-D-aspartate subunit 1 induced by lipopolysaccharide in microglial cells N9 and EOC 20.

PubMed

Cui, Jie; Yu, Siyuan; Li, Yihui; Li, Pan; Liu, Feng

2018-03-01

Microglia, the primary immune cells in the brain, are the predominant cells regulating inflammation-mediated neuronal damage. In response to immunological challenges, such as lipopolysaccharide (LPS), microglia are activated and the inflammatory process is subsequently initiated. The aim of the present study was to determine whether LPS induces interactions between the Toll-like receptor 4 (TLR4) and the ionotropic glutamate receptor N-methyl-D‑aspartate subunit 1 (GluN1) in N9 and EOC 20 microglial cells. Immunocytochemistry demonstrated co-localization of TLR4 and GluN1 in response to LPS, and the direct binding of TLR4 and GluN1 was further validated by antibody-based Fluorescence Resonance Energy Transfer technology. Inhibition of the group I metabotropic glutamate receptor 5 with its selective antagonist, MTEP, abolished LPS-induced direct binding of TLR4 to GluN1. Therefore, these data demonstrated that GluN1 and TLR4 act reciprocally in response to LPS in N9 and EOC 20 microglial cells.

Interaction of amphotericin B and its low toxic derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester, with fungal, mammalian and bacterial cells measured by the energy transfer method.

PubMed

Szlinder-Richert, Joanna; Cybulska, Barbara; Grzybowska, Jolanta; Bolard, Jacques; Borowski, Edward

2004-04-01

Amphotericin B (AMB) derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester (MFAME) retains the broad antifungal spectrum and potency of the parent antibiotic, whereas its toxicity towards mammalian cells is reduced by about two orders of magnitude. The purpose of this work was to find out whether the differences observed in the toxicity of MFAME and native AMB are due to the differential drugs affinity to fungal and mammalian cell membranes. Comparative studies on AMB and MFAME biological activity and their affinity to fungal, mammalian and bacterial cells were performed. The interaction of AMB and MFAME with cells have been studied by fluorescence method based on the energy transfer between membrane fluorescent probe (donor) and the polyenic chromophore of the antibiotic (acceptor) simultaneously present in the cell membrane. The amount of the antibiotic bound to cells was indicated by the extent of fluorescence quenching of 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) or 1,6-diphenyl-1,3,5-hexatriene (DPH) by polyenic chromophore of the antibiotic. The results obtained indicate that binding extent and characteristics for both antibiotics are comparable in the three types of cells studied. Dramatically lower toxicity of MFAME as compared to AMB towards mammalian cells is not related to the antibiotic-cell affinity, but rather to different consequences of these interactions for cells, reflected in membrane permeabilization. MFAME is definitely less effective than parent AMB in the permeabilizing species formation in mammalian cell membrane.

Positive Modulators of the N-Methyl-d-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters.

PubMed

Krausova, Barbora; Slavikova, Barbora; Nekardova, Michaela; Hubalkova, Pavla; Vyklicky, Vojtech; Chodounska, Hana; Vyklicky, Ladislav; Kudova, Eva

2018-05-24

Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure-activity relationship (SAR) for their modulation of N-methyl-d-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC 50 varying from 1.8 to 151.4 μM and E max varying from 48% to 452%). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC 50 = 21.7 μM). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications. A selected compound, 20-oxo-pregnenolone hemiadipate, potentiated native NMDARs to a similar extent as GluN1/GluN2A-D receptors and inhibited AMPARs and GABA A R responses. These results provide a unique opportunity for the development of new steroid based drugs with potential use in the treatment of neuropsychiatric disorders involving hypofunction of NMDARs.

-HPLC determination of acidic d-amino acids and their N-methyl derivatives in biological tissues

PubMed Central

Tsesarskaia, Mara; Galindo, Erika; Szókán, Gyula; Fisher, George

2015-01-01

d-aspartate (d-Asp) and N-methyl-d-aspartate (NMDA) occur in the neuroendocrine systems of vertebrates and invertebrates where they play a role in hormone release and synthesis, neurotransmission, and memory and learning. N-methyl-d-glutamate (NMDG) has also been detected in marine bivalves. Several methods have been used to detect these amino acids, but they require pretreatment of tissue samples with o-phthaldialdehyde (OPA) to remove primary amino acids which interfere with the detection of NMDA and NMDG. We report here a one step derivatization procedure with the chiral reagent N-α-(5-fluoro-2,4-dinitrophenyl)-(d or l)-valine amide, FDNP-Val-NH2, a close analog of Marfey’s reagent but with better resolution and higher molar absorptivity. The diastereomers formed are separated by HPLC on an ODS-Hypersil column eluted with TFA/water – TFA/MeCN. UV absorption at 340 nm permits detection levels as low as 5–10 picomoles. D-Asp, NMDA and NMDG peaks are not obscured by other primary or secondary amino acids; hence pretreatment of tissues with OPA is not required. This method is highly reliable and fast (less than 40 minutes HPLC run). Using this method, we have detected D-Asp, NMDA and NMDG in several biological tissues (octopus brain, optical lobe, and bucchal mass; foot and mantle of the mollusk Scapharca broughtonii), confirming the results of other researchers. PMID:19277955

Characterization of N-methyl-D-aspartate-evoked taurine release in the developing and adult mouse hippocampus.

PubMed

Saransaari, P; Oja, S S

2003-01-01

Taurine is an inhibitory amino acid acting as an osmoregulator and neuroromodulator in the brain, with neuroprotective properties. The ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) greatly potentiates taurine release from brain preparations in both normal and ischemic conditions, the effect being particularly marked in the developing hippocampus. We now characterized the regulation of NMDA-stimulated taurine release from hippocampal slices from adult (3-month-old) and developing (7-day-old) mouse using a superfusion system. The NMDA-stimulated taurine release was receptor-mediated in both adult and developing mouse hippocampus. In adults, only NO-generating compounds, sodium nitroprusside, S-nitroso-N-acetylpenicillamine and hydroxylamine reduced the release, as did also NO synthase inhibitors, 7-nitroindazole and nitroarginine, indicating that the release is mediated by the NO/cGMP pathway. On the other hand, the regulation of the NMDA-evoked taurine release proved to be somewhat complex in the immature hippocampus. It was not affected by the NOergic compounds, but enhanced by the protein kinase C activator 4 beta-phorbol 12-myristate 13-acetate and adenosine receptor A(1) agonists, N(6)-cyclohexyladenosine and R(-)N(6)-(2-phenylisopropyl)adenosine in a receptor-mediated manner. The activation of both ionotropic 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors and metabotropic glutamate group I receptors also enhanced the evoked release. The NMDA-receptor-stimulated taurine release could be a part of the neuroprotective properties of taurine, being important particularly under cell-damaging conditions in the developing hippocampus and hence preventing excitotoxicity.

Crystal structure of N′-[(E)-(1S,3R)-(3-isopropyl-1-methyl-2-oxo­cyclo­pent­yl)methyl­idene]-4-methyl­benzene­sulfono­hydrazide

PubMed Central

Tymann, David; Dragon, Dina Christina; Golz, Christopher; Preut, Hans; Strohmann, Carsten; Hiersemann, Martin

2015-01-01

The title compound, C17H24N2O3S, was synthesized in order to determine the relative configuration of the corresponding β-keto aldehyde. In the U-shaped mol­ecule, the five-membered ring approximates an envelope, with the methyl­ene C atom adjacent to the quaternary C atom being the flap, and the methyl and isopropyl substituents lying to the same side of the ring. The dihedral angles between the four nearly coplanar atoms of the five-membered ring and the flap and the aromatic ring are 35.74 (15) and 55.72 (9)°, respectively. The bond angles around the S atom are in the range from 103.26 (12) to 120.65 (14)°. In the crystal, mol­ecules are linked via N—H⋯O hydrogen bonds, forming a chain along the a axis. PMID:26870519

Psychiatric Autoimmunity: N-Methyl-D-Aspartate Receptor IgG and Beyond.

PubMed

Kruse, Jennifer L; Lapid, Maria I; Lennon, Vanda A; Klein, Christopher J; Toole, Orna O'; Pittock, Sean J; Strand, Edythe A; Frye, Mark A; McKeon, Andrew

2015-01-01

Descriptions of psychiatric autoimmunity beyond N-methyl-D-aspartate (NMDA) receptor encephalitis are sparse. To report the autoimmune psychiatric spectrum currently recognized in Mayo Clinic practice. Medical record review, testing of stored serum and cerebrospinal fluid for IgGs reactive with synaptic receptors and ion channels, neuronal nuclear and cytoplasmic antigens (including glutamic acid decarboxylase 65-kDa isoform) and case-control comparison were conducted. Patients were categorized into group 1, all adult psychiatric inpatients tested for neural autoantibodies (2002-2011; n = 213), and group 2, all Mayo NMDA receptor IgG-positive patients (2009-2013; n = 13); healthy control subjects were also included (n = 173). In group 1, at least 1 serum autoantibody (but not NMDA receptor IgG) was detected in 36 of 213 psychiatric inpatients. In total, 12 patients were determined retrospectively to have high-likelihood autoimmune encephalitic diagnoses. The most commonly detected autoantibody specificities were voltage-gated potassium channel ([Kv1] VGKC) complex (6) and calcium channel (P/Q type or N type; 5). Symptoms seen were as follows: depressive (8), anxious (7), psychotic (7), disorganized (5), suicidal (3), manic (1) and catatonic (1). In group 2, among 13 NMDA receptor IgG-positive patients, 12 had encephalitis; their psychiatric symptoms were as follows: depressive (9), catatonic (9), disorganized (8), anxious (8), psychotic (7), manic (6), and suicidal (3). Catatonic symptoms were more common in the 12 NMDA receptor IgG-positive patients than in the 12 group 1 patients with high likelihood of encephalitis (p = 0.002). Antibody positivities were usually low positive in value among healthy controls (12 of 16 vs 3 of 12 group 1 encephalitis cases, p = 0.025). NMDA receptor IgG was not detected in any healthy control subject. A spectrum of psychiatric autoimmunity beyond NMDA-R IgG may be under-recognized. Diagnosis is facilitated by combining results of

Solubility of pioglitazone hydrochloride in binary mixtures of polyethylene glycol 400 with ethanol, propylene glycol, N-methyl-2-pyrrolidone, and water at 25 degrees C.

PubMed

Jouyban, Abolghasem; Soltanpour, Shahla

2010-09-01

The solubility of pioglitazone hydrochloride in binary mixtures of polyethylene glycol 400 with ethanol, N-methyl-2-pyrrolidone, propylene glycol, and water at 25 degrees C are reported. The generated data are fitted to the Jouyban-Acree model and the mean relative deviations are 2.6%, 1.5%, 5.8%, and 7.4%, respectively for ethanol, N-methyl-2-pyrrolidone, propylene glycol, and water.

The Role of IGFs in the Dietary Lipid Regulation of Breast Cancer

DTIC Science & Technology

1998-01-01

study examining the development of n-methyl nitrosourea (NMU) induced mammary tumors in female Harlan Sprague Dawley rats. These rats received an IV...34 synthesis of growth hormone by pituitaries from rats on different quantitative omega-6 PUFA diets despite significant diet induced differences in

Implication of Genes for the N-Methyl-D-Aspartate (NMDA) Receptor in Substance Addictions.

PubMed

Chen, Jiali; Ma, Yunlong; Fan, Rongli; Yang, Zhongli; Li, Ming D

2018-02-10

Drug dependence is a chronic brain disease with harmful consequences for both individual users and society. Glutamate is a primary excitatory neurotransmitter in the brain, and both in vivo and in vitro experiments have implicated N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor, as an element in various types of addiction. Recent findings from genetics-based approaches such as genome-wide linkage, candidate gene association, genome-wide association (GWA), and next-generation sequencing have demonstrated the significant association of NMDA receptor subunit genes such as GluN3A, GluN2B, and GluN2A with various addiction-related phenotypes. Of these genes, GluN3A has been the most studied, and it has been revealed to play crucial roles in the etiology of addictions. In this communication, we provide an updated view of the genetic effects of NMDA receptor subunit genes and their functions in the etiology of addictions based on the findings from investigation of both common and rare variants as well as SNP-SNP interactions. To better understand the molecular mechanisms underlying addiction-related behaviors and to promote the development of specific medicines for the prevention and treatment of addictions, current efforts aim not only to identify more causal variants in NMDA receptor subunits by using large independent samples but also to reveal the molecular functions of these variants in addictions.

Direct determination of N-methyl-2-pyrrolidone metabolites in urine by HPLC-electrospray ionization-MS/MS using deuterium-labeled compounds as internal standard.

PubMed

Suzuki, Yoshihiro; Endo, Yoko; Ogawa, Masanori; Yamamoto, Shinobu; Takeuchi, Akito; Nakagawa, Tomoo; Onda, Nobuhiko

2009-11-01

N-methyl-2-pyrrolidone (NMP) has been used in many industries and biological monitoring of NMP exposure is preferred to atmospheric monitoring in occupational health. We developed an analytical method that did not include solid phase extraction (SPE) but utilized deuterium-labeled compounds as internal standard for high-performance liquid chromatography-electrospray ionization-mass spectrometry using a C30 column. Urinary concentrations of NMP and its known metabolites 5-hydoxy-N-methyl-2-pyrrolidone (5-HNMP), N-methyl-succinimide (MSI), and 2-hydroxy-N-methylsuccinimide (2-HMSI) were determined in a single run. The method provided baseline separation of these compounds. Their limits of detection in 10-fold diluted urine were 0.0001, 0.006, 0.008, and 0.03 mg/L, respectively. Linear calibration covered a biological exposure index (BEI) for urinary concentration. The within-run and total precisions (CV, %) were 5.6% and 9.2% for NMP, 3.4% and 4.2% for 5-HNMP, 3.7% and 6.0% for MSI, and 6.5% and 6.9% for 2-HMSI. The method was evaluated using international external quality assessment samples, and urine samples from workers exposed to NMP in an occupational area.

Association of serum N(ε)-Carboxy methyl lysine with severity of diabetic retinopathy.

PubMed

Mishra, Nibha; Saxena, Sandeep; Shukla, Rajendra K; Singh, Vinita; Meyer, Carsten H; Kruzliak, Peter; Khanna, Vinay K

2016-04-01

To correlate serum levels of N-epsilon-carboxy methyl lysine (N(ε)-CML) with severity of retinopathy, in vivo macular edema and disruption of external limiting membrane (ELM) and photoreceptor ellipsoid zone in type 2 diabetes mellitus (DM). Consecutive cases of type 2 DM [diabetes mellitus with no retinopathy (No DR) (n=20); non- proliferative diabetic retinopathy (NPDR) with diabetic macular edema (n=20); proliferative diabetic retinopathy with diabetic macular edema (PDR) (n=20)] and healthy controls (n=20) between the ages of 40 and 65 years were included (power of study=93.8%). In vivo histology of retinal layers was assessed using spectral domain optical coherence tomography. Every study subject underwent macular thickness analysis using the macular cube 512×128 feature. Disruption of ELM and photoreceptor ellipsoid zone was graded: grade 0, no disruption of ELM and ellipsoid zone; grade 1, ELM disrupted and ellipsoid zone intact; grade 2, both ELM and ellipsoid zone disrupted. Data were statistically analyzed. The mean levels of N(ε)-CML were 31.34±21.23 ng/ml, 73.88±35.01 ng/ml, 91.21±66.65 ng/ml, and 132.08±84.07 ng/ml in control, No DR, NPDR and PDR respectively. N(ε)-CML level was significantly different between the study groups (control, No DR, NPDR and PDR) (p<0.001). Mean logMAR visual acuity decreased with increased levels of N(ε)-CML (p<0.001). The association of N(Ɛ)CML with the grades of disruption was found to be statistically significant (F value=18.48, p<0.001). Univariate analysis was done with N(Ɛ)-CML as a dependent variable. The values of N(Ɛ)-CML were normalized (log10) and were subjected to univariate analysis with fasting blood glucose level, glycosylated hemoglobin, central subfield macular thickness and cube average thickness among the diseased groups (NPDR and PDR) that act as confounders. It was found that none of the variables had significant effect on N(Ɛ)-CML (fasting blood glucose p=0.12, HBA1c p=0.65, central

Identification of ω-N-Methyl-4-hydroxytryptamine (Norpsilocin) as a Psilocybe Natural Product.

PubMed

Lenz, Claudius; Wick, Jonas; Hoffmeister, Dirk

2017-10-27

We report the identification of ω-N-methyl-4-hydroxytryptamine (norpsilocin, 1) from the carpophores of the hallucinogenic mushroom Psilocybe cubensis. The structure was elucidated by 1D and 2D NMR spectroscopy and high-resolution mass spectrometry. Norpsilocin has not previously been reported as a natural product. It likely represents the actual psychotropic agent liberated from its 4-phosphate ester derivative, the known natural product baeocystin. We further present a simple and artifact-free extraction method that prevents dephosphorylation and therefore helps reflect the naturally occurring metabolic profile of Psilocybe mushrooms in subsequent analyses.

Poly(vinyl methyl ether/maleic anhydride)-Doped PEG-PLA Nanoparticles for Oral Paclitaxel Delivery To Improve Bioadhesive Efficiency.

PubMed

Wang, Qian; Li, Chan; Ren, Tianyang; Chen, Shizhu; Ye, Xiaoxia; Guo, Hongbo; He, Haibing; Zhang, Yu; Yin, Tian; Liang, Xing-Jie; Tang, Xing

2017-10-02

Bioadhesive nanoparticles based on poly(vinyl methyl ether/maleic anhydride) (PVMMA) and poly(ethylene glycol) methyl ether-b-poly(d,l-lactic acid) (mPEG-b-PLA) were produced by the emulsification solvent evaporation method. Paclitaxel was utilized as the model drug, with an encapsulation efficiency of up to 90.2 ± 4.0%. The nanoparticles were uniform and spherical in shape and exhibited a sustained drug release compared with Taxol. m-NPs also exhibited favorable bioadhesive efficiency at the same time. Coumarin 6 or DiR-loaded nanoparticles with/without PVMMA (C6-m-NPs/DiR-m-NPs or C6-p-NPs/DiR-p-NPs) were used for cellular uptake and intestinal adhesion experiments, respectively. C6-m-NPs were shown to enhance cellular uptake, and caveolae/lipid raft mediated endocytosis was the primary route for the uptake of the nanoparticles. Favorable bioadhesive efficiency led to prolonged retention in the intestine reflected by the fluorescence in isolated intestines ex vivo. In a ligated intestinal loops model, C6-m-NPs showed a clear advantage for transporting NPs across the mucus layer over C6-p-NPs and free C6. The apparent permeability coefficient (Papp) of PTX-m-NPs through Caco-2/HT29 monolayers was 1.3- and 1.6-fold higher than PTX-p-NPs and Taxol, respectively, which was consistent with the AUC 0-t of different PTX formulations after oral administration in rats. PTX-m-NPs also exhibited a more effective anticancer efficacy, with an IC 50 of 0.2 ± 1.4 μg/mL for A549 cell lines, further demonstrating the advantage of bioadhesive nanoparticles. The bioadhesive nanoparticles m-NPs demonstrated both mucus permeation and epithelial absorption, and thus, this bioadhesive drug delivery system has the potential to improve the bioavailability of drugs that are insoluble in the gastrointestinal environment.

PEGylated N-methyl-S-methyl dithiocarbazate as a new reagent for the high-yield preparation of nitrido Tc-99m and Re-188 radiopharmaceuticals.

PubMed

Boschi, Alessandra; Massi, Alessandro; Uccelli, Licia; Pasquali, Micol; Duatti, Adriano

2010-11-01

A novel nitrido nitrogen atom donor for the preparation of (99m)Tc and (188)Re radiopharmaceuticals containing a metal-nitrogen multiple bond is presented. HO(2)C-PEG(600)-DTCZ was obtained by conjugation of N-methyl-S-methyl dithiocarbazate [H(2)N-N(CH(3))-C(S)SCH(3), HDTCZ] with polyethylene glycol 600 (PEG(600)). Asymmetrical heterocomplexes of the type [M(N)(PNP)(B)](0/+) (M=(99m)Tc, (188)Re; PNP=diphosphine ligands, B=DBODC, DEDC, NSH, H(2)OS, CysNAc, HDTCZ) and symmetrical nitride compounds of the type [M(N)(L)(2)] (L=DEDC, DPDC) have been prepared in high yield by using the newly designed nitride nitrogen atom donor HO(2)C-PEG(600)-DTCZ. A two-step procedure was applied for preparing the above symmetrical and asymmetrical complexes. The first step involved the preliminary formation of a mixture of nitride Tc-99m or Re-188 precursors, which contained the [M≡N](2+) core, through reduction of generator-eluted (99m)Tc-pertechnetate or (188)Re-perrhenate with thin (II) chloride in the presence of HO(2)C-PEG(600)-DTCZ. In the second step, the intermediate mixture was converted either in the final mixed asymmetrical complex by the simultaneous addition of diphosphine ligand and the suitable bidentate ligand B, or in the final symmetrical complex by the only addition of the bidentate ligand L. It was also demonstrated that the novel water-soluble nitride nitrogen atom donor HO(2)C-PEG(600)-DTCZ did not show coordinating properties toward the M≡N ((99m)Tc, (188)Re) core. Biodistribution studies in rats of the hitherto unreported [(99m)Tc(N)(PNP(3))DTCZ](+) and [(99m)Tc(N)(PNP(5))DTCZ](+) complexes showed that they selectively localize in the myocardium of rats with a favourable heart-to-lung and heart-to-liver uptake ratios. In particular, the heart-to-lung and heart-to-liver uptake ratios dramatically increased in the interval between 60 and 120 min postinjection. Hence, the combination of the favourable chemical and biological properties of HO(2)C-PEG(600)-DTCZ

Aluminum–phthalocyanine chloride associated to poly(methyl vinyl ether-co-maleic anhydride) nanoparticles as a new third-generation photosensitizer for anticancer photodynamic therapy

PubMed Central

Muehlmann, Luis Alexandre; Ma, Beatriz Chiyin; Longo, João Paulo Figueiró; Almeida Santos, Maria de Fátima Menezes; Azevedo, Ricardo Bentes

2014-01-01

Photodynamic therapy is generally considered to be safer than conventional anticancer therapies, and it is effective against different kinds of cancer. However, its clinical application has been significantly limited by the hydrophobicity of photosensitizers. In this work, a system composed of the hydrophobic photosensitizer aluminum–phthalocyanine chloride (AlPc) associated with water dispersible poly(methyl vinyl ether-co-maleic anhydride) nanoparticles is described. AlPc was associated with nanoparticles produced by a method of solvent displacement. This system was analyzed for its physicochemical characteristics, and for its photodynamic activity in vitro in cancerous (murine mammary carcinoma cell lineage 4T1, and human mammary adenocarcinoma cells MCF-7) and noncancerous (murine fibroblast cell lineage NIH/3T3, and human mammary epithelial cell lineage MCF-10A) cell lines. Cell viability and the elicited mechanisms of cell death were evaluated after the application of photodynamic therapy. This system showed improved photophysical and photochemical properties in aqueous media in comparison to the free photosensitizer, and it was effective against cancerous cells in vitro. PMID:24634582

N,N,N′,N′,N′′-Penta­methyl-N′′-[3-(1,3,3-trimethyl­ureido)prop­yl]guanidinium tetra­phenyl­borate

PubMed Central

Tiritiris, Ioannis; Kantlehner, Willi

2012-01-01

In the crystal structure of the title molecular salt, C13H30N5O+·C24H20B−, discrete guanidinium cations and tetra­phenyl­borate anions are present. The C—N bond lengths in the CN3 unit are 1.3427 (12), 1.3445 (12) and 1.3453 (13) Å, indicating double-bond character. The central C atom is surrounded in a nearly ideal trigonal-planar geometry by three N atoms and the positive charge is delocalized on the CN3 plane. The bonds between the N atoms and the terminal C-methyl groups all have values close to a typical single bond [1.4595 (15)–1.4688 (12) Å]. In the crystal, cations are connected by C—H⋯O contacts generating a chain along the c axis. PMID:22798881

Rebamipide induces dendritic cell recruitment to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-exposed rat gastric mucosa based on IL-1β upregulation.

PubMed

Yamamichi, Nobutake; Oka, Masashi; Inada, Ken-ichi; Konno-Shimizu, Maki; Kageyama-Yahara, Natsuko; Tamai, Hideyuki; Kato, Jun; Fujishiro, Mitsuhiro; Kodashima, Shinya; Niimi, Keiko; Ono, Satoshi; Tsutsumi, Yutaka; Ichinose, Masao; Koike, Kazuhiko

2012-07-20

Rebamipide is usually used for mucosal protection, healing of gastric ulcers, treatment of gastritis, etc., but its effects on gastric malignancy have not been elucidated. Using Lewis and Buffalo rat strains treated with peroral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), we evaluated the effect of rebamipide on the induction of tumor-suppressive dendritic cells, which are known to be heterogeneous antigen-presenting cells of bone marrow origin and are critical for the initiation of primary T-cell responses. Using CD68 as a marker for dendritic cells, the stomach pyloric mucosae of Lewis and Buffalo rats were immunohistochemically analyzed in the presence or absence of rebamipide and MNNG. After a 14-day treatment of rebamipide alone, no significant change in number of CD68-expressing cells was detected in either rat strain. However, after concurrent exposure to MNNG for 14 days, treatment with rebamipide slightly increased CD68-positive cells in the Lewis strain, and significantly increased them in the Buffalo strain. Analysis of two chemotactic factors of dendritic cells, IL-1β and TNF-α, in the gastric cancer cells showed that expression of IL-1β, but not TNF-α, was induced by rebamipide in a dose-dependent manner. A luciferase promoter assay using gastric SH-10-TC cells demonstrated that an element mediating rebamipide action exists in the IL-1β gene promoter region. In conclusion, rebamipide has potential tumor-suppressive effects on gastric tumorigenesis via the recruitment of dendritic cells, based on the upregulation of the IL-1β gene in gastric epithelial cells. Copyright © 2012 Elsevier Inc. All rights reserved.

Intricate Effects of α-Amino and Lysine Modifications on Arginine Methylation of the N-Terminal Tail of Histone H4.

PubMed

Fulton, Melody D; Zhang, Jing; He, Maomao; Ho, Meng-Chiao; Zheng, Y George

2017-07-18

Chemical modifications of the DNA and nucleosomal histones tightly control the gene transcription program in eukaryotic cells. The "histone code" hypothesis proposes that the frequency, combination, and location of post-translational modifications (PTMs) of the core histones compose a complex network of epigenetic regulation. Currently, there are at least 23 different types and >450 histone PTMs that have been discovered, and the PTMs of lysine and arginine residues account for a crucial part of the histone code. Although significant progress has been achieved in recent years, the molecular basis for the histone code is far from being fully understood. In this study, we investigated how naturally occurring N-terminal acetylation and PTMs of histone H4 lysine-5 (H4K5) affect arginine-3 methylation catalyzed by both type I and type II PRMTs at the biochemical level. Our studies found that acylations of H4K5 resulted in decreased levels of arginine methylation by PRMT1, PRMT3, and PRMT8. In contrast, PRMT5 exhibits an increased rate of arginine methylation upon H4K5 acetylation, propionylation, and crotonylation, but not upon H4K5 methylation, butyrylation, or 2-hydroxyisobutyrylation. Methylation of H4K5 did not affect arginine methylation by PRMT1 or PRMT5. There was a small increase in the rate of arginine methylation by PRMT8. Strikingly, a marked increase in the rate of arginine methylation was observed for PRMT3. Finally, N-terminal acetylation reduced the rate of arginine methylation by PRMT3 but had little influence on PRMT1, -5, and -8 activity. These results together highlight the underlying mechanistic differences in substrate recognition among different PRMTs and pave the way for the elucidation of the complex interplay of histone modifications.

Maternal melatonin or N-acetylcysteine therapy regulates hydrogen sulfide-generating pathway and renal transcriptome to prevent prenatal NG-Nitro-L-arginine-methyl ester (L-NAME)-induced fetal programming of hypertension in adult male offspring.

PubMed

Tain, You-Lin; Lee, Chien-Te; Chan, Julie Y H; Hsu, Chien-Ning

2016-11-01

Pregnancy is a critical time for fetal programming of hypertension. Nitric oxide deficiency during pregnancy causes hypertension in adult offspring. We examined whether maternal melatonin or N-acetylcysteine therapy can prevent N G -nitro-L-arginine-methyl ester-induced fetal programming of hypertension in adult offspring. Next, we aimed to identify potential gatekeeper pathways that contribute to N G -nitro-L-arginine-methyl ester -induced programmed hypertension using the next generation RNA sequencing technology. Pregnant Sprague-Dawley rats were assigned to 4 groups: control, N G -nitro-L-arginine-methyl ester, N G -nitro-L-arginine-methyl ester +melatonin, and N G -nitro-L-arginine-methyl ester+N-acetylcysteine. Pregnant rats received N G -nitro-L-arginine-methyl ester administration at 60 mg/kg/d subcutaneously during pregnancy alone, with additional 0.01% melatonin in drinking water, or with additional 1% N-acetylcysteine in drinking water during the entire pregnancy and lactation. Male offspring (n=8/group) were killed at 12 weeks of age. N G -nitro-L-arginine-methyl ester exposure during pregnancy induced programmed hypertension in adult male offspring, which was prevented by maternal melatonin or N-acetylcysteine therapy. Protective effects of melatonin and N-acetylcysteine against N G -nitro-L-arginine-methyl ester-induced programmed hypertension were associated with an increase in hydrogen sulfide-generating enzymes and hydrogen sulfide synthesis in the kidneys. Nitric oxide inhibition by N G -nitro-L-arginine-methyl ester in pregnancy caused >2000 renal transcripts to be modified during nephrogenesis stage in 1-day-old offspring kidney. Among them, genes belong to the renin-angiotensin system, and arachidonic acid metabolism pathways were potentially involved in the N G -nitro-L-arginine-methyl ester-induced programmed hypertension. However, melatonin and N-acetylcysteine reprogrammed the renin-angiotensin system and arachidonic acid pathway

N(4)-Methyl-N(4)-(2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine-ethanol-hydrazine (1/0.865/0.135): hydrogen-bonded ribbons containing four independent ring types.

PubMed

Trilleras, Jorge; Quiroga, Jairo; Cobo, Justo; Glidewell, Christopher

2009-06-01

N(4)-Methyl-N(4)-(2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine crystallizes from ethanol as a mixed solvate, C(13)H(14)N(6).0.865C(2)H(6)O.0.135N(2)H(4), (I), where the hydrazine has been carried through from the initial preparation. Within the heterocyclic component, the 2-methylphenyl substituent is disordered over two sets of sites. There is an intramolecular C-H...pi(arene) hydrogen bond, which may control the molecular conformation of the heterocycle. The heterocyclic molecules are linked by two independent N-H...N hydrogen bonds in a chain containing two types of R(2)(2)(8) ring. The ethanol component is linked to this chain by a combination of O-H...N and N-H...O hydrogen bonds and the hydrazine component by two N-H...N hydrogen bonds, so generating two R(3)(3)(9) rings and thus forming a ribbon containing four distinct ring types.

Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-d-Aspartate Receptor

PubMed Central

Chang, Eric H.; Volpe, Bruce T.; Mackay, Meggan; Aranow, Cynthia; Watson, Philip; Kowal, Czeslawa; Storbeck, Justin; Mattis, Paul; Berlin, RoseAnn; Chen, Huiyi; Mader, Simone; Huerta, Tomás S.; Huerta, Patricio T.; Diamond, Betty

2015-01-01

Patients with systemic lupus erythematosus (SLE) experience cognitive abnormalities in multiple domains including processing speed, executive function, and memory. Here we show that SLE patients carrying antibodies that bind DNA and the GluN2A and GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), termed DNRAbs, displayed a selective impairment in spatial recall. Neural recordings in a mouse model of SLE, in which circulating DNRAbs penetrate the hippocampus, revealed that CA1 place cells exhibited a significant expansion in place field size. Structural analysis showed that hippocampal pyramidal cells had substantial reductions in their dendritic processes and spines. Strikingly, these abnormalities became evident at a time when DNRAbs were no longer detectable in the hippocampus. These results suggest that antibody-mediated neurocognitive impairments may be highly specific, and that spatial cognition may be particularly vulnerable to DNRAb-mediated structural and functional injury to hippocampal cells that evolves after the triggering insult is no longer present. PMID:26286205

Preliminary individualized chemotherapy for malignant astrocytomas based on O6-methylguanine-deoxyribonucleic acid methyltransferase methylation analysis.

PubMed

Watanabe, Takao; Katayama, Yoichi; Ogino, Akiyoshi; Ohta, Takashi; Yoshino, Atsuo; Fukushima, Takao

2006-08-01

O(6)-methylguanine-deoxyribonucleic acid methyltransferase gene (MGMT) methylation is apparently correlated with responsiveness to nitrosourea chemotherapy, suggesting this alkylating agent should be effective against MGMT-methylated tumors. MGMT appears not to be linked to platinum resistance, so platinum chemotherapy should be used for MGMT-unmethylated tumors. This study was a preliminary trial of individualized chemotherapy based on MGMT methylation status in a total of 20 patients with newly diagnosed malignant astrocytomas (9 anaplastic astrocytomas and 11 glioblastomas multiforme). The procarbazine, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-2(2-chloroethyl)-3-nitrosourea, and vincristine (PAV) regimen was administered to seven patients with MGMT-methylated tumors, and the carboplatin and etoposide (CE) regimen was administered to 13 patients with MGMT-unmethylated tumors. Objective response to the PAV therapy was noted in all three patients with measurable residual tumor (2 complete responses and 1 partial response). Five of the seven patients continued to be disease-free after initiation of the PAV therapy. Objective response to the CE therapy was seen in only one of seven patients with measurable residual tumor (1 partial response). Three of the 13 patients were free from progression, whereas the remaining 10 patients showed early progression. The PAV regimen is effective against MGMT-methylated malignant astrocytomas, but the CE regimen is not useful at the given dose and schedule in MGMT-unmethylated tumors.

Preparation of Poly-(Methyl vinyl ether-co-maleic Anhydride) Nanoparticles by Solution-Enhanced Dispersion by Supercritical CO2

PubMed Central

Chen, Ai-Zheng; Wang, Guang-Ya; Wang, Shi-Bin; Feng, Jian-Gang; Liu, Yuan-Gang; Kang, Yong-Qiang

2012-01-01

The supercritical CO2-based technologies have been widely used in the formation of drug and/or polymer particles for biomedical applications. In this study, nanoparticles of poly-(methyl vinyl ether-co-maleic anhydride) (PVM/MA) were successfully fabricated by a process of solution-enhanced dispersion by supercritical CO2 (SEDS). A 23 factorial experiment was designed to investigate and identify the significance of the processing parameters (concentration, flow and solvent/nonsolvent) for the surface morphology, particle size, and particle size distribution of the products. The effect of the concentration of PVM/MA was found to be dominant in the results regarding particle size. Decreasing the initial solution concentration of PVM/MA decreased the particle size significantly. After optimization, the resulting PVM/MA nanoparticles exhibited a good spherical shape, a smooth surface, and a narrow particle size distribution. Fourier transform infrared spectroscopy (FTIR) spectra demonstrated that the chemical composition of PVM/MA was not altered during the SEDS process and that the SEDS process was therefore a typical physical process. The absolute value of zeta potential of the obtained PVM/MA nanoparticles was larger than 40 mV, indicating the samples’ stability in aqueous suspension. Analysis of thermogravimetry-differential scanning calorimetry (TG-DSC) revealed that the effect of the SEDS process on the thermostability of PVM/MA was negligible. The results of gas chromatography (GC) analysis confirmed that the SEDS process could efficiently remove the organic residue.

A Riboproteomic Platform to Identify Novel Targets for Prostate Cancer Therapy

DTIC Science & Technology

2015-10-01

cell lines derived from RWPE1 prostatic epithelial cells after exposure to N-methyl-N- nitrosourea (MNU) (these cell lines are commercially available...is well established that the malignancy of cells is strongly linked to and dependent on aberrant protein synthesis . Current knowledge clearly...highlights deregulation of protein synthesis , in the development of prostate cancer, through aberrant activation of classical signaling pathways. It has

Comparative Biochemistry and Metabolism. Part 1. Carcinogenesis

DTIC Science & Technology

1982-08-01

1968), Nitrosamine-induced carcino- genesis. The alkylation of nucleic acids of the rat by N-methvl- N- nitrosourea , dimethylnitrosamine...inorganic reducing agent , hydrazine, is toxic and weakly carcinogenic. In earlier studies it was found that oral administration of a toxic dose of...metabolically activated to a methylatinj agent . Liver DNA from mice and hamsters contained considerably more 7-methyl- guanine and 0 6-methylguanine

Brain MRI Characteristics of Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis and Their Associations with 2-Year Clinical Outcome.

PubMed

Zhang, T; Duan, Y; Ye, J; Xu, W; Shu, N; Wang, C; Li, K; Liu, Y

2018-05-01

Anti- N -methyl-D-aspertate receptor encephalitis is an autoimmune-mediated disease without specific brain MRI features. Our aim was to investigate the brain MR imaging characteristics of anti- N -methyl-D-aspartate receptor encephalitis and their associations with clinical outcome at a 2-year follow-up. We enrolled 53 patients with anti- N -methyl-D-aspartate receptor encephalitis and performed 2-year follow-up. Brain MRIs were acquired for all patients at the onset phase. The brain MR imaging manifestations were classified into 4 types: type 1: normal MR imaging findings; type 2: only hippocampal lesions; type 3: lesions not involving the hippocampus; and type 4: lesions in both the hippocampus and other brain areas. The modified Rankin Scale score at 2-year follow-up was assessed, and the association between the mRS and onset brain MR imaging characteristics was evaluated. Twenty-eight (28/53, 53%) patients had normal MR imaging findings (type 1), and the others (25/53, 47%) had abnormal MRI findings: type 2: 7 patients (13%); type 3: seven patients (13%); and type 4: eleven patients (21%). Normal brain MRI findings were more common in female patients ( P = .02). Psychiatric and behavioral abnormalities were more common in adults ( P = .015), and autonomic symptoms ( P = .025) were more common in pediatric patients. The presence of hippocampal lesions ( P = .008, OR = 9.584; 95% CI, 1.803-50.931) and relapse ( P = .043, OR = 0.111; 95% CI, 0.013-0.930) was associated with poor outcome. Normal brain MRI findings were observed in half of the patients. Lesions in the hippocampus were the most common MR imaging abnormal finding. The presence of hippocampal lesions is the main MR imaging predictor for poor prognosis in patients with anti- N -methyl-D-aspartate receptor encephalitis. © 2018 by American Journal of Neuroradiology.

Evaluation of N-[(11)C]methyl-AMD3465 as a PET tracer for imaging of CXCR4 receptor expression in a C6 glioma tumor model.

PubMed

Hartimath, S V; van Waarde, A; Dierckx, R A J O; de Vries, E F J

2014-11-03

The chemokine receptor CXCR4 and its ligand CXCL12 play an important role in tumor progression and metastasis. CXCR4 receptors are expressed by many cancer types and provide a potential target for treatment. Noninvasive detection of CXCR4 may aid diagnosis and improve therapy selection. It has been demonstrated in preclinical studies that positron emission tomography (PET) with a radiolabeled small molecule could enable noninvasive monitoring of CXCR4 expression. Here, we prepared N-[(11)C]methyl-AMD3465 as a new PET tracer for CXCR4. N-[(11)C]Methyl-AMD3465 was readily prepared by N-methylation with [(11)C]CH3OTf. The tracer was obtained in a 60 ± 2% yield (decay corrected), the purity of the tracer was >99%, and specific activity was 47 ± 14 GBq/μmol. Tracer stability was tested in vitro using liver microsomes and rat plasma; excellent stability was observed. The tracer was evaluated in rat C6 glioma and human PC-3 cell lines. In vitro cellular uptake of N-[(11)C]methyl-AMD3465 was receptor mediated. The effect of transition metal ions (Cu(2+), Ni(2+), and Zn(2+)) on cellular binding was examined in C6 cells, and the presence of these ions increased the cellular binding of the tracer 9-, 7-, and 3-fold, respectively. Ex vivo biodistribution and PET imaging of N-[(11)C]methyl-AMD3465 were performed in rats with C6 tumor xenografts. Both PET and biodistribution studies demonstrated specific accumulation of the tracer in the tumor (SUV 0.6 ± 0.2) and other CXCR4 expressing organs, such as lymph node (1.5 ± 0.2), liver (8.9 ± 1.0), bone marrow (1.0 ± 0.3), and spleen (1.0 ± 0.1). Tumor uptake was significantly reduced (66%, p < 0.01) after pretreatment with Plerixafor (AMD3100). Biodistribution data indicates a tumor-to-muscle ratio of 7.85 and tumor-to-plasma ratio of 1.14, at 60 min after tracer injection. Our data demonstrated that N-[(11)C]methyl-AMD3465 is capable of detecting physiologic CXCR4 expression in tumors and other CXCR4 expressing tissues

Investigation of hydrazide derivatives inhibitory effect on peroxidase enzyme purified from turnip roots

NASA Astrophysics Data System (ADS)

Almaz, Züleyha; Öztekin, Aykut; Özdemir, Hasan

2017-04-01

Peroxidases (EC: 1.11.1.7) are haem proteins and contain iron (III) protoporphyrin IX (ferriprotoporphyrin IX) as the prosthetic group [1]. They are found in all cells and play a critical role in many biological processes, such as the host-defense mechanism [2]. Peroxidases (PODs) are widely used in clinical biochemistry, enzyme immunoassays, synthesis of various aromatic chemicals, treatment of waste water containing phenolic compounds [3, 4]. In this study, peroxidase enzyme was purified with Para amino benzohydrazide (PABH)-L-Tyrosine Sepharose 4B affinity chromatography to investigate the inhibitory effect of hydrazide derivatives on Turnip (Brassica rapa L.). IC50 values and Ki constants were calculated for the molecules of 6-Amino nicotinic hydrazide, 6-Amino-5-bromo nicotinic hydrazide, 2-Amino-5-hydroxy benzohydrazide, 4-Amino-3-hydroxy benzohydrazide on purified enzyme and inhibition type of these molecules were determined.

Antimicrobial activity of N-alkoxycarbonylmethyl-N-alkyl-piperidinium chlorides.

PubMed

Woźniak, Edyta; Mozrzymas, Anna; Czarny, Anna; Kocieba, Maja; Rózycka-Roszak, Bozenna; Dega-Szafran, Zofia; Dulewicz, Ewa; Petryna, Magdalena

2004-01-01

The aim of the study was to assay antibacterial and antifungal activity of newly synthesised N-alkoxycarbonylmethyl-N-alkyl-piperidinium chlorides. The compounds tested were found to inhibit the growth of some Gram-negative bacteria, Gram-positive strains and some representatives of yeast-type Candida. From microbiological experiments two of the compounds tested, N-dodecyloxycarbonylmethyl-N-methyl-piperidinium chloride (3) and N-dodecyl-N-ethoxycarbonylmethyl-piperidinium chloride (6), emerged as more active than the other compounds. Since the resistance of biofilms to biocides should be noted during the design and testing of new antimicrobial agents therefore, we have analysed antibacterial properties of the most active compounds towards biofilms. Our study focused on strains of Pseudomonas aeruginosa and Staphylococcus aureus that served as main model organisms for the biofilm studies.

Synthesis ofN-(2-chloro-5-methylthiophenyl)-N'-(3-methyl-thiophenyl)-N'-[3H3]methylguanidine, l brace [3H3]CNS-5161 r brace

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gibbs, Andrew R.; Morimoto, Hiromi; VanBrocklin, Henry F.

2001-09-28

The preparation of the title compound, [{sup 3}H{sub 3}]CNS-5161, was accomplished in three steps starting with the production of [{sup 3}H{sub 3}]iodomethane (CT{sub 3}I). The intermediate N-[{sup 3}H{sub 3}]methyl-3-(thiomethylphenyl)cyanamide was prepared in 77% yield by the addition of CT{sub 3}I to 3-(thiomethylphenyl)cyanamide, previously treated with sodium hydride. Reaction of this tritiated intermediate with 2-chloro-5-thiomethylaniline hydrochloride formed the guanidine compound [{sup 3}H{sub 3}]CNS-5161. Purification by HPLC gave the desired labeled product in an overall yield of 9% with greater than 96% radiochemical purity and a final specific activity of 66 Ci mmol{sup -1}.

Mechanism of error-free DNA synthesis across N1-methyl-deoxyadenosine by human DNA polymerase-ι

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jain, Rinku; Choudhury, Jayati Roy; Buku, Angeliki

N1-methyl-deoxyadenosine (1-MeA) is formed by methylation of deoxyadenosine at the N1 atom. 1-MeA presents a block to replicative DNA polymerases due to its inability to participate in Watson-Crick (W-C) base pairing. Here we determine how human DNA polymerase-ι (Polι) promotes error-free replication across 1-MeA. Steady state kinetic analyses indicate that Polι is ~100 fold more efficient in incorporating the correct nucleotide T versus the incorrect nucleotide C opposite 1-MeA. To understand the basis of this selectivity, we determined ternary structures of Polι bound to template 1-MeA and incoming dTTP or dCTP. In both structures, template 1-MeA rotates to the synmore » conformation but pairs differently with dTTP versus dCTP. Thus, whereas dTTP partakes in stable Hoogsteen base pairing with 1-MeA, dCTP fails to gain a “foothold” and is largely disordered. Together, our kinetic and structural studies show how Polι maintains discrimination between correct and incorrect incoming nucleotide opposite 1-MeA in preserving genome integrity.« less

Rotational Spectrum and Conformational Analysis of N-methyl-2-aminoethanol: Insights into the Shape of Adrenergic Neurotransmitters

NASA Astrophysics Data System (ADS)

Calabrese, Camilla; Maris, Assimo; Evangelisti, Luca; Piras, Anna; Parravicini, Valentina; Melandri, Sonia

2018-02-01

Abstract We describe an experimental and quantum chemical study for the accurate determination of the conformational space of small molecular systems governed by intramolecular non-covalent interactions. The model systems investigated belong to the biological relevant aminoalcohol’s family, and include 2-aminophenylethanol, 2-methylaminophenylethanol, noradrenaline, adrenaline 2-aminoethanol and N-methyl-2-aminoethanol. For the latter molecule, the rotational spectrum in the 6-18 and 59.6-74.4 GHz ranges was recorded in the isolated conditions of a free jet expansion. Based on the analysis of the rotational spectra, two different conformational species and 11 isotopologues were observed and their spectroscopic constants, including 14N-nuclear hyperfine coupling constants and methyl internal rotation barriers, were determined. From the experimental data a structural determination was obtained, which was also used to benchmark accurate quantum chemical calculations on the whole conformational space. Atom in molecules and non-covalent interactions theories allowed the characterization of the position of the intramolecular non-covalent interactions and the energies involved, highlighting the subtle balance responsible of the stabilization of all the molecular systems.

40 CFR 721.10316 - Dicyclopentadiene polymer with maleic anhydride and alkyl alcohols (generic).

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Dicyclopentadiene polymer with maleic... Significant New Uses for Specific Chemical Substances § 721.10316 Dicyclopentadiene polymer with maleic.... (1) The chemical substance identified generically as dicyclopentadiene polymer with maleic anhydride...

40 CFR 721.10316 - Dicyclopentadiene polymer with maleic anhydride and alkyl alcohols (generic).

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Dicyclopentadiene polymer with maleic... Significant New Uses for Specific Chemical Substances § 721.10316 Dicyclopentadiene polymer with maleic.... (1) The chemical substance identified generically as dicyclopentadiene polymer with maleic anhydride...

40 CFR 721.10316 - Dicyclopentadiene polymer with maleic anhydride and alkyl alcohols (generic).

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Dicyclopentadiene polymer with maleic... Significant New Uses for Specific Chemical Substances § 721.10316 Dicyclopentadiene polymer with maleic.... (1) The chemical substance identified generically as dicyclopentadiene polymer with maleic anhydride...

Poly(2,5-bis(N-Methyl-N-Hexylamino)Phenylene Vinylene) (BAM-PPV) as Pretreatment Coating for Aerospace Applications: Laboratory and Field Studies

PubMed Central

Zarras, Peter; Buhrmaster, Diane; Webber, Cindy; Anderson, Nicole; Stenger-Smith, John D.; Goodman, Paul A.

2014-01-01

In this study, an electroactive polymer (EAP), poly(2,5-bis(N-methyl-N-hexylamino)phenylene vinylene) (BAM-PPV) was investigated as a potential alternative surface pretreatment for hexavalent chromium (Cr(VI))-based aerospace coatings. BAM-PPV was tested as a pretreatment coating on an aerospace aluminum alloy (AA2024-T3) substrate in combination with a non-Cr(VI) epoxy primer and a polyurethane Advanced Performance Coating (APC) topcoat. This testing was undertaken to determine BAM-PPV’s adhesion, corrosion-inhibition, compatibility and survivability in laboratory testing and during outdoor field-testing. BAM-PPV showed excellent adhesion and acceptable corrosion performance in laboratory testing. The BAM-PPV aerospace coating system (BAM-PPV, non-Cr(VI) epoxy primer and polyurethane APC topcoat) was field tested for one year on the rear hatch door of the United States Air Force C-5 cargo plane. After one year of field testing there was no evidence of delamination or corrosion of the BAM-PPV aerospace coating system. PMID:28788292

Poly(2,5-bis(N-Methyl-N-Hexylamino)Phenylene Vinylene) (BAM-PPV) as Pretreatment Coating for Aerospace Applications: Laboratory and Field Studies.

PubMed

Zarras, Peter; Buhrmaster, Diane; Webber, Cindy; Anderson, Nicole; Stenger-Smith, John D; Goodman, Paul A

2014-12-17

In this study, an electroactive polymer (EAP), poly(2,5-bis( N -methyl- N -hexylamino)phenylene vinylene) (BAM-PPV) was investigated as a potential alternative surface pretreatment for hexavalent chromium (Cr(VI))-based aerospace coatings. BAM-PPV was tested as a pretreatment coating on an aerospace aluminum alloy (AA2024-T3) substrate in combination with a non-Cr(VI) epoxy primer and a polyurethane Advanced Performance Coating (APC) topcoat. This testing was undertaken to determine BAM-PPV's adhesion, corrosion-inhibition, compatibility and survivability in laboratory testing and during outdoor field-testing. BAM-PPV showed excellent adhesion and acceptable corrosion performance in laboratory testing. The BAM-PPV aerospace coating system (BAM-PPV, non-Cr(VI) epoxy primer and polyurethane APC topcoat) was field tested for one year on the rear hatch door of the United States Air Force C-5 cargo plane. After one year of field testing there was no evidence of delamination or corrosion of the BAM-PPV aerospace coating system.

Selol nanocapsules with a poly(methyl vinyl ether-co-maleic anhydride) shell conjugated to doxorubicin for combinatorial chemotherapy against murine breast adenocarcinoma in vivo.

PubMed

Ganassin, Rayane; Horst, Frederico Hillesheim; Camargo, Nichollas Serafim; Chaves, Sacha Braun; Morais, Paulo César; Mosiniewicz-Szablewska, Ewa; Suchocki, Piotr; Figueiró Longo, João Paulo; Azevedo, Ricardo Bentes; Muehlmann, Luis Alexandre

2018-05-29

Nanocapsules containing selol and doxorubicin (NCS-DOX) with an oily core of selol and a shell of poly(methyl vinyl ether-co-maleic anhydride) covalently conjugated to doxorubicin were developed in a previous work. In this study, these nanocapsules showed a similar antitumour effect in comparison to the free doxorubicin (DOX) treatment, but showed no evident DOX-related cardiotoxicity, as evidenced by serum creatine kinase-MB (CK-MB) activity. The histopathological analysis showed that the free DOX treatment induced more intense morphological damage to myocardial tissues in comparison to NCS-DOX treatment. Animals treated with free DOX presented important muscle fibre degradation and animals treated with NCS-DOX, heart tissue did not present signals of muscle fibre degeneration. These results indicate that the cardiotoxicity related to DOX is reduced when this drug is carried by the NCS-DOX. Noteworthy, biodistribution analyses showed that NCS-DOX accumulated more intensely in tumours than the free DOX. Thus, this study reinforces the importance of the development of nanocapsules as drug carriers for the treatment of cancer.

Crystal structures of HIV-1 nonnucleoside reverse transcriptase inhibitors: N-benzyl-4-methyl-benzimidazoles

NASA Astrophysics Data System (ADS)

Ziółkowska, Natasza E.; Michejda, Christopher J.; Bujacz, Grzegorz D.

2009-07-01

HIV-1 nonnucleoside reverse transcriptase inhibitors are potentially specific and effective drugs in AIDS therapy. The presence of two aromatic systems with an angled orientation in the molecule of the inhibitor is crucial for interactions with HIV-1 RT. The inhibitor drives like a wedge into the cluster of aromatic residues of RT HIV-1 and restrains the enzyme in a conformation that blocks the chemical step of nucleotide incorporation. Structural studies provide useful information for designing new, more active inhibitors. The crystal structures of four NNRTIs are presented here. The investigated compounds are derivatives of N-benzyl-4-methyl-benzimidazole with various aliphatic and aromatic substituents at carbon 2 positions and a 2,6-dihalogeno-substituted N-benzyl moiety. Structural data reported here show that the conformation of the investigated compounds is relatively rigid. Such feature is important for the nonnucleoside inhibitor binding to HIV-1 reverse transcriptase.

Crystal structure of fac-[2-(4-methyl-5-phenyl-pyridin-2-yl)phenyl-κ2C1,N]bis-[2-(pyridin-2-yl)phenyl-κ2C1,N]iridium(III).

PubMed

Lee, Chi-Heon; Moon, Suk-Hee; Park, Ki-Min; Kang, Youngjin

2016-12-01

In the title compound, [Ir(C 11 H 8 N) 2 (C 18 H 14 N)], the Ir III ion adopts a distorted octa-hedral coordination environment defined by three C , N -chelating ligands, one stemming from a 2-(4-phenyl-5-methyl-pyridin-2-yl)phenyl ligand and two from 2-(pyridin-2-yl)phenyl ligands, arranged in a facial manner. The Ir III ion lies almost in the equatorial plane [deviation = 0.0069 (15) Å]. In the crystal, inter-molecular π-π stacking inter-actions, as well as inter-molecular C-H⋯π inter-actions, are present, leading to a three-dimensional network.

Chemoprevention of Prostate Cancer by Phenethyl Isothiocyanate

DTIC Science & Technology

2007-03-01

AD cells were exposed to PEITC, protein synthesis inhibitor cycloheximide (CHX), or proteasome inhibitor MG-132 alone, or to the combination of...The results indicated that down-regulation of Sp1 may require protein synthesis for a proteasome activity, thereby enhancing Sp1 protein degradation...carcinogen N- methyl-N- nitrosourea (MNU) for the formation of prostate tumors. The experimental group of rats was provided with PEITC, to evaluate the

Cloning and Characterizing Genes Involved in Monoterpene Induced Mammary Tumor Regression.

DTIC Science & Technology

1996-10-01

causes morphologic differentiation within 4 hours as characterized by neurite outgrowths (12). Monoterpenes inhibit enzymes in the mevalonate-lipid...metabolism pathway, including a selective inhibition of isoprenylation of 21-26 kDa small G proteins (13-15) and inhibition of ubiquinone ( CoQ ) and...Letters 269(2), 305-10 18 FOOTNOTES 1 The abbreviations used are: DMBA, 7,12-dimethylbenz[a]anthracene; NMU, N-methyl-N- nitrosourea; CoQ , ubiquinone

The role of N-methyl-D-aspartate receptors and nitric oxide in cochlear dopamine release.

PubMed

Halmos, G; Horváth, T; Polony, G; Fekete, A; Kittel, A; Vizi, E S; van der Laan, B F A M; Zelles, T; Lendvai, B

2008-06-23

Dopamine (DA) released from lateral olivocochlear (LOC) terminals may have a neuroprotective effect in the cochlea. To explore the role of N-methyl-d-aspartate (NMDA) receptors and nitric oxide (NO) in the modulation of a cochlear DA release, we measured the release of [3H]DA from isolated mouse cochlea in response to the application of NMDA. NMDA at 100 muM significantly increased the electrical-field stimulation-evoked and resting release of DA from the cochlea. The NO donor sodium nitroprusside enhanced the basal outflow of DA but failed to influence the evoked release. The administration of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) alone was ineffective, but it significantly inhibited the initial phase of the NMDA-induced elevation of DA outflow, which suggested the role of NO in the NMDA-induced DA release. The DA uptake inhibitor nomifensine increased the electrically evoked release of DA. Nomifensine failed to change the effect of NMDA on the resting or electrically-evoked DA release, which suggested that the uptake mechanism does not play a role in NMDA-evoked and NO-mediated DA release. In summary, we provide evidence that NO can modulate the release of DA from the cochlea following NMDA receptor activation, but does not affect the uptake of DA.

New curing system for urea-formaldehyde resins with polyhydrazides. I. Curing with poly(methycrylol hydrazide)

Treesearch

Katsumasa Miyake; Bunichiro Tomita; Chung-Yun Hse; George E. Myers

1989-01-01

A new curing system for urea-formaldehyde (UF) resins was investigated using poly(methacryloyl hydrazide) as the curing reagent. Results were as follows: 1) Gel time and the water-soluble part of cured resins were determined as function of pH and molar ratio [hydrazide group/(free formaldehyde+methylol group)]. It was found that the reaction in this system proceeds for...

Neurosteroid-like Inhibitors of N-Methyl-d-aspartate Receptor: Substituted 2-Sulfates and 2-Hemisuccinates of Perhydrophenanthrene.

PubMed

Slavikova, Barbora; Chodounska, Hana; Nekardova, Michaela; Vyklicky, Vojtech; Ladislav, Marek; Hubalkova, Pavla; Krausova, Barbora; Vyklicky, Ladislav; Kudova, Eva

2016-05-26

N-Methyl-d-aspartate receptors (NMDARs) display a critical role in various diseases of the central nervous system. The activity of NMDARs can be modulated by neurosteroids. Herein, we report a structure-activity relationship study for perhydrophenanthrene analogues possessing a framework that mimics the steroidal ring system. This study comprises the design, synthesis, and assessment of the biological activity of a library of perhydrophenanthrene 2-sulfates and 2-hemisuccinates (1-10). Their ability to modulate NMDAR-induced currents was tested on recombinant GluN1/GluN2B receptors. Our results demonstrate that such structural optimization leads to compounds that are inhibitors of NMDARs. Notably, compound 9 (IC50 = 15.6 μM) was assessed as a more potent inhibitor of NMDAR-induced currents than the known endogenous neurosteroid, pregnanolone sulfate (IC50 = 24.6 μM).

RNA N6-adenosine methylation (m6A) steers epitranscriptomic control of herpesvirus replication

PubMed Central

Ye, Fengchun

2017-01-01

Latency is a hallmark of all herpesviruses, during which the viral genomes are silenced through DNA methylation and suppressive histone modifications. When latent herpesviruses reactivate to undergo productive lytic replication, the suppressive epigenetic marks are replaced with active ones to allow for transcription of viral genes. Interestingly, by using Kaposi’s sarcoma-associated herpesvirus (KSHV) as a model, we recently demonstrated that the newly transcribed viral RNAs are also subjected to post-transcriptional N6-adenosine methylation (m6A). Blockade of this post-transcriptional event abolishes viral protein expression and halts virion production. We found that m6A modification controls RNA splicing, stability, and protein translation to regulate viral lytic gene expression and replication. Thus, our finding for the first time reveals a critical role of this epitranscriptomic mechanism in the control of herpesviral replication, which shall shed lights on development of novel strategies for the control of herpesviral infection. PMID:29082271

N-tert-Butyl-N'-(5,7-dimethyl-1,8-naphthyridin-2-yl)urea.

PubMed

Lüning, U; Kühl, C; Bolte, M

2001-08-01

The title compound, C(15)H(20)N(4)O, has been synthesized as an AADD recognition unit for quadruple hydrogen bonds. All non-H atoms of the molecule apart from two methyl groups of the tert-butyl group lie in a common plane. An intramolecular hydrogen bond is formed connecting two N atoms. In the solid state, the title compound crystallizes as a centrosymmetric dimer connected by N-H...O=C interactions with an N...O distance of 2.824 (2) A.

Effectiveness of sodium azide alone compared to sodium azide in combination with methyl nitrosurea for rice mutagenesis

USDA-ARS?s Scientific Manuscript database

Rice seeds of the temperate japonica cultivar Kitaake were mutagenized with sodium azide alone and in combination with methyl nitrosourea. Using the reduced representation sequencing method Restriction Enzyme Sequence Comparative Analysis (RESCAN), the mutation densities, types and local sequence co...

Copper-catalyzed aerobic oxidative N-S bond functionalization for C-S bond formation: regio- and stereoselective synthesis of sulfones and thioethers.

PubMed

Li, Xianwei; Xu, Yanli; Wu, Wanqing; Jiang, Chang; Qi, Chaorong; Jiang, Huanfeng

2014-06-23

A regio- and stereoselective synthesis of sulfones and thioethers by means of Cu(I)-catalyzed aerobic oxidative N-S bond cleavage of sulfonyl hydrazides, followed by cross-coupling reactions with alkenes and aromatic compounds to form the C sp 2-S bond, is described herein. N2 and H2O are the byproducts of this transformation, thus offering an environmentally benign process with a wide range of potential applications in organic synthesis and medicinal chemistry. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DNA replication after mutagenic treatment in Hordeum vulgare.

PubMed

Kwasniewska, Jolanta; Kus, Arita; Swoboda, Monika; Braszewska-Zalewska, Agnieszka

2016-12-01

The temporal and spatial properties of DNA replication in plants related to DNA damage and mutagenesis is poorly understood. Experiments were carried out to explore the relationships between DNA replication, chromatin structure and DNA damage in nuclei from barley root tips. We quantitavely analysed the topological organisation of replication foci using pulse EdU labelling during the S phase and its relationship with the DNA damage induced by mutagenic treatment with maleic hydrazide (MH), nitroso-N-methyl-urea (MNU) and gamma ray. Treatment with mutagens did not change the characteristic S-phase patterns in the nuclei; however, the frequencies of the S-phase-labelled cells after treatment differed from those observed in the control cells. The analyses of DNA replication in barley nuclei were extended to the micronuclei induced by mutagens. Replication in the chromatin of the micronuclei was rare. The results of simultanous TUNEL reaction to identify cells with DNA strand breaks and the labelling of the S-phase cells with EdU revealed the possibility of DNA replication occurring in damaged nuclei. For the first time, the intensity of EdU fluorescence to study the rate of DNA replication was analysed. Copyright © 2016 Elsevier B.V. All rights reserved.

G2 accumulation and melanin overproduction in malignant melanocytes treated with a new nitrosourea.

PubMed

Buchdahl, C; Papon, J; Communal, Y; Bourges, M; Madelmont, J C

1998-12-01

Cystemustine (N'-(2-chloroethyl)-N-(2-(methylsulphonyl)ethyl)-N'-nitrosourea), a new anticancer chloroethylnitrosourea (CENU) is being tested in a phase II clinical trial of disseminated melanoma. The antitumour effect of this drug is mainly due to DNA damage in malignant melanocytes. Recently, we have shown that this damage can induce apoptosis in some melanoma cell lines. In others, apoptosis is not clearly observed, although there is a strong cytostatic effect. In this paper, we have characterized the cytological effect of cystemustine on murine malignant melanocytes (B16 cell line) which are resistant to apoptosis induced by this CENU. The results show that 3 days after cystemustine treatment, these melanocytes had accumulated in phase G2 of the cell cycle. There was then a strong morphological modification during a long cytostatic phase up to 30 days after treatment. During this cytostatic phase, there was uncontrolled DNA synthesis and marked swelling. Also, tyrosinase activity, melanin content and the number of mature melanosomes were greatly increased. These results suggest that when malignant melanocytes are not able to undergo apoptosis after treatment with CENU, they accumulate in G2 and this is followed by enhancement of melanogenesis.

Synthesis, radiolabeling, and preliminary biological evaluation of [3H]-1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(o-tolyl)-piperazine, a potent antagonist radioligand for the P2X7 receptor.

PubMed

Romagnoli, Romeo; Baraldi, Pier Giovanni; Pavani, Maria Giovanna; Tabrizi, Mojgan Aghazadeh; Moorman, Allan R; Di Virgilio, Francesco; Cattabriga, Elena; Pancaldi, Cecilia; Gessi, Stefania; Borea, Pier Andrea

2004-11-15

The design, synthesis, and preliminary biological evaluation of the first potent radioligand antagonist for the P2X(7) receptor, named [(3)H]-1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(o-tolyl)-piperazine (compound 13), are reported. This compound bound to human P2X(7) receptors expressed in HEK transfected cells with K(D) and B(max) value of 3.46+/-0.1 nM and 727+/-73 fmol/mg of protein, respectively. The high affinity and facile labeling makes it a promising radioligand for a further characterization of P2X(7) receptor subtype.

21 CFR 872.3500 - Polyvinylmethylether maleic anhydride (PVM-MA), acid copolymer, and carboxymethylcellulose sodium...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Polyvinylmethylether maleic anhydride (PVM-MA...) MEDICAL DEVICES DENTAL DEVICES Prosthetic Devices § 872.3500 Polyvinylmethylether maleic anhydride (PVM-MA.... Polyvinylmethylether maleic anhydride (PVM-MA), acid copolymer, and carboxymethylcellulose sodium (NACMC) denture...

21 CFR 872.3500 - Polyvinylmethylether maleic anhydride (PVM-MA), acid copolymer, and carboxymethylcellulose sodium...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Polyvinylmethylether maleic anhydride (PVM-MA...) MEDICAL DEVICES DENTAL DEVICES Prosthetic Devices § 872.3500 Polyvinylmethylether maleic anhydride (PVM-MA.... Polyvinylmethylether maleic anhydride (PVM-MA), acid copolymer, and carboxymethylcellulose sodium (NACMC) denture...

21 CFR 872.3500 - Polyvinylmethylether maleic anhydride (PVM-MA), acid copolymer, and carboxymethylcellulose sodium...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Polyvinylmethylether maleic anhydride (PVM-MA...) MEDICAL DEVICES DENTAL DEVICES Prosthetic Devices § 872.3500 Polyvinylmethylether maleic anhydride (PVM-MA.... Polyvinylmethylether maleic anhydride (PVM-MA), acid copolymer, and carboxymethylcellulose sodium (NACMC) denture...

21 CFR 872.3500 - Polyvinylmethylether maleic anhydride (PVM-MA), acid copolymer, and carboxymethylcellulose sodium...

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Polyvinylmethylether maleic anhydride (PVM-MA...) MEDICAL DEVICES DENTAL DEVICES Prosthetic Devices § 872.3500 Polyvinylmethylether maleic anhydride (PVM-MA.... Polyvinylmethylether maleic anhydride (PVM-MA), acid copolymer, and carboxymethylcellulose sodium (NACMC) denture...

21 CFR 872.3500 - Polyvinylmethylether maleic anhydride (PVM-MA), acid copolymer, and carboxymethylcellulose sodium...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Polyvinylmethylether maleic anhydride (PVM-MA...) MEDICAL DEVICES DENTAL DEVICES Prosthetic Devices § 872.3500 Polyvinylmethylether maleic anhydride (PVM-MA.... Polyvinylmethylether maleic anhydride (PVM-MA), acid copolymer, and carboxymethylcellulose sodium (NACMC) denture...

Structural basis for substrate recognition by the human N-terminal methyltransferase 1

DOE PAGES

Dong, Cheng; Mao, Yunfei; Tempel, Wolfram; ...

2015-11-05

α-N-terminal methylation represents a highly conserved and prevalent post-translational modification, yet its biological function has remained largely speculative. The recent discovery of α-N-terminal methyltransferase 1 (NTMT1) and its physiological substrates propels the elucidation of a general role of α-N-terminal methylation in mediating DNA-binding ability of the modified proteins. The phenotypes, observed from both NTMT1 knockdown in breast cancer cell lines and knockout mouse models, suggest the potential involvement of α-N-terminal methylation in DNA damage response and cancer development. In this study, we report the first crystal structures of human NTMT1 in complex with cofactor S-adenosyl-L-homocysteine (SAH) and six substrate peptides,more » respectively, and reveal that NTMT1 contains two characteristic structural elements (a β hairpin and an N-terminal extension) that contribute to its substrate specificity. Our complex structures, coupled with mutagenesis, binding, and enzymatic studies, also present the key elements involved in locking the consensus substrate motif XPK (X indicates any residue type other than D/E) into the catalytic pocket for α-N-terminal methylation and explain why NTMT1 prefers an XPK sequence motif. We propose a catalytic mechanism for α-N-terminal methylation. Overall, this study gives us the first glimpse of the molecular mechanism of α-N-terminal methylation and potentially contributes to the advent of therapeutic agents for human diseases associated with deregulated α-N-terminal methylation.« less

Synthesis, characterization, DNA-Binding, enzyme inhibition and antioxidant studies of new N-methylated derivatives of pyridinium amine

NASA Astrophysics Data System (ADS)

Zafar, Muhammad Naveed; Perveen, Fouzia; Nazar, Muhammad Faizan; Mughal, Ehsan Ullah; Rafique, Humera; Tahir, Muhammad Nawaz; Akbar, Muhammad Sharif; Zahra, Sabeen

2017-06-01

A series of novel N-methylated derivatives of pyridinium amine, [L1][Tf]-[L5][Tf], were synthesized and characterized by FTIR, NMR, MS and XRD analyses. Preliminary biological screening of these compounds including antioxidant, enzyme inhibition and DNA (salmon sperm) interaction studies were also carried out. The targeted compounds were synthesized by a melt reaction between 4-chloro-N-methyl pyridinium triflate and corresponding amines (1-naphthyl amine, o-ansidine, 2-nitroaniline, p-ansidine and cyclohexyl amine) at temperature of 230 °C. The DPPH radical antioxidant scavenging activities of these compounds at maximum concentration of 50 μg/mL were observed in the range of 60-70%. Acetylcholine esterase (AChE) and Butylcholine esterase (BChE) inhibitory activities of synthesized compounds at 2 mM concentration were also measured to be at maximum of 79 and 71% respectively. The spectral behavior of ligand-DNA obtained from photo-luminescent measurements showed that all ligands bind with DNA via non-covalent interactions. The binding constant values were determined by UV-visible and fluorescence spectroscopy and were quite close to that obtained from molecular docking studies.

Functional clay supported bimetallic nZVI/Pd nanoparticles used for removal of methyl orange from aqueous solution.

PubMed

Wang, Ting; Su, Jin; Jin, Xiaoying; Chen, Zuliang; Megharaj, Mallavarapu; Naidu, Ravendra

2013-11-15

Bentonite supported Fe/Pd nanoparticles (B/nZVI/Pd) were synthesized as composites that exhibit functionalities assisting in the removal of methyl orange (MO) from aqueous solution. The results showed that 91.87% of MO was removed using B/nZVI/Pd, while only 85% and 1.41% of MO were removed using nZVI/Pd and bentonite after 10 min, respectively. The new findings include that the presence of bentonite decreased the aggregation of nZVI/Pd and nZVI in the composite played its role as a reductant, while Pd(0) acted as the catalyst to enhance the degradation of MO, which were confirmed by scanning electron microscopy (SEM), X-ray diffraction (XRD), UV-vis analysis and the batch experiments. The increase in B/nZVI/Pd loading led to greater removal efficiency, while decolorization efficiency declined in the presence of anions such as nitrate, sulfite and carbonate, especially nitrate, which decreased the apparent rate constant k(obs) almost 17.06-fold. The kinetics study indicated that the degradation of MO fitted well to the pseudo-first-order model, where the k(obs) was 0.0721 min(-1). Finally, the reactivity of aged B/nZVI/Pd was investigated, and the application of B/nZVI/Pd in wastewater indicated a removal efficiency higher than 93.75%. This provided a new environmental pollution management option for dyes-contaminated sites. Copyright © 2013 Elsevier B.V. All rights reserved.

Weak Maser Emission of Methyl Formate toward Sagittarius B2(N) in the Green Bank Telescope PRIMOS Survey

NASA Astrophysics Data System (ADS)

Faure, A.; Remijan, A. J.; Szalewicz, K.; Wiesenfeld, L.

2014-03-01

A non-LTE radiative transfer treatment of cis-methyl formate (HCOOCH3) rotational lines is presented for the first time using a set of theoretical collisional rate coefficients. These coefficients have been computed in the temperature range 5-30 K by combining coupled-channel scattering calculations with a high accuracy potential energy surface for HCOOCH3-He. The results are compared to observations toward the Sagittarius B2(N) molecular cloud using the publicly available PRIMOS survey from the Green Bank Telescope. A total of 49 low-lying transitions of methyl formate, with upper levels below 25 K, are identified. These lines are found to probe a presumably cold (~30 K), moderately dense (~104 cm-3), and extended region surrounding Sgr B2(N). The derived column density of ~4 × 1014 cm-2 is only a factor of ~10 larger than the column density of the trans conformer in the same source. Provided that the two conformers have the same spatial distribution, this result suggests that strongly non-equilibrium processes must be involved in their synthesis. Finally, our calculations show that all detected emission lines with a frequency below 30 GHz are (collisionally pumped) weak masers amplifying the continuum of Sgr B2(N). This result demonstrates the importance and generality of non-LTE effects in the rotational spectra of complex organic molecules at centimeter wavelengths.

N-[2-(2,2-Di-methyl-propanamido)-pyrimidin-4-yl]-2,2-di-methyl-propanamide n-hexane 0.25-solvate hemihydrate.

PubMed

Ośmiałowski, Borys; Valkonen, Arto; Chęcińska, Lilianna

2013-10-05

The asymmetric unit of the title compound, C14H22N4O2·0.25C6H14·0.5H2O, contains two independent mol-ecules of 2,4-bis-(pivaloyl-amino)-pyrimidine (M) with similar conformations, one water mol-ecule and one-half n-hexane solvent mol-ecule situated on an inversion center. In one independent M mol-ecule, one of the two tert-butyl groups is rotationally disordered between two orientations in a 3:2 ratio. The n-hexane solvent mol-ecule is disordered between two conformations in the same ratio. The water mol-ecule bridges two independent M mol-ecules via O-H⋯O, N-H⋯O and O-H⋯N hydrogen bonds into a 2M·H2O unit, and these units are further linked by N-H⋯N hydrogen bonds into chains running in the [010] direction. Weak C-H⋯O inter-actions are observed between the adjacent chains.

Inhibition of N-methyl-D-aspartate receptors increases paraoxon-induced apoptosis in cultured neurons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu Xuan; Tian Feng; Okagaki, Peter

2005-10-01

Organophosphorus (OP) compounds, used as insecticides and chemical warfare agents, are potent neurotoxins. We examined the neurotoxic effect of paraoxon (O,O-diethyl O-p-nitrophenyl phosphate), an organophosphate compound, and the role of NMDA receptors as a mechanism of action in cultured cerebellar granule cells. Paraoxon is neurotoxic to cultured rat cerebellar granule cells in a time- and concentration-dependent manner. Cerebellar granule cells are less sensitive to the neurotoxic effects of paraoxon on day in vitro (DIV) 4 than neurons treated on DIV 8. Surprisingly, the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, enhances paraoxon-mediated neurotoxicity suggesting that NMDA receptors may play a protective role.more » Pretreatment with a subtoxic concentration of N-methyl-D-aspartate (NMDA) [100 {mu}M] protects about 40% of the vulnerable neurons that would otherwise die from paraoxon-induced neurotoxicity. Moreover, addition of a neuroprotective concentration of NMDA 3 h after treatment with paraoxon provides the same level of protection. Because paraoxon-mediated neuronal cell death is time-dependent, we hypothesized that apoptosis may be involved. Paraoxon increases apoptosis about 10-fold compared to basal levels. The broad-spectrum caspase inhibitor (Boc-D-FMK) and the caspase-9-specific inhibitor (Z-LEHD-FMK) protect against paraoxon-mediated apoptosis, paraoxon-stimulated caspase-3 activity and neuronal cell death. MK-801 increases, whereas NMDA blocks paraoxon-induced apoptosis and paraoxon-stimulated caspase-3 activity. These results suggest that activation of NMDA receptors protect neurons against paraoxon-induced neurotoxicity by blocking apoptosis initiated by paraoxon.« less

Blockade of N-methyl-D-aspartate Receptors May Protect against Ischemic Damage in the Brain

NASA Astrophysics Data System (ADS)

Simon, R. P.; Swan, J. H.; Griffiths, T.; Meldrum, B. S.

1984-11-01

In rats ischemia of the forebrain induced by a 30-minute occlusion of the carotid artery, followed by 120 minutes of arterial reperfusion, produced ischemic lesions of selectively vulnerable pyramidal cells in both hippocampi. Focal microinfusion into the dorsal hippocampus of 2-amino-7-phosphonoheptanoic acid, an antagonist of excitation at the N-methyl-d-asparate-preferring receptor, before ischemia was induced protected against the development of ischemic damage. It is proposed that excitatory neurotransmission plays an important role in selective neuronal loss due to cerebral ischemia.

Intramolecular cyclization of N-phenyl N'(2-chloroethyl)ureas leads to active N-phenyl-4,5-dihydrooxazol-2-amines alkylating β-tubulin Glu198 and prohibitin Asp40.

PubMed

Trzeciakiewicz, Anna; Fortin, Sébastien; Moreau, Emmanuel; C-Gaudreault, René; Lacroix, Jacques; Chambon, Christophe; Communal, Yves; Chezal, Jean-Michel; Miot-Noirault, Elisabeth; Bouchon, Bernadette; Degoul, Françoise

2011-05-01

The cyclization of anticancer drugs into active intermediates has been reported mainly for DNA alkylating molecules including nitrosoureas. We previously defined the original cytotoxic mechanism of anticancerous N-phenyl-N'-(2-chloroethyl)ureas (CEUs) that involves their reactivity towards cellular proteins and not against DNA; two CEU subsets have been shown to alkylate β-tubulin and prohibitin leading to inhibition of cell proliferation by G₂/M or G₁/S cell cycle arrest. In this study, we demonstrated that cyclic derivatives of CEUs, N-phenyl-4,5-dihydrooxazol-2-amines (Oxas) are two- to threefold more active than CEUs and share the same cytotoxic properties in B16F0 melanoma cells. Moreover, the CEU original covalent binding by an ester linkage on β-tubulin Glu198 and prohibitin Asp40 was maintained with Oxas. Surprisingly, we observed that Oxas were spontaneously formed from CEUs in the cell culture medium and were also detected within the cells. Our results suggest that the intramolecular cyclization of CEUs leads to active Oxas that should then be considered as the key intermediates for protein alkylation. These results will be useful for the design of new prodrugs for cancer chemotherapy. Copyright © 2011 Elsevier Inc. All rights reserved.

(R)-N-Methyl-3-(3′-[18F]fluoropropyl)phenoxy)-3-phenylpropanamine (18F-MFP3) as a potential PET imaging agent for norepinephrine transporter

PubMed Central

Nguyen, Vivien L.; Pichika, Rama; Bhakta, Paayal H.; Kant, Ritu; Mukherjee, Jogeshwar

2010-01-01

A decline of norepinephrine transporter (NET) level is associated with several psychiatric and neurological disorders. Therefore positron emission tomography (PET) imaging agents are greatly desired to study the NET pathway. We have developed a C-fluoropropyl analog of nisoxetine: (R)-N-methyl-3-(3′-[18F]fluoropropyl)phenoxy)-3-phenylpropanamine (18F-MFP3) as a new potential PET radiotracer for NET with the advantage of the longer half-life of fluorine-18 (110 min compared with carbon-11 (20 min). Synthesis of (R)-N-methyl-3-(3′-fluoropropyl)phenoxy)-3-phenylpropanamine (MFP3) was achieved in five steps starting from (S)-N-methyl-3-ol-3-phenylpropanamine in approx. 3–5% overall yields. In vitro binding affinity of nisoxetine and MFP3 in rat brain homogenates labeled with 3H-nisoxetine gave Ki values of 8.02 nM and 23 nM, respectively. For radiosynthesis of 18F-MFP3, fluorine-18 was incorporated into a tosylate precursor, followed by the deprotection of the N-BOC-protected amine group with a 15% decay corrected yield in 2.5 h. Reverse-phase chromatographic purification provided 18F-MFP3 in specific activities of >2000 Ci/mmol. Fluorine-18 labeled 18F-MFP3 has been produced in modest radiochemical yields and in high specific activities. Evaluation of 18F-MFP3 in animal imaging studies is in progress in order to validate this new fluorine-18 radiotracer for PET imaging of NET. PMID:20495670

Characterisation of a proposed internet synthesis of N,N-dimethyltryptamine using liquid chromatography/electrospray ionisation tandem mass spectrometry.

PubMed

Martins, Cláudia P B; Freeman, Sally; Alder, John F; Brandt, Simon D

2009-08-14

The psychoactive properties of N,N-dimethyltryptamine (DMT) are known to induce altered states of consciousness in humans. These properties attract great interest from clinical, neuroscientific, clandestine and forensic communities. The Breath of Hope Synthesis was reported on an internet website as a convenient two-step methodology for the preparation of DMT. The analytical characterisation of the first stage was the subject of previous publications by the authors and involved the thermal decarboxylation of tryptophan and the formation of tryptamine. The present study reports on the characterisation of the second step of this procedure which was based on the methylation of tryptamine. This employed methyl iodide and benzyltriethylammonium chloride/sodium hydroxide as a phase transfer catalyst. The reaction product was characterised by liquid chromatography/electrospray ionisation tandem mass spectrometry and orthogonal acceleration time-of-flight mass spectrometry. Quantitative evaluation was carried out in positive multiple reaction monitoring mode (MRM), which included synthesis of the identified reaction products. MRM screening of the product did not lead to the detection of DMT. Instead, 11.1% tryptamine starting material, 21.0% N,N,N-trimethyltryptammonium iodide (TMT) and 47.4% 1-N-methyl-TMT were detected. A 0.5% trace of the monomethylated N-methyltryptamine was also detected. This study demonstrated the impact on product purity of doubtful synthetic methodologies discussed on the internet.

Properties of styrene-maleic anhydride copolymers containing wood-based fillers

Treesearch

John Simonsen; Rodney Jacobson; Roger Rowell

1998-01-01

Recycled newsprint (ONP) and dry process aspen fiber were combined with styrene maleic anhydride (SMA) copolymers containing either 7 or 14 percent maleic anhydride. The fiber-filled SMA composites were equivalent or superior to unfilled SMA in strength, stiffness, and notched Izod impact strength. ONP performed surprisingly well as a filler. Unnotched Izod impact...

Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia.

PubMed

Kort, Naomi S; Ford, Judith M; Roach, Brian J; Gunduz-Bruce, Handan; Krystal, John H; Jaeger, Judith; Reinhart, Robert M G; Mathalon, Daniel H

2017-03-15

Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia. In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared. N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen's d = 1.14) and schizophrenia (Cohen's d = .85). Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Hydrazide and hydrazine reagents as reactive matrices for MALDI-MS to detect gaseous aldehydes.

PubMed

Shigeri, Yasushi; Ikeda, Shinya; Yasuda, Akikazu; Ando, Masanori; Sato, Hiroaki; Kinumi, Tomoya

2014-08-01

The reagents 19 hydrazide and 14 hydrazine were examined to function as reactive matrices for matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to detect gaseous aldehydes. Among them, two hydrazide (2-hydroxybenzohydrazide and 3-hydroxy-2-naphthoic acid hydrazide) and two hydrazine reagents [2-hydrazinoquinoline and 2,4-dinitrophenylhydrazine (DNPH)] were found to react efficiently with carbonyl groups of gaseous aldehydes (formaldehyde, acetaldehyde and propionaldehyde); these are the main factors for sick building syndrome and operate as reactive matrices for MALDI-MS. Results from accurate mass measurements by JMS-S3000 Spiral-TOF suggested that protonated ion peaks corresponding to [M + H](+) from the resulting derivatives were observed in all cases with the gaseous aldehydes in an incubation, time-dependent manner. The two hydrazide and two hydrazine reagents all possessed absorbances at 337 nm (wavelength of MALDI nitrogen laser), with, significant electrical conductivity of the matrix crystal and functional groups, such as hydroxy group and amino group, being important for desorption/ionization efficiency in MALDI-MS. To our knowledge, this is the first report that gaseous molecules could be derivatized and detected directly in a single step by MALDI-MS using novel reactive matrices that were derivatizing agents with the ability to enhance desorption/ionization efficiency. Copyright © 2014 John Wiley & Sons, Ltd.

Crystal structure of the co-crystal fac-tri-aqua-tris(thio-cyanato-κN)iron(III)-2,3-di-methyl-pyrazine (1/3).

PubMed

Kucheriv, Olesia I; Shylin, Sergii I; Ilina, Tetiana A; Dechert, Sebastian; Gural'skiy, Il'ya A

2015-04-01

In the crystal of the title compound, [Fe(NCS)3(H2O)3]·3C6H8N2, the Fe(III) cation is located on a threefold rotation axis and is coordinated by three N atoms of the thiocyanate anions and three water mol-ecules in a fac arrangement, forming a slightly distorted N3O3 octa-hedron. Stabilization within the crystal structure is provided by O-H⋯N hydrogen bonds; the H atoms from coordinating water mol-ecules act as donors to the N atoms of guest 2,3-di-methyl-pyrazine mol-ecules, leading to a three-dimensional supra-molecular framework.

Modulatory effect of phytoglycoprotein (38 kDa) on cyclin D1/CDK4 in BNL CL.2 cells induced by N-methyl-N'-nitro-N-nitrosoguanidine.

PubMed

Lee, Jin; Lim, Kye-Taek

2012-02-01

In the developmental stages of cancer, cell transformation occurs after the promotion stage and is a marker of cancer progression. This cell transformation is related to abnormal proliferation during the cancer initiation stage. The purpose of this study was to evaluate the effect of Styrax japonica Siebold et al. Zuccarin (SJSZ) glycoprotein on cell transformation in murine embryonic liver cells (BNL CL.2) following N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatment. To determine abnormal proliferation during the initiation stage, intracellular reactive oxygen species (ROS), phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), activities of cell cycle-related factors [cyclin D1/cyclin dependent kinase (CDK) 4], cell cycle inhibitors (p53, p21, and p27), nuclear factor (NF)-κB, and proliferating cell nuclear antigen (PCNA) were evaluated using Western blot analysis and real-time PCR. Our study demonstrated that SJSZ glycoprotein (50 μg/ml) reduces foci formation with combined treatment [MNNG and 12-O-tetradecanoyl phorbol-13-acetate] of BNL CL.2 cells. With regard to proliferation-related signals, our finding indicated that SJSZ glycoprotein (50 μg/ml) diminished the production of intracellular ROS, activity of phosphorylated ERK, p38 MAPK, NF-κB (p50 and p65), PCNA, and cyclin D1/CDK4 in MNNG-induced BNL CL.2 cells. Taken together, these results lead us to speculate that SJSZ glycoprotein can inhibit abnormal cell proliferation at the initiation stage of hepatocarcinogenesis.

Nitric oxide donors attenuate clongenic potential in rat C6 glioma cells treated with alkylating chemotherapeutic agents.

PubMed

Yang, Jir-Jei; Yin, Jiu-Haw; Yang, Ding-I

2007-05-11

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) kills tumor cells via multiple actions including alkylation and carbamoylation. Previously, we have reported that formation of S-nitrosoglutathione (GSNO) in glioma cells overexpressing inducible nitric oxide synthase (iNOS) contributed to nitric oxide (NO)-dependent carbamoylating chemoresistance against BCNU. To further characterize the effects of NO on alkylating cytotoxicity, colony formation assay was applied to evaluate the effects of various NO donors on rat C6 glioma cells challenged with alkylating agents. We demonstrate that NO donors including GSNO, diethylamine NONOate (DEA/NO), and sodium nitroprusside (SNP) substantially reduced the extent of colony formation in glioma cells treated with alkylating agents, namely methyl methanesulfonate (MMS), N-methyl-N-nitrosourea (MNU), and N-ethyl-N-nitrosourea (ENU). Without alkylating agents these NO-releasing agents alone had no effects on clongenic potential of rat C6 glioma cells. Among these three NO donors used, the effectiveness in potentiating alkylating cytotoxicity is in the order of "GSNO>DEA/NO>SNP" when applied at the same dosages. GSNO also exerted similar synergistic actions reducing the extents of colony formation when co-administrated with 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-hydrazine (compound #1), another alkylating agent that mimics the chloroethylating action of BCNU. Together with our previous findings, we propose that NO donors may be used as adjunct chemotherapy with alkylating agents for such malignant brain tumors as glioblastoma multiforme (GBM). In contrast, production of NO as a result of iNOS induction, such as that occurring after surgical resection of brain tumors, may compromise the efficacy of carbamoylating chemotherapy.

Chemopreventive effect of epigallocatechin-3-gallate (EGCG) and folic acid on the N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastrointestinal cancer in rat model.

PubMed

Xu, Qi; Yang, Chuan Hua; Liu, Qiang; Jin, Xi Feng; Xu, Xi Tao; Tong, Jin Lu; Xiao, Shu Dong; Ran, Zhi Hua

2011-06-01

To investigate the chemopreventive effect and mechanisms of epigallocatechin-3-gallate (EGCG) and folic acid on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastrointestinal cancer in rats, and to investigate and compare the combinatorial effects of EGCG and folic acid on the chemoprevention of gastrointestinal carcinogenesis. A total of 159 healthy male Wistar rats were randomly divided into seven groups to have the MNNG in drink (group M), MNNG in drink and EGCG in the feed (group ME), MNNG in drink and folic acid in the feed (group MF), MNNG in drink and EGCG+folic acid in the feed (group MEF), EGCG in the feed (group E), folic acid in the feed (group F) or normal feed (group C), respectively. At 44 weeks, all the rats were killed and assessed for the presence of gastrointestinal tumor. The occurrence of cancer was evaluated by histology. Ki-67 in cancerous tissues and in situ apoptosis were determined by immunohistochemical staining or terminal deoxyribonucleotide transferase-mediated nick-end labeling (TUNEL) assay, respectively. The experiment was completed in 157 rats (98.74%). As compared with group M, the tumor incidence of group MEF decreased significantly (P=0.011). Ki-67 expression in cancerous tissues of group ME and MEF also decreased significantly (P=0.038, P=0.009), while apoptosis of group ME, MF and MEF increased significantly (P=0.000, P=0.003, P=0.000). EGCG combined with folic acid has an obvious chemopreventive effect on gastrointestinal carcinogenesis induced by MNNG in rats. © 2011 The Authors. Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

Crystal structures of two mixed-valence copper cyanide complexes with N-methyl­ethylenedi­amine

PubMed Central

Sabatino, Alexander

2017-01-01

The crystal structures of two mixed-valence copper cyanide compounds involving N-methyl­ethylenedi­amine (meen), are described. In compound (I), poly[bis(μ3-cyanido-κ3 C:C:N)tris(μ2-cyanido-κ2 C:N)bis(N-methylethane-1,2-di­amine-κ2 N,N′)tricopper(I)copper(II)], [Cu4(CN)5(C3H10N2)2] or Cu4(CN)5meen2, cyanide groups link CuI atoms into a three-dimensional network containing open channels parallel to the b axis. In the network, two tetra­hedrally bound CuI atoms are bonded by the C atoms of two end-on bridging CN groups to form Cu2(CN)6 moieties with the Cu atoms in close contact at 2.560 (1) Å. Other trigonally bound CuI atoms link these units together to form the network. The CuII atoms, coordinated by two meen units, are covalently linked to the network via a cyanide bridge, and project into the open network channels. In the mol­ecular compound (II), [(N-methylethylenediamine-κ2 N,N′)copper(II)]-μ2-cyanido-κ2 C:N-[bis(cyanido-κC)copper(I)] monohydrate, [Cu2(CN)3(C3H10N2)2]·H2O or Cu2(CN)3meen2·H2O, a CN group connects a CuII atom coordinated by two meen groups with a trigonal–planar CuI atom coordinated by CN groups. The mol­ecules are linked into centrosymmetric dimers via hydrogen bonds to two water mol­ecules. In both compounds, the bridging cyanide between the CuII and CuI atoms has the N atom bonded to CuII and the C atom bonded to CuI, and the CuII atoms are in a square-pyramidal coordination. PMID:28217329

Nitrosoureas inhibit the stathmin-mediated migration and invasion of malignant glioma cells.

PubMed

Liang, Xing-Jie; Choi, Yong; Sackett, Dan L; Park, John K

2008-07-01

Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule-destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of nitrosoureas on these cell movement-related processes. Scratch wound-healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down-regulation of cellular stathmin levels and in the absence and presence of sublethal nitrosourea ([1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]; CCNU) concentrations. We show that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 micromol/L, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain, and that nitrosoureas may have therapeutic benefits in addition to their antiproliferative effects.

Nitrosoureas Inhibit the Stathmin Mediated Migration and Invasion of Malignant Glioma Cells

PubMed Central

Liang, Xing-Jie; Choi, Yong; Sackett, Dan L.; Park, John K.

2008-01-01

Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of nitrosoureas on these cell movement related processes. Scratch-wound healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down regulation of cellular stathmin levels and in the absence and presence of sub-lethal nitrosourea (CCNU; [1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]) concentrations. We demonstrate that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 μM, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain and that nitrosoureas may have therapeutic benefits in addition to their anti-proliferative effects. PMID:18593927

Synthesis, structural characterization and antitumor activity of a Ca(II) coordination polymer based on 4-formyl-1,3-benzenedisulfonate-2-furoic acid hydrazide ligands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tai, Xi-Shi, E-mail: taixs@wfu.edu.cn; Wang, Xin

2017-03-15

A new Ca(II) coordination polymer, ([CaL(H{sub 2}O){sub 4}] · (H{sub 2}O){sub 4}){sub n} (L = 4-formyl-1,3-benzenedisulfonate-2-furoic acid hydrazide) has been prepared by one-pot synthesis method. And it was characterized by elemental analysis, IR and thermal analysis. The result of X-ray single-crystal diffraction analysis shows that the Ca(II) complex molecules form one-dimensional chain structure by the bridging oxygen atoms. The anti-tumor activity of L ligand and the Ca(II) coordination polymer has also been studied.

Preparation and characterization of mucoadhesive nanoparticles of poly (methyl vinyl ether-co-maleic anhydride) containing glycyrrhizic acid intended for vaginal administration.

PubMed

Aguilar-Rosas, Irene; Alcalá-Alcalá, Sergio; Llera-Rojas, Viridiana; Ganem-Rondero, Adriana

2015-01-01

Traditional vaginal preparations reside in the vaginal cavity for relatively a short period of time, requiring multiple doses in order to attain the desired therapeutic effect. Therefore, mucoadhesive systems appear to be appropriate to prolong the residence time in the vaginal cavity. In the current study, mucoadhesive nanoparticles based on poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) intended for vaginal delivery of glycyrrhizic acid (GA) (a drug with well-known antiviral properties) were prepared and characterized. Nanoparticles were generated by a solvent displacement method. Incorporation of GA was performed during nanoprecipitation, followed by adsorption of drug once nanoparticles were formed. The prepared nanoparticles were characterized in terms of size, Z-potential, morphology, drug loading, interaction of GA with PVM/MA (by differential scanning calorimetry) and the in vitro interaction of nanoparticles with pig mucin (at two pH values, 3.6 and 5; with and without GA adsorbed). The preparation method led to nanoparticles of a mean diameter of 198.5 ± 24.3 nm, zeta potential of -44.8 ± 2.8 mV and drug loading of 15.07 ± 0.86 µg/mg polymer. The highest mucin interaction resulted at pH 3.6 for nanoparticles without GA adsorbed. The data obtained suggest the promise of using mucoadhesive nanoparticles of PVM/MA for intravaginal delivery of GA.

N-methyl-d-aspartate (NMDA) receptor antibodies encephalitis mimicking an autistic regression.

PubMed

Hacohen, Yael; Wright, Sukhvir; Gadian, Jonathan; Vincent, Angela; Lim, Ming; Wassmer, Evangeline; Lin, Jean-Pierre

2016-10-01

Expressive dysphasia and mutism are common clinical features in children and adults with N-methyl-d-aspartate receptor antibodies (NMDAR-Ab) encephalitis, and are likely to result from NMDAR hypofunction. A prodromal loss of social and communication skills can typify that of an autistic regression, particularly when presenting under the age of 3 years. Here we describe two toddlers who presented with developmental regression, particularly of their social communication skills, mimicking an autistic regression, who were found to have NMDAR-Ab in the serum and cerebrospinal fluid. Although both patients had some other neurological features, they were subtle, which resulted in delayed diagnosis of NMDAR-Ab encephalitis. Importantly, immunotherapy was beneficial in both patients, with significant improvement of their language skills and behaviour. © 2016 Mac Keith Press.

Physicochemical properties of an insensitive munitions compound, N-methyl-4-nitroaniline (MNA).

PubMed

Boddu, Veera M; Abburi, Krishnaiah; Maloney, Stephen W; Damavarapu, Reddy

2008-06-30

Accurate information on physicochemical properties of an organic contaminant is essential for predicting its environmental impact and fate. These properties also provide invaluable information for the overall understanding of environmental distribution, biotransformation, and potential treatment processes. In this study the aqueous solubility (Sw), octanol-water partition coefficient (Kow), and Henry's law constant (K(H)) were determined for an insensitive munitions (IM) compound, N-methyl-4-nitroaniline (MNA), at 298.15, 308.15, and 318.15 K. Effect of ionic strength on solubility, using electrolytes such as NaCl and CaCl2, was also studied. The data on the physicochemical parameters were correlated using the standard Van't Hoff equation. All three properties exhibited a linear relationship with reciprocal temperature. The enthalpy and entropy of phase transfer were derived from the experimental data.

DNA methylation profiling identifies global methylation differences and markers of adrenocortical tumors.

PubMed

Rechache, Nesrin S; Wang, Yonghong; Stevenson, Holly S; Killian, J Keith; Edelman, Daniel C; Merino, Maria; Zhang, Lisa; Nilubol, Naris; Stratakis, Constantine A; Meltzer, Paul S; Kebebew, Electron

2012-06-01

It is not known whether there are any DNA methylation alterations in adrenocortical tumors. The objective of the study was to determine the methylation profile of normal adrenal cortex and benign and malignant adrenocortical tumors. Genome-wide methylation status of CpG regions were determined in normal (n = 19), benign (n = 48), primary malignant (n = 8), and metastatic malignant (n = 12) adrenocortical tissue samples. An integrated analysis of genome-wide methylation and mRNA expression in benign vs. malignant adrenocortical tissue samples was also performed. Methylation profiling revealed the following: 1) that methylation patterns were distinctly different and could distinguish normal, benign, primary malignant, and metastatic tissue samples; 2) that malignant samples have global hypomethylation; and 3) that the methylation of CpG regions are different in benign adrenocortical tumors by functional status. Normal compared with benign samples had the least amount of methylation differences, whereas normal compared with primary and metastatic adrenocortical carcinoma samples had the greatest variability in methylation (adjusted P ≤ 0.01). Of 215 down-regulated genes (≥2-fold, adjusted P ≤ 0.05) in malignant primary adrenocortical tumor samples, 52 of these genes were also hypermethylated. Malignant adrenocortical tumors are globally hypomethylated as compared with normal and benign tumors. Methylation profile differences may accurately distinguish between primary benign and malignant adrenocortical tumors. Several differentially methylated sites are associated with genes known to be dysregulated in malignant adrenocortical tumors.

Promoter hypermethylation of mismatch repair gene hMLH1 predicts the clinical response of malignant astrocytomas to nitrosourea.

PubMed

Fukushima, Takao; Katayama, Yoichi; Watanabe, Takao; Yoshino, Atsuo; Ogino, Akiyoshi; Ohta, Takashi; Komine, Chiaki

2005-02-15

In certain types of human cancers, transcriptional inactivation of hMLH1 by promoter hypermethylation plays a causal role in the loss of mismatch repair functions that modulate cytotoxic pathways in response to DNA-damaging agents. The aim of the present study was to investigate the role of promoter methylation of the hMLH1 gene in malignant astrocytomas. We examined the hMLH1 promoter methylation in a homogeneous cohort of patients with 41 malignant astrocytomas treated by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-2(2-chloroethyl)-3-nitrosourea chemotherapy in combination with radiation and interferon therapy, and assessed the correlation of such methylation with clinical outcome. hMLH1 promoter methylation was found in 6 (15%) of the 41 newly diagnosed malignant astrocytomas. Hypermethylation of the hMLH1 promoter corresponded closely with a loss of immunohistochemical staining for hMLH1 protein (P = 0.0013). Patients with hMLH1-methylated tumors displayed a greater chance of responding to adjuvant therapy as compared with those with hMLH1-unmethylated tumors (P = 0.0150). The presence of hMLH1 hypermethylation was significantly associated with a longer progression-free survival on both univariate analysis (P = 0.0340) and multivariate analysis (P = 0.0161). The present study identified hMLH1 methylation status as a predictor of the clinical response of malignant astrocytomas to chloroethylnitrosourea-based adjuvant therapy. The findings obtained suggest that determination of the methylation status of hMLH1 could provide a potential basis for designing rational chemotherapeutic strategies, as well as for predicting prognosis.

Photolabeling of tonoplast from sugar beet cell suspensions by [h]5-(N-methyl-N-isobutyl)-amiloride, an inhibitor of the vacuolar na/h antiport.

PubMed

Barkla, B J; Charuk, J H; Cragoe, E J; Blumwald, E

1990-07-01

The effects of 5-(N-methyl-N-isobutyl)-amiloride (MIA), an amiloride analog, was tested on the Na(+)/H(+) antiport activity of intact vacuoles and tonoplast vesicles isolated from sugar beet (Beta vulgaris L.) cell suspension cultures. MIA inhibited Na(+)/H(+) exchange in a competitive manner with a K(i) of 2.5 and 5.9 micromolar for DeltapH-dependent (22)Na(+) influx in tonoplast vesicles and Na(+)-dependent H(+) efflux in intact vacuoles, respectively. Scatchard analysis of the binding of [(3)H]MIA to tonoplast membranes revealed a high affinity binding component with a K(d) of 1.3 micromolar. The close relationship between the dissociation constant value obtained and the constants of inhibition for MIA obtained by fluorescence quenching and isotope exchange suggests that the high affinity component represents a class of sites associated with the tonoplast Na(+)/H(+) antiport. Photolabeling of the tonoplast with [(3)H]MIA revealed two sets of polypeptides with a different affinity to amiloride and its analog.

New nitrosoureas and their spin-labeled derivatives influence dopa-oxidase activity of tyrosinase.

PubMed

Rachkova, M; Raikova, E; Raikov, Z

1991-06-01

Tyrosinase is a key enzyme in melanine biosynthesis. The modulating effect of cytostatic agents on DOPA-oxidase activity of tyrosinase could be linked with the drug treatment of melanoma tumors. Two groups of nitrosoureas which influence DOPA-oxidase activity of tyrosinase were studied: new nitrosoureas and their spin-labeled derivatives synthesized in our laboratory. Using Burnett's spectrophotometric method (Burnett et al., 1967) the following effects were established: inhibition by CCNU, inhibition and the activating effects of the other investigated nitrosoureas depend on their physicochemical half-life. The predominant activating effect of the spin-labeled derivatives is due to the nitroxyl radical present in these compounds.

Antinociceptive effect and mechanism of action of isatin, N-methyl isatin and oxopropyl isatin in mice.

PubMed

Giorno, Thais Biondino Sardella; Silva, Bárbara Vasconcellos da; Pinto, Angelo da Cunha; Fernandes, Patricia Dias

2016-04-15

There has been growing interest in the synthesis of new derivatives from isatin, found in Isatis genus. Our objectives were to characterize the antinociceptive mechanism of action of isatin, N-methyl-isatin (MI) and N-methyl-3-(2-oxopropyl)-3-hydroxy-2-oxindole (MOI). Substances (0.1-10mg/kg, p.o.) were studied in chemical (paw licking induced by formalin, capsaicin or glutamate) or thermal (hot plate) models of nociception. The involvement of several systems was evaluated using different receptor antagonists. All three substances inhibit both phases of formalin-induced licking, increase the area under the curve and MI and MOI have a higher effect than that of morphine (in hot plate). Capsaicin and glutamate-induced licking were also reduced by all three substances. In the hot plate model, the antinociceptive effect of isatin was reduced by naloxone and atropine; naloxone, atropine and L-NAME reduced MI effect while naloxone, atropine, L-NAME, mecamylamine and ondansetron reduced MOI effect. Our results suggest that isatin, MI and MOI: 1) present activity in models of nociception; 2) capsaicin and glutamate receptors seems to participate in the mechanism of action; 3) opioid, cholinergic, serotoninergic, nitrergic and adrenergic systems may be involved, at least in part, in the mechanism of action of some of these substances. Copyright © 2016 Elsevier Inc. All rights reserved.

Prediction of N-Methyl-D-Aspartate Receptor GluN1-Ligand Binding Affinity by a Novel SVM-Pose/SVM-Score Combinatorial Ensemble Docking Scheme.

PubMed

Leong, Max K; Syu, Ren-Guei; Ding, Yi-Lung; Weng, Ching-Feng

2017-01-06

The glycine-binding site of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN1 is a potential pharmacological target for neurodegenerative disorders. A novel combinatorial ensemble docking scheme using ligand and protein conformation ensembles and customized support vector machine (SVM)-based models to select the docked pose and to predict the docking score was generated for predicting the NMDAR GluN1-ligand binding affinity. The predicted root mean square deviation (RMSD) values in pose by SVM-Pose models were found to be in good agreement with the observed values (n = 30, r 2  = 0.928-0.988,  = 0.894-0.954, RMSE = 0.002-0.412, s = 0.001-0.214), and the predicted pK i values by SVM-Score were found to be in good agreement with the observed values for the training samples (n = 24, r 2  = 0.967,  = 0.899, RMSE = 0.295, s = 0.170) and test samples (n = 13, q 2  = 0.894, RMSE = 0.437, s = 0.202). When subjected to various statistical validations, the developed SVM-Pose and SVM-Score models consistently met the most stringent criteria. A mock test asserted the predictivity of this novel docking scheme. Collectively, this accurate novel combinatorial ensemble docking scheme can be used to predict the NMDAR GluN1-ligand binding affinity for facilitating drug discovery.

Prediction of N-Methyl-D-Aspartate Receptor GluN1-Ligand Binding Affinity by a Novel SVM-Pose/SVM-Score Combinatorial Ensemble Docking Scheme

NASA Astrophysics Data System (ADS)

Leong, Max K.; Syu, Ren-Guei; Ding, Yi-Lung; Weng, Ching-Feng

2017-01-01

The glycine-binding site of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN1 is a potential pharmacological target for neurodegenerative disorders. A novel combinatorial ensemble docking scheme using ligand and protein conformation ensembles and customized support vector machine (SVM)-based models to select the docked pose and to predict the docking score was generated for predicting the NMDAR GluN1-ligand binding affinity. The predicted root mean square deviation (RMSD) values in pose by SVM-Pose models were found to be in good agreement with the observed values (n = 30, r2 = 0.928-0.988,  = 0.894-0.954, RMSE = 0.002-0.412, s = 0.001-0.214), and the predicted pKi values by SVM-Score were found to be in good agreement with the observed values for the training samples (n = 24, r2 = 0.967,  = 0.899, RMSE = 0.295, s = 0.170) and test samples (n = 13, q2 = 0.894, RMSE = 0.437, s = 0.202). When subjected to various statistical validations, the developed SVM-Pose and SVM-Score models consistently met the most stringent criteria. A mock test asserted the predictivity of this novel docking scheme. Collectively, this accurate novel combinatorial ensemble docking scheme can be used to predict the NMDAR GluN1-ligand binding affinity for facilitating drug discovery.

Weak maser emission of methyl formate toward Sagittarius B2(N) in the green bank telescope PRIMOS survey

DOE Office of Scientific and Technical Information (OSTI.GOV)

Faure, A.; Wiesenfeld, L.; Remijan, A. J.

A non-LTE radiative transfer treatment of cis-methyl formate (HCOOCH{sub 3}) rotational lines is presented for the first time using a set of theoretical collisional rate coefficients. These coefficients have been computed in the temperature range 5-30 K by combining coupled-channel scattering calculations with a high accuracy potential energy surface for HCOOCH{sub 3}-He. The results are compared to observations toward the Sagittarius B2(N) molecular cloud using the publicly available PRIMOS survey from the Green Bank Telescope. A total of 49 low-lying transitions of methyl formate, with upper levels below 25 K, are identified. These lines are found to probe a presumablymore » cold (∼30 K), moderately dense (∼10{sup 4} cm{sup –3}), and extended region surrounding Sgr B2(N). The derived column density of ∼4 × 10{sup 14} cm{sup –2} is only a factor of ∼10 larger than the column density of the trans conformer in the same source. Provided that the two conformers have the same spatial distribution, this result suggests that strongly non-equilibrium processes must be involved in their synthesis. Finally, our calculations show that all detected emission lines with a frequency below 30 GHz are (collisionally pumped) weak masers amplifying the continuum of Sgr B2(N). This result demonstrates the importance and generality of non-LTE effects in the rotational spectra of complex organic molecules at centimeter wavelengths.« less

Study on Desorption Process of n-Heptane and Methyl Cyclohexane Using UiO-66 with Hierarchical Pores.

PubMed

Chen, Sijia; Zhang, Lin; Zhang, Zhao; Qian, Gang; Liu, Zongjian; Cui, Qun; Wang, Haiyan

2018-06-06

UiO-66 (UiO for University of Oslo), is a zirconium-based MOF with reverse shape selectivity, gives an alternative way to produce high purity n-heptane used for the manufacture of high-purity pharmaceuticals. Couple of studies have shown that UiO-66 gives a high selectivity on the separation of n-/iso-alkanes. However, the microporous structure of UiO-66 causes poor mass transport during the desorption process. In this work, hierarchical-pore UiO-66 (H-UiO-66) was synthesized and utilized as an adsorbent of n-heptane (nHEP) and methyl cyclohexane (MCH) for systematically studying the desorption process of n/iso-alkanes. A suite of physical methods, including XRD patterns verified the UiO-66 structures and HRTEM showed the existence of hierarchical pores. N2 adsorption-desorption isotherms further confirmed the size distribution of hierarchical pores in H-UiO-66. Of particular note, the MCH/nHEP selectivity of H-UiO-66 is similar with UiO-66 in the same adsorption conditions, the desorption process of nHEP/MCH from H-UiO-66 is dramatically enhanced, viz, the desorption rates for nHEP/MCH from H-UiO-66 is enhanced by 30%/23% as comparing to UiO-66 at most. Moreover, desorption activation energy (Ed) derived from temperature-programmed desorption (TPD) experiments indicate that the Ed for nHEP/MCH is lower on H-UiO-66, i.e., the Ed of MCH on H-UiO-66 is ~37% lower than that on UiO-66 at most, leading to a milder condition for the desorption process. The introduction of hierarchical structures will be applicable for the optimization of desorption process during separation on porous materials.

Selective inhibition of ammonium oxidation and nitrification-linked N2O formation by methyl fluoride and dimethyl ether

USGS Publications Warehouse

Miller, L.G.; Coutlakis, M.D.; Oremland, R.S.; Ward, B.B.

1993-01-01

Methyl fluoride (CH3F) and dimethyl ether (DME) inhibited nitrification in washed-cell suspensions of Nitrosomonas europaea and in a variety of oxygenated soils and sediments. Headspace additions of CH3F (10% [vol/vol]) and DME (25% [vol/vol]) fully inhibited NO2- and N2O production from NH4+ in incubations of N. europaea, while lower concentrations of these gases resulted in partial inhibition. Oxidation of hydroxylamine (NH2OH) by N. europaea and oxidation of NO2- by a Nitrobacter sp. were unaffected by CH3F or DME. In nitrifying soils, CH3F and DME inhibited N2O production. In field experiments with surface flux chambers and intact cores, CH3F reduced the release of N2O from soils to the atmosphere by 20- to 30-fold. Inhibition by CH3F also resulted in decreased NO3- + NO2- levels and increased NH4+ levels in soils. CH3F did not affect patterns of dissimilatory nitrate reduction to ammonia in cell suspensions of a nitrate- respiring bacterium, nor did it affect N2O metabolism in denitrifying soils. CH3F and DME will be useful in discriminating N2O production via nitrification and denitrification when both processes occur and in decoupling these processes by blocking NO2- and NO3- production.

21 CFR 872.3490 - Carboxymethylcellulose sodium and/or polyvinylmethylether maleic acid calcium-sodium double salt...

Code of Federal Regulations, 2011 CFR

2011-04-01

... polyvinylmethylether maleic acid calcium-sodium double salt denture adhesive. 872.3490 Section 872.3490 Food and Drugs... maleic acid calcium-sodium double salt denture adhesive. (a) Identification. A carboxymethylcellulose sodium and/or polyvinylmethylether maleic acid calcium-sodium double salt denture adhesive is a device...

21 CFR 872.3490 - Carboxymethylcellulose sodium and/or polyvinylmethylether maleic acid calcium-sodium double salt...

Code of Federal Regulations, 2013 CFR

2013-04-01

... polyvinylmethylether maleic acid calcium-sodium double salt denture adhesive. 872.3490 Section 872.3490 Food and Drugs... maleic acid calcium-sodium double salt denture adhesive. (a) Identification. A carboxymethylcellulose sodium and/or polyvinylmethylether maleic acid calcium-sodium double salt denture adhesive is a device...

21 CFR 872.3490 - Carboxymethylcellulose sodium and/or polyvinylmethylether maleic acid calcium-sodium double salt...

Code of Federal Regulations, 2014 CFR

2014-04-01

... polyvinylmethylether maleic acid calcium-sodium double salt denture adhesive. 872.3490 Section 872.3490 Food and Drugs... maleic acid calcium-sodium double salt denture adhesive. (a) Identification. A carboxymethylcellulose sodium and/or polyvinylmethylether maleic acid calcium-sodium double salt denture adhesive is a device...

21 CFR 872.3490 - Carboxymethylcellulose sodium and/or polyvinylmethylether maleic acid calcium-sodium double salt...

Code of Federal Regulations, 2012 CFR

2012-04-01

... polyvinylmethylether maleic acid calcium-sodium double salt denture adhesive. 872.3490 Section 872.3490 Food and Drugs... maleic acid calcium-sodium double salt denture adhesive. (a) Identification. A carboxymethylcellulose sodium and/or polyvinylmethylether maleic acid calcium-sodium double salt denture adhesive is a device...

21 CFR 872.3490 - Carboxymethylcellulose sodium and/or polyvinylmethylether maleic acid calcium-sodium double salt...

Code of Federal Regulations, 2010 CFR

2010-04-01

... polyvinylmethylether maleic acid calcium-sodium double salt denture adhesive. 872.3490 Section 872.3490 Food and Drugs... maleic acid calcium-sodium double salt denture adhesive. (a) Identification. A carboxymethylcellulose sodium and/or polyvinylmethylether maleic acid calcium-sodium double salt denture adhesive is a device...

Continuous treatment of N-Methyl-p-nitro aniline (MNA) in an Upflow Anaerobic Sludge Blanket (UASB) bioreactor

PubMed Central

Olivares, Christopher I.; Wang, Junqin; Silva Luna, Carlos D.; Field, Jim A.; Abrell, Leif; Sierra-Alvarez, Reyes

2017-01-01

N-methyl-p-nitroaniline (MNA) is an ingredient of insensitive munitions (IM) compounds that serves as a plasticizer and helps reduce unwanted detonations. As its use becomes widespread, MNA waste streams will be generated, necessitating viable treatment options. We studied MNA biodegradation and its inhibition potential to, a representative anaerobic microbial population in wastewater treatment, methanogens. Anaerobic biodegradation and toxicity assays were performed and an up-flow anaerobic sludge blanket reactor (UASB) was operated to test continuous degradation of MNA. MNA was transformed almost stoichiometrically to N-methyl-p-phenylenediamine (MPD). MPD was not mineralized, however, it was readily autoxidized and polymerized extensively upon aeration at pH = 9. In the UASB reactor, MNA was fully degraded up to a loading rate of 297.5 μM MNA d-1). Regarding toxicity, MNA was very inhibitory to acetoclastic methanogens (IC50 = 103 μM) whereas MPD was much less toxic, causing only 13.9% inhibition at the highest concentration tested (1025 μM). The results taken as a whole indicate that anaerobic sludge can transform MNA to MPD continuously, and that the transformation decreases the cytotoxicity of the parent pollutant. MPD can be removed through extensive polymerization. These insights could help define efficient treatment options for waste streams polluted with MNA. PMID:26454121

Gestational N-hexane inhalation alters the expression of genes related to ovarian hormone production and DNA methylation states in adult female F1 rat offspring.

PubMed

Li, Hong; Zhang, Chenyun; Ni, Feng; Guo, Suhua; Wang, Wenxiang; Liu, Jing; Lu, Xiaoli; Huang, Huiling; Zhang, Wenchang

2015-12-15

Research has revealed that n-hexane can disrupt adult female endocrine functions; however, few reports have focused on endocrine changes in adult F1 females after maternal exposure during gestation. In this study, female Wistar rats inhaled 100, 500, 2500, or 12,500 ppm n-hexane for 4 h daily during their initial 20 gestational days. The F1 female offspring exhibited abnormal oestrus cycles. Compared with the controls, the in vitro-cultured ovarian granulosa cells of the 12,500 ppm group showed significantly reduced in vitro progesterone and oestradiol secretion. Elevated progesterone secretion was observed in the 500 ppm group, and decreased and significantly upregulated mRNA expression of the Star, Cyp11a1, Cyp17a1, and Hsd3b genes was observed in the 12,500 ppm and 500 ppm groups, respectively. The protein expression levels were consistent with the mRNA expression levels. Methylation screening of the promoter regions of these genes was performed using MeDIP-chip and confirmed by methylation-sensitive high-resolution melting (MS-HRM), and the observed methylation state changes of the promoter regions were correlated with the gene expression levels. The results suggest that the hormone levels in the female offspring after gestational n-hexane inhalation correspond to the expression levels and DNA methylation states of the hormone production genes. Copyright © 2015. Published by Elsevier Ireland Ltd.

N4-cytosine DNA methylation regulates transcription and pathogenesis in Helicobacter pylori

PubMed Central

Kumar, Sumith; Karmakar, Bipul C; Nagarajan, Deepesh; Mukhopadhyay, Asish K; Morgan, Richard D; Rao, Desirazu N

2018-01-01

Abstract Many bacterial genomes exclusively display an N4-methyl cytosine base (m4C), whose physiological significance is not yet clear. Helicobacter pylori is a carcinogenic bacterium and the leading cause of gastric cancer in humans. Helicobacter pylori strain 26695 harbors a single m4C cytosine methyltransferase, M2.HpyAII which recognizes 5′ TCTTC 3′ sequence and methylates the first cytosine residue. To understand the role of m4C modification, M2.hpyAII deletion strain was constructed. Deletion strain displayed lower adherence to host AGS cells and reduced potential to induce inflammation and apoptosis. M2.hpyAII gene deletion strain exhibited reduced capacity for natural transformation, which was rescued in the complemented strain carrying an active copy of M2.hpyAII gene in the genome. Genome-wide gene expression and proteomic analysis were carried out to discern the possible reasons behind the altered phenotype of the M2.hpyAII gene deletion strain. Upon the loss of m4C modification a total of 102 genes belonging to virulence, ribosome assembly and cellular components were differentially expressed. The present study adds a functional role for the presence of m4C modification in H. pylori and provides the first evidence that m4C signal acts as a global epigenetic regulator in H. pylori. PMID:29481677

Solubility of nitrous oxide in aqueous blends of N-methyldiethanolamine and 2-amino-2-methyl-1-propanol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Davis, R.A.; Pogainis, B.J.

1995-11-01

Aqueous solutions of alkanolamines have applications in acid gas treatment for the removal of acid gases such as carbon dioxide and hydrogen sulfide. The solubility of nitrous oxide in aqueous blends of N-methyldiethanolamine and 2-amino-2-methyl-1 propanol was measured over the temperature range 10--60 C. The total composition of the alkanolamines in water ranged from 30 to 50 mass %. The experimental results were interpreted in terms of Henry`s constants.

Octahedral d[sup 6] Bis(maleimide) and Bis(maleic anhydride) complexes of molybdenum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lai, Chen-Hsing; Cheng, Chien-Hong; Liao, Fen-Ling

1993-12-08

Mo(CO)[sub 3](CH[sub 3]CN)[sub 3] reacts with 2 equiv of alkene, where the alkene is maleimide (MI), N-phenylmaleimide (PhMI), or N-methylmaleimide, to give the corresponding Mo(CO)[sub 2](alkene)[sub 2](CH[sub 3]CN)[sub 2] complex (1a-c, respectively) in excellent yield. Dissolution of 1 in DMSO led to the substitution of acetonitrile ligands by DMSO to form the corresponding cis bis(DMSO) complexes 2a-c. Addition of 1 equiv of NN to 1 yields MO(CO)[sub 2](alkene)[sub 2](alkene)[sub 2](NN) (NN = en, alkene = PhMI (3b), MeMI (3c); NN = o-phenylenediamine, alkene = PhMI (4)). Treatment of Mo-(CO)[sub 4](NN) (NN = phen or bpy), with 2 equiv of alkenemore » in refluxed acetonitrile for 2 h gave Mo(CO)[sub 2]-(alkene)[sub 2](NN) (NN = phen, alkene = MI (5a), PhMI (5b); NN = bpy, alkene = MI (6a), PhMI (6b)). Treatment of Mo(CO)[sub 3](CH[sub 3]CN)[sub 3] with 2 equiv of maleic anhydride (MA) gave Mo(CO)[sub 2](MA)[sub 2](CH[sub 3]CN)[sub 2] (7). The acetonitrile ligands in 7 were replaced by DMSO molecules to give complex 8 as 7 was dissolved in DMSO. Similarly, the reaction of 7 with a bidentate ligand NN (phen or bpy) gave the substituted product Mo(CO)[sub 2](MA)[sub 2](NN) (9 or 10). The structures and conformations of 1b and 7 were determined by X-ray diffraction. Both molecules adopt an octahedral geometry with mutually perpendicular trans alkene ligands and each alkene ligand eclipses a N-Mo-CO vector. Each PhMI or MA is oriented so that the central nitrogen or oxygen atom points to a carbonyl group. 1b crystallizes in triclinic space group P1. There are three possible conformations for a trans bis(maleimide) or bis(maleic anhydride) complex (I-III). The results of X-ray and NMR studies indicated that the main conformation of complexes 1-10 is I both in the solid state and in solution.« less

A new comprehensive technique of catheterisation, blood sampling, sample preparation and sample analysis by means of high-pressure liquid chromatography for pharmacokinetic studies with estradiol-linked nitrosoureas and their metabolites.

PubMed

Betsch, B; Berger, M R; Spiegelhalder, B

1990-09-01

Estradiol-linked nitrosoureas are offering new perspectives in the antineoplastic chemotherapy of estradiol-receptor positive mammary carcinomas. In such a molecule estradiol has the function of a carrier which brings about a specific accumulation of the anticancer drug in estradiol-receptor containing tumor cells. However, there is only little knowledge about the pharmacokinetic behavior of this new group of anticancer agents. For that reason a new comprehensive technique of catheterisation, blood sampling, sample preparation and sample analysis with high-pressure liquid chromatography (HPLC) for preclinical pharmacokinetic studies with estradiol-linked nitrosoureas and their metabolites has been developed. N-(2-Chloroethyl)-N-nitroso-carbamoyl-L-alanine-estradiol-17-ester (CNC-alanine-estradiol-17-ester) and N-(2-chloroethyl)-N-nitroso-carbamoyl-L-alanine (CNC-alanine) were used as test compounds. The drugs were tested in female Sprague-Dawley rats with chemically induced mammary carcinomas. The laboratory animals were supplied with two catheters prior to the pharmacokinetic experiments. The blood samples were drawn from the vena cava catheter after the drug had been applied through a vena jugularis catheter. The compounds were extracted from plasma with C18 silicagel reversed phase cartridges. The clean-up technique delivered clear samples only slightly contaminated with the biological matrix. The recovery from plasma was 75 +/- 5% for the hormone-linked CNC-alanine-estradiol-17-ester and 70 +/- 5% for the unlinked CNC-alanine. The analysis was carried out by means of HPLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-N-Methyl-D-aspartate Receptor Encephalitis: A Severe, Potentially Reversible Autoimmune Encephalitis.

PubMed

Liu, Cai-Yun; Zhu, Jie; Zheng, Xiang-Yu; Ma, Chi; Wang, Xu

2017-01-01

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is potentially lethal, but it is also a treatable autoimmune disorder characterized by prominent psychiatric and neurologic symptoms. It is often accompanied with teratoma or other neoplasm, especially in female patients. Anti-NMDAR antibodies in cerebrospinal fluid (CSF) and serum are characteristic features of the disease, thereby suggesting a pathogenic role in the disease. Here, we summarize recent studies that have clearly documented that both clinical manifestations and the antibodies may contribute to early diagnosis and multidisciplinary care. The clinical course of the disorder is reversible and the relapse could occur in some patients. Anti-NMDAR encephalitis coexisting with demyelinating disorders makes the diagnosis more complex; thus, clinicians should be aware of the overlapping diseases.

Anti-N-Methyl-D-aspartate Receptor Encephalitis: A Severe, Potentially Reversible Autoimmune Encephalitis

PubMed Central

Liu, Cai-yun; Zheng, Xiang-Yu; Ma, Chi

2017-01-01

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is potentially lethal, but it is also a treatable autoimmune disorder characterized by prominent psychiatric and neurologic symptoms. It is often accompanied with teratoma or other neoplasm, especially in female patients. Anti-NMDAR antibodies in cerebrospinal fluid (CSF) and serum are characteristic features of the disease, thereby suggesting a pathogenic role in the disease. Here, we summarize recent studies that have clearly documented that both clinical manifestations and the antibodies may contribute to early diagnosis and multidisciplinary care. The clinical course of the disorder is reversible and the relapse could occur in some patients. Anti-NMDAR encephalitis coexisting with demyelinating disorders makes the diagnosis more complex; thus, clinicians should be aware of the overlapping diseases. PMID:28698711

Cutoff in Potency Implicates Alcohol Inhibition of N-Methyl-D-Aspartate Receptors in Alcohol Intoxication

NASA Astrophysics Data System (ADS)

Peoples, Robert W.; Weight, Forrest F.

1995-03-01

As the number of carbon atoms in an aliphatic n-alcohol is increased from one to five, intoxicating potency, lipid solubility, and membrane lipid disordering potency all increase in a similar exponential manner. However, the potency of aliphatic n-alcohols for producing intoxication reaches a maximum at six to eight carbon atoms and then decreases. The molecular basis of this "cutoff" effect is not understood, as it is not correlated with either the lipid solubility or the membrane disordering potency of the alcohols, which continue to increase exponentially. Since it has been suggested that inhibition of N-methyl-D-aspartate (NMDA) receptors by alcohols may play a role in alcohol intoxication, we investigated whether a series of aliphatic n-alcohols would exhibit a cutoff in potency for inhibition of NMDA receptors. We found that although potency for inhibition of NMDA receptors increased exponentially for alcohols with one to five carbon atoms, potency for inhibition of NMDA receptors reached a maximum at six to eight carbon atoms and then abruptly disappeared. This cutoff for alcohol inhibition of NMDA receptors is consistent with an interaction of the alcohols with a hydrophobic pocket on the receptor protein. In addition, the similarity of the cutoffs for alcohol inhibition of NMDA receptors and alcohol intoxication suggests that the cutoff for NMDA receptor inhibition may contribute to the cutoff for alcohol intoxication, which is consistent with an important role of NMDA receptors in alcohol intoxication.

Fluorescence labeling of carbonylated lipids and proteins in cells using coumarin-hydrazide

PubMed Central

Vemula, Venukumar; Ni, Zhixu; Fedorova, Maria

2015-01-01

Carbonylation is a generic term which refers to reactive carbonyl groups present in biomolecules due to oxidative reactions induced by reactive oxygen species. Carbonylated proteins, lipids and nucleic acids have been intensively studied and often associated with onset or progression of oxidative stress related disorders. In order to reveal underlying carbonylation pathways and biological relevance, it is crucial to study their intracellular formation and spatial distribution. Carbonylated species are usually identified and quantified in cell lysates and body fluids after derivatization using specific chemical probes. However, spatial cellular and tissue distribution have been less often investigated. Here, we report coumarin-hydrazide, a fluorescent chemical probe for time- and cost-efficient labeling of cellular carbonyls followed by fluorescence microscopy to evaluate their intracellular formation both in time and space. The specificity of coumarin-hydrazide was confirmed in time- and dose-dependent experiments using human primary fibroblasts stressed with paraquat and compared with conventional DNPH-based immunocytochemistry. Both techniques stained carbonylated species accumulated in cytoplasm with strong perinuclear clustering. Using a complimentary array of analytical methods specificity of coumarin-hydrazide probe towards both protein- and lipid-bound carbonyls has been shown. Additionally, co-distribution of carbonylated species and oxidized phospholipids was demonstrated. PMID:25974625

Crystal structure of bis-(N-methyl-N-phenyl-amino)-tris-ulfane.

PubMed

Barany, George; Henley, Matthew J; Polski, Lauren A; Schroll, Alayne L; Young, Victor G

2015-07-01

The title compound, C14H16N2S3, crystallized with two independent mol-ecules [(1 a ) and (1 b )] in the asymmetric unit. Both mol-ecules display a pseudo-trans conformation. The two consecutive S-S bond lengths of the tris-ulfane unit of mol-ecule (1 a ) are 2.06 (3) and 2.08 (3) Å, and 2.08 (3) and 2.07 (2) Å for mol-ecule (1 b ). Torsion angles about each of the two S-S bonds are 86.6 (2) and 87.0 (2)° for (1 a ), and -84.6 (2) and -85.9 (2)° for (1 b ). The core atoms, viz. the N-S-S-S-N moiety, of the two mol-ecules superimpose well if one is inverted on the other, but the phenyl groups do not. Thus, the two units are essentially conformational enanti-omers. In mol-ecule (1 a ), the two phenyl rings are inclined to one another by 86.7 (3)°, and in mol-ecule (1 b ), by 81.1 (3)°. In the crystal, mol-ecules are linked via C-H⋯π inter-actions, forming sheets lying parallel to (010).

Cfr and RlmN contain a single [4Fe-4S] cluster, which directs two distinct reactivities for S-adenosylmethionine: methyl transfer by SN2 displacement and radical generation.

PubMed

Grove, Tyler L; Radle, Matthew I; Krebs, Carsten; Booker, Squire J

2011-12-14

The radical SAM (RS) proteins RlmN and Cfr catalyze methylation of carbons 2 and 8, respectively, of adenosine 2503 in 23S rRNA. Both reactions are similar in scope, entailing the synthesis of a methyl group partially derived from S-adenosylmethionine (SAM) onto electrophilic sp(2)-hybridized carbon atoms via the intermediacy of a protein S-methylcysteinyl (mCys) residue. Both proteins contain five conserved Cys residues, each required for turnover. Three cysteines lie in a canonical RS CxxxCxxC motif and coordinate a [4Fe-4S]-cluster cofactor; the remaining two are at opposite ends of the polypeptide. Here we show that each protein contains only the one "radical SAM" [4Fe-4S] cluster and the two remaining conserved cysteines do not coordinate additional iron-containing species. In addition, we show that, while wild-type RlmN bears the C355 mCys residue in its as-isolated state, RlmN that is either engineered to lack the [4Fe-4S] cluster by substitution of the coordinating cysteines or isolated from Escherichia coli cultured under iron-limiting conditions does not bear a C355 mCys residue. Reconstitution of the [4Fe-4S] cluster on wild-type apo RlmN followed by addition of SAM results in rapid production of S-adenosylhomocysteine (SAH) and the mCys residue, while treatment of apo RlmN with SAM affords no observable reaction. These results indicate that in Cfr and RlmN, SAM bound to the unique iron of the [4Fe-4S] cluster displays two reactivities. It serves to methylate C355 of RlmN (C338 of Cfr), or to generate the 5'-deoxyadenosyl 5'-radical, required for substrate-dependent methyl synthase activity. © 2011 American Chemical Society

GluN2B N-methyl-D-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats: implication for opiate-induced hyperalgesia.

PubMed

Gong, Kerui; Bhargava, Aditi; Jasmin, Luc

2016-01-01

The contribution of the peripheral nervous system to opiate-induced hyperalgesia (OIH) is not well understood. In this study, we determined the changes in excitability of primary sensory neurons after sustained morphine administration for 7 days. Changes in the expression of glutamate receptors and glutamate transporters after morphine administration were ascertained in dorsal root ganglions. Patch clamp recordings from intact dorsal root ganglions (ex vivo preparation) of morphine-treated rats showed increased excitability of small diameter (≤30 μm) neurons with respect to rheobase and membrane threshold, whereas the excitability of large diameter (>30 μm) neurons remained unchanged. Small diameter neurons also displayed increased responses to glutamate, which were mediated mainly by GluN2B containing N-methyl-D-aspartate (NMDA) receptors, and to a lesser degree by the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1. Coadministration in vivo of the GluN2B selective antagonist Ro 25-6981 with morphine for 7 days prevented the appearance of OIH and increased morphine-induced analgesia. Administration of morphine for 7 days led to an increased expression of GluN2B and excitatory amino acid transporter 3/excitatory amino acid carrier 1, but not of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate, kainate, or group I metabotropic glutamate receptors, or of the vesicular glutamate transporter 2. These results suggest that peripheral glutamatergic neurotransmission contributes to OIH and that GluN2B subunit of NMDA receptors in the periphery may be a target for therapy.

Chemical structure of carbamoylating groups and their relationship to bone marrow toxicity and antiglioma activity of bifunctionally alkylating and carbamoylating nitrosoureas.

PubMed

Ali-Osman, F; Giblin, J; Berger, M; Murphy, M J; Rosenblum, M L

1985-09-01

Although the antitumor effects of chloroethylnitrosoureas have been shown to be due primarily to DNA-DNA cross-linking by the alkylating moieties of these agents, the basis of the often accompanying bone marrow toxicity has been more controversial. We report on the relative bone marrow toxicity of four model nitrosoureas with different alkylating and carbamoylating activities: 1,3-bis(2-chloroethyl)-1-nitrosourea; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea; chlorozotozin, (2-[3-(2-chloroethyl)-3 -nitrosoureido]-2-deoxy-D-glucopyranose); and -3-(beta-D-glucopyranosyl)-1-nitrosourea. Inhibitions of DNA, RNA, and protein synthesis in murine bone marrow cells and of colony growth of myeloid precursor cells (granulocyte-macrophage colony-forming units) were used as in vitro end points of myelotoxicity. Further, we determined the antiglioma activity of the four nitrosoureas on two human gliomas in a clonogenic tumor cell assay and studied the effect of the non-nitrosourea carbamoylators potassium cyanate, chloroethyl isocyanate, cyclohexyl isocyanate, ethyl isocyanate, and ethyl isothiocyanate on granulocyte-macrophage colony-forming units. The results show that, at equivalent drug exposures, clonogenic glioma cell kill was significant and comparative for 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea, and chlorozotocin; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea showed little activity. In contrast, granulocyte-macrophage colony-forming unit toxicity was low with chlorozotocin and 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea and very high with 1,3-bis(2-chloroethyl)-1-nitrosourea and 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea. Of the isocyanates, bone marrow toxicity was highest with chloroethyl isocyanate and cyclohexyl isocyanate, intermediate with ethyl isocyanate, and lowest with KOCN and ethyl isothiocyanate. Our results indicate that (a) bifunctional alkylation is essential for

N-(/sup 11/C)-methyl-p-substituted phentermine analogs as potential brain blood flow agents for positron tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kizuka, H.; Elmaleh, D.R.; Boudreaux, G.J.

The addition of a methyl group to the ..cap alpha..-position of amphetamine increases both the lipophilicity of the agent and its resistance to metabolism by monoamine oxidase. In addition, since tritium substituted phenteramine analog studies suggested that the p-halo phentermines had a greater concentration in the brain and prolonged retention time, the authors evaluated the biological behavior of positron labeled ..cap alpha..-methylamphetamine (phenteramine) in rats, dogs and monkeys. The N-(/sup 11/C) methyl analogs of p-chloro (I) and p-fluoro (II) phentermines were prepared by methylation of their primary amines using /sup 11/Ch/sub 3/I. Biodistribution studies in rats shows brain uptake ismore » in the range of 1% dose/gr at 5 and 15 min for both agents. The activity in blood and eyes is low. Sequential images of the dogs' brain over 1 hour revealed a clearance of <15%. Images of the monkey brain were also obtained using a MGH positron camera PCR-I.« less

[Autoimmune encephalitis associated to antibodies against the N-methyl-D-aspartate receptor: Report of two cases].

PubMed

Bustos, José; Sánchez, Yasmin; Medina, Jhon; Olivieri, Rommy; Mojica, Julián; Ortiz, Johan

2017-04-01

Anti-N-methyl-D-aspartate receptor encephalitis is a neurological syndrome that is more common in young women and is often associated with ovarian teratoma. It is characterized by acute general unspecific symptoms that evolve to neurological deterioration, psychosis and seizures. In its more advanced stage it is associated with abnormal movements and dysautonomia.We report two cases in women of 23 and 12 years of age. Given its low incidence, we present the clinical exercise that led to their diagnoses and the treatment options employed.

Kinetics of Maleic Acid and Aluminum Chloride Catalyzed Dehydration and Degradation of Glucose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Ximing; Hewetson, Barron B.; Mosier, Nathan S.

We report the positive effect of maleic acid, a dicarboxylic acid, on the selectivity of hexose dehydration to 5-hydroxymethyfurfural (HMF) and subsequent hydrolysis to levulinic and formic acids. We also describe the kinetic analysis of a Lewis acid (AlCl3) alone and in combination with HCl or maleic acid to catalyze the isomerization of glucose to fructose, dehydration of fructose to HMF, hydration of HMF to levulinic and formic acids, and degradation of these compounds to humins. The results show that AlCl3 significantly enhances the rate of glucose conversion to HMF and levulinic acid in the presence of both maleic acidmore » and HCl. In addition, the degradation of HMF to humins, rather than levulinic and formic acids, is reduced by 50% in the presence of maleic acid and AlCl3 compared to HCl combined with AlCl3. The results suggest different reaction mechanisms for the dehydration of glucose and rehydration of HMF between maleic acid and HCl.« less

USE OF EXPOSURE-RELATED DOSE ESTIMATING MODEL (ERDEM) FOR ASSESSMENT OF AGGREGATE EXPOSURE OF INFANT AND CHILDREN TO N-METHYL CARBAMATE INSECTICIDES

EPA Science Inventory

A physiologically based pharmacokinetic (PBPK) model was developed within the Exposure Related Dose Estimating Model (ERDEM) framework to investigate selected exposure inputs related to recognized exposure scenarios of infants and children to N-methyl carbamate pesticides as spec...

Alkyl sulfonic acide hydrazides: Synthesis, characterization, computational studies and anticancer, antibacterial, anticarbonic anhydrase II (hCA II) activities

NASA Astrophysics Data System (ADS)

O. Ozdemir, Ummuhan; İlbiz, Firdevs; Balaban Gunduzalp, Ayla; Ozbek, Neslihan; Karagoz Genç, Zuhal; Hamurcu, Fatma; Tekin, Suat

2015-11-01

Methane sulfonic acide hydrazide, CH3SO2NHNH2 (1), ethane sulfonic acide hydrazide, CH3CH2SO2NHNH2 (2), propane sulfonic acide hydrazide, CH3CH2CH2SO2NHNH2 (3) and butane sulfonic acide hydrazide, CH3CH2CH2CH2SO2NHNH2 (4) have been synthesized as homologous series and characterized by using elemental analysis, spectrophotometric methods (1H-13C NMR, FT-IR, LC-MS). In order to gain insight into the structure of the compounds, we have performed computational studies by using 6-311G(d, p) functional in which B3LYP functional were implemented. The geometry of the sulfonic acide hydrazides were optimized at the DFT method with Gaussian 09 program package. A conformational analysis of compounds were performed by using NMR theoretical calculations with DFT/B3LYP/6-311++G(2d, 2p) level of theory by applying the (GIAO) approach. The anticancer activities of these compounds on MCF-7 human breast cancer cell line investigated by comparing IC50 values. The antibacterial activities of synthesized compounds were studied against Gram positive bacteria; Staphylococcus aureus ATCC 6538, Bacillus subtilis ATCC 6633, Bacillus cereus NRRL-B-3711, Enterococcus faecalis ATCC 29212 and Gram negative bacteria; Escherichia coli ATCC 11230, Pseudomonas aeruginosa ATCC 15442, Klebsiella pneumonia ATCC 70063 by using the disc diffusion method. The inhibition activities of these compounds on carbonic anhydrase II enzyme (hCA II) have been investigated by comparing IC50 and Ki values. The biological activity screening shows that butane sulfonic acide hydrazide (4) has more activity than the others against tested breast cancer cell lines MCF-7, Gram negative/Gram positive bacteria and carbonic anhydrase II (hCA II) isoenzyme.

Anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis show distinct patterns of brain glucose metabolism in 18F-fluoro-2-deoxy-d-glucose positron emission tomography

PubMed Central

2014-01-01

Background Pathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis. A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis. Methods The brain 18F-fluoro-2-deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N-methyl-D-aspartate receptor encephalitis patients and four patients with anti-leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls. Results Group analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism. Conclusions This retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis. PMID:24950993

Sensitization of human carcinoma cells to alkylating agents by small interfering RNA suppression of 3-alkyladenine-DNA glycosylase.

PubMed

Paik, Johanna; Duncan, Tod; Lindahl, Tomas; Sedgwick, Barbara

2005-11-15

One of the major cytotoxic lesions generated by alkylating agents is DNA 3-alkyladenine, which can be excised by 3-alkyladenine DNA glycosylase (AAG). Inhibition of AAG may therefore result in increased cellular sensitivity to chemotherapeutic alkylating agents. To investigate this possibility, we have examined the role of AAG in protecting human tumor cells against such agents. Plasmids that express small interfering RNAs targeted to two different regions of AAG mRNA were transfected into HeLa cervical carcinoma cells and A2780-SCA ovarian carcinoma cells. Stable derivatives of both cell types with low AAG protein levels were sensitized to alkylating agents. Two HeLa cell lines with AAG protein levels reduced by at least 80% to 90% displayed a 5- to 10-fold increase in sensitivity to methyl methanesulfonate, N-methyl-N-nitrosourea, and the chemotherapeutic drugs temozolomide and 1,3-bis(2-chloroethyl)-1-nitrosourea. These cells showed no increase in sensitivity to UV light or ionizing radiation. After treatment with methyl methanesulfonate, AAG knockdown HeLa cells were delayed in S phase but accumulated in G2-M. Our data support the hypothesis that ablation of AAG activity in human tumor cells may provide a useful strategy to enhance the efficacy of current chemotherapeutic regimens that include alkylating agents.

Prediction of N-Methyl-D-Aspartate Receptor GluN1-Ligand Binding Affinity by a Novel SVM-Pose/SVM-Score Combinatorial Ensemble Docking Scheme

PubMed Central

Leong, Max K.; Syu, Ren-Guei; Ding, Yi-Lung; Weng, Ching-Feng

2017-01-01

The glycine-binding site of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN1 is a potential pharmacological target for neurodegenerative disorders. A novel combinatorial ensemble docking scheme using ligand and protein conformation ensembles and customized support vector machine (SVM)-based models to select the docked pose and to predict the docking score was generated for predicting the NMDAR GluN1-ligand binding affinity. The predicted root mean square deviation (RMSD) values in pose by SVM-Pose models were found to be in good agreement with the observed values (n = 30, r2 = 0.928–0.988,  = 0.894–0.954, RMSE = 0.002–0.412, s = 0.001–0.214), and the predicted pKi values by SVM-Score were found to be in good agreement with the observed values for the training samples (n = 24, r2 = 0.967,  = 0.899, RMSE = 0.295, s = 0.170) and test samples (n = 13, q2 = 0.894, RMSE = 0.437, s = 0.202). When subjected to various statistical validations, the developed SVM-Pose and SVM-Score models consistently met the most stringent criteria. A mock test asserted the predictivity of this novel docking scheme. Collectively, this accurate novel combinatorial ensemble docking scheme can be used to predict the NMDAR GluN1-ligand binding affinity for facilitating drug discovery. PMID:28059133

Identification of radiolytic products from N-nitrosodimethylamine and N-nitrosopyrrolidine by gas chromatography and mass spectrometry

NASA Astrophysics Data System (ADS)

Ahn, Hyun-Joo; Lee, Cherl-Ho; Kim, Jae-Hyun; Han, Sang-Bae; Jo, Cheorun; Kim, Sung; Byun, Myung-Woo

2004-01-01

The radiolytic products of N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR) dissolved in dichloromethane (DCM) were identified after gamma irradiation. The UV spectra of NDMA and NPYR indicated that irradiation reduced the typical peak of NDMA at 258 nm and NPYR at 260 nm.The major radiolytic components identified in irradiated NDMA were ethyl acetate and 2-dimethyl propanol. The irradiated NPYR dissolved in DCM and produced 2-butanone and 2-methyl-6-propyl piperidine as the major radiolytic components. 2-Methyl-6-propyl piperidine was the component detected in the greatest concentration in irradiated NPYR.

Dermal absorption and urinary elimination of N-methyl-2-pyrrolidone.

PubMed

Bader, Michael; Keener, Stephen A; Wrbitzky, Renate

2005-09-01

The dermal absorption of the solvent N-methyl-2-pyrrolidone (NMP) and its elimination in urine was investigated in an experimental study. Seven volunteers were exposed to 1045 mg of liquid NMP under occlusive conditions for 2 h. Urine was collected before, during and up to 72 h after the exposure and analysed for NMP by GC/MS after liquid-liquid extraction. Additionally, the remaining NMP in the pads was determined to estimate the total dermal uptake. The concentration of NMP in urine increased rapidly after beginning of the exposure up to 1 h after the exposure was completed. A peak concentration of 1,836+/-863 microg/l was observed, the half-life in urine was 3.2 h. About 0.5% of the absorbed dose was excreted metabolically unchanged. An average dermal absorption of 5.5 mg cm(-2) h(-1) was calculated. The results of this study show that the percutaneous absorption of NMP may contribute significantly to the overall uptake of the solvent, e.g. in the workplace. Therefore, a biological monitoring of NMP exposed workers is essential for occupational-medical surveillance.

Crystal structure of ammonium/potassium trans-bis­(N-methyl­iminodi­acetato-κ3 O,N,O′)chromate(III) from synchrotron data

PubMed Central

Moon, Dohyun; Choi, Jong-Ha

2016-01-01

The structure of the title compound, [(NH4)0.8K0.2][Cr(C5H7NO4)2] (C5H7NO4 is methyl­iminodi­acetate; mida), has been determined from synchrotron data. The CrIII atom is located on a centre of symmetry and is coordinated by two N atoms and four O atoms of two facially arranged tridentate mida ligands, displaying a slightly distorted octa­hedral coordination environment. The Cr—N and mean Cr—O bond lengths are 2.0792 (14) and 1.958 (14) Å, respectively. The cation site is located on a twofold rotation axis and shows occupational disorder, being occupied by ammonium and potassium cations in a 0.8:0.2 ratio. In the crystal, inter­molecular hydrogen bonds involving the N—H groups of the ammonium cation as donor and the two non-coordinating O atoms of the carboxyl­ate group as acceptor groups consolidate the three-dimensional packing. PMID:27536411

Development of the sigma-1 receptor in C-terminals of motoneurons and colocalization with the N,N'-dimethyltryptamine forming enzyme, indole-N-methyl transferase.

PubMed

Mavlyutov, T A; Epstein, M L; Liu, P; Verbny, Y I; Ziskind-Conhaim, L; Ruoho, A E

2012-03-29

The function of the sigma-1 receptor (S1R) has been linked to modulating the activities of ion channels and G-protein-coupled receptors (GPCR). In the CNS, the S1R is expressed ubiquitously but is enriched in mouse motoneurons (MN), where it is localized to subsurface cisternae of cholinergic postsynaptic densities, also known as C-terminals. We found that S1R is enriched in mouse spinal MN at late stages of embryonic development when it is first visualized in the endoplasmic reticulum. S1Rs appear to concentrate at C-terminals of mouse MN only on the second week of postnatal development. We found that indole-N-methyl transferase (INMT), an enzyme that converts tryptamine into the sigma-1 ligand dimethyltryptamine (DMT), is also localized to postsynaptic sites of C-terminals in close proximity to the S1R. This close association of INMT and S1Rs suggest that DMT is synthesized locally to effectively activate S1R in MN. Published by Elsevier Ltd.

Choline exposure reduces potentiation of N-methyl-D-aspartate toxicity by corticosterone in the developing hippocampus.

PubMed

Mulholland, Patrick J; Self, Rachel L; Harris, Barton R; Littleton, John M; Prendergast, Mark A

2004-11-25

Exposure to high levels of glucocorticoids (GCs) may adversely affect neuronal viability, particularly in the developing hippocampus, via increased function or sensitivity of N-methyl-D-aspartate (NMDA)-type glutamate receptors. Conversely, choline supplementation in the developing brain may reduce the severity of subsequent insult. The present studies aimed to examine the extent to which short-term exposure to high concentrations of corticosterone would produce neuronal injury mediated by NMDA receptor activity. These studies also assessed the ability of choline to prevent this form of injury via interactions with nicotinic acetylcholine receptors (nAChRs) expressing the alpha7 subunit. Organotypic hippocampal slice cultures derived from neonatal rat were pre-treated for 72 h with corticosterone (100 nM) alone or with choline (0.1-10 mM), prior to a brief (1 h) NMDA exposure (5 microM). NMDA exposure produced significant cellular damage, reflected as increased fluorescence of the non-vital marker propidium iodide, in the CA1 region. While exposure to corticosterone alone did not produce damage, pre-treatment of cultures with corticosterone markedly exacerbated NMDA-induced toxicity. Pre-treatment with choline (> or =1 mM) alone or in combination with corticosterone markedly reduced subsequent NMDA toxicity, effects blocked by co-exposure to methyllycaconitine (100 nM), an antagonist active at nAChRs expressing the alpha7 subunit. These data suggest that even short-term exposure to high concentrations of GCs may adversely affect neuronal viability and that choline supplementation protects the brain from NMDA receptor-mediated damage, including that associated with hypercortisolemia.

ICAM-1 and AMPK regulate cell detachment and apoptosis by N-methyl-N Prime -nitro-N-nitrosoguanidine, a widely spread environmental chemical, in human hormone-refractory prostate cancers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Yi-Cheng; Lu, Pin-Hsuan; Hsu, Jui-Ling

2011-12-15

Poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, plays a crucial role in the regulation of DNA repair. PARP-1 hyperactivation causes DNA damage and cell death. The underlying mechanism is complicated and is through diverse pathways. The understanding of responsible signaling pathways may offer implications for effective therapies. After concentration-response determination of N-Methyl-N Prime -Nitro-N-Nitrosoguanidine (MNNG, a PARP-1 activating agent and an environmental mutagen) in human hormone-refractory prostate cancers, the data showed that concentrations below 5 {mu}M did not change cell survival but cause a time-dependent up-regulation of intracellular adhesion molecule-1 (ICAM-1) in mRNA, total protein and cell surface levels.more » Detection of phosphorylation and degradation of I{kappa}B-{alpha} and nuclear translocation of NF-{kappa}B showed that MNNG induced the activation of NF-{kappa}B that was responsible for the ICAM-1 up-regulation since PDTC (a NF-{kappa}B inhibitor) significantly abolished this effect. However, higher concentrations (e.g., 10 {mu}M) of MNNG induced a 61% detachment of the cells which were apoptosis associated with the activation of AMP-activated protein kinase (AMPK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Further identification showed that both AMPK and JNK other than p38 MAPK functionally contributed to cell death. The remaining 39% attached cells were survival associated with high ICAM-1 expression. In conclusion, the data suggest that NF-{kappa}B-dependent up-regulation of ICAM-1 plays a key role on cell attachment and survival; whereas, activation of AMPK and JNK participates in cytotoxic signaling pathways in detached cells caused by PARP-1 activation. Highlights: Black-Right-Pointing-Pointer Low level of DNA damage helps cell attachment and survival via ICAM-1 upregulation. Black-Right-Pointing-Pointer High level of DNA damage causes AMPK- and JNK-involved cell

Crystal structure of (E)-N′-{[(1R,3R)-3-isopropyl-1-methyl-2-oxo­cyclo­pent­yl]methyl­idene}-4-methyl­benzene­sulfono­hydrazide

PubMed Central

Tymann, David; Dragon, Dina Christina; Golz, Christopher; Preut, Hans; Strohmann, Carsten; Hiersemann, Martin

2015-01-01

The title compound, C17H24N2O3S, was synthesized in order to determine the relative configuration of the corresponding β-keto aldehyde. In the U-shaped mol­ecule, the five-membered ring approximates an envelope with the methyl­ene atom adjacent to the quaternary C atom being the flap. The dihedral angles between the four nearly coplanar atoms of the five-membered ring and the flap and the aromatic ring are 38.8 (4) and 22.9 (2)°, respectively. The bond angles around the S atom are in the range 104.11 (16)–119.95 (16)°. In the crystal, mol­ecules are linked via N—H⋯O by hydrogen bonds, forming a chain along the a-axis direction. PMID:25878892

N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia.

PubMed

Anticevic, Alan; Corlett, Philip R; Cole, Michael W; Savic, Aleksandar; Gancsos, Mark; Tang, Yanqing; Repovs, Grega; Murray, John D; Driesen, Naomi R; Morgan, Peter T; Xu, Ke; Wang, Fei; Krystal, John H

2015-03-15

Prefrontal cortex (PFC) function contributes to schizophrenia onset and progression. However, little is known about neural mechanisms behind PFC functional alterations along illness stages. Recent pharmacologic studies indicate that glutamate dysfunction may produce increased functional connectivity. However, pharmacologic models of schizophrenia overlook effects of illness progression on PFC function. This study compared N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist effects in healthy volunteers with stages of schizophrenia with respect to PFC functional connectivity. First, we tested ketamine effects on PFC functional connectivity in healthy volunteers in a data-driven way (n = 19). Next, we compared healthy subjects (n = 96) with three clinical groups: individuals at high risk for schizophrenia (n = 21), people early in their course of schizophrenia (EC-SCZ) (n = 28), and patients with chronic illness (n = 20). Across independent analyses, we used data-driven global brain connectivity techniques restricted to PFC to identify functional dysconnectivity. Results revealed robust PFC hyperconnectivity in healthy volunteers administered ketamine (Cohen's d = 1.46), resembling individuals at high risk for schizophrenia and EC-SCZ. Hyperconnectivity was not found in patients with chronic illness relative to EC-SCZ patients. Results provide the first evidence that ketamine effects on PFC functional connectivity resemble early course but not chronic schizophrenia. Results suggest an illness phase-specific relevance of NMDAR antagonist administration for prefrontal dysconnectivity associated with schizophrenia. This finding has implications for the neurobiology of illness progression and for the widespread use of NMDAR antagonists in the development of therapeutics for schizophrenia. Copyright © 2015. Published by Elsevier Inc.

Ultrasound assisted cocrystallization from solution (USSC) containing a non-congruently soluble cocrystal component pair: Caffeine/maleic acid.

PubMed

Aher, Suyog; Dhumal, Ravindra; Mahadik, Kakasaheb; Paradkar, Anant; York, Peter

2010-12-23

Ultrasound assisted solution cocrystallization (USSC) has been studied using a non-congruently soluble pair of caffeine and maleic acid in methanol. USSC was compared with solvent cooling and slurry sonication using different molar ratios of caffeine:maleic acid (1:0.5, 1:1, 1:2, 1:3 and 1:3.5) in solution/slurry. Products were characterized by PXRD and Raman spectroscopy techniques. In USSC trials, the content of cocrystal in the product was observed to increase with increase in amount of maleic acid in solution. Only USSC offered pure caffeine/maleic acid 2:1 cocrystal product when caffeine:maleic acid; 1:3.5 molar ratio was taken in solution. Caffeine/maleic acid 1:1 cocrystal and maleic acid were not obtained in neither of the techniques. Products of solvent cooling and slurry sonication experiments were mixtures of caffeine and caffeine/maleic acid 2:1 cocrystal in varying amounts. In USSC, ultrasound application must have attained simultaneous supersaturation of cocrystal components in solution due to altered supersaturation conditions resulting in cocrystal formation. For this simultaneous attainment of supersaturation, molar ratio of cocrystal components in solution was identified as an important parameter while designing experiments for a non-congruently soluble pair having large solubility difference. Copyright © 2010 Elsevier B.V. All rights reserved.

Role of choline and glycine betaine in the formation of N,N-dimethylpiperidinium (mepiquat) under Maillard reaction conditions.

PubMed

Bessaire, Thomas; Tarres, Adrienne; Stadler, Richard H; Delatour, Thierry

2014-01-01

This study is the first to examine the role of choline and glycine betaine, naturally present in some foods, in particular in cereal grains, to generate N,N-dimethylpiperidinium (mepiquat) under Maillard conditions via transmethylation reactions involving the nucleophile piperidine. The formation of mepiquat and its intermediates piperidine - formed by cyclisation of free lysine in the presence of reducing sugars - and N-methylpiperidine were monitored over time (240°C, up to 180 min) using high-resolution mass spectrometry in a model system comprised of a ternary mixture of lysine/fructose/alkylating agent (choline or betaine). The reaction yield was compared with data recently determined for trigonelline, a known methylation agent present naturally in coffee beans. The role of choline and glycine betaine in nucleophilic displacement reactions was further supported by experiments carried out with stable isotope-labelled precursors (¹³C- and deuterium-labelled). The results unequivocally demonstrated that the piperidine ring of mepiquat originates from the carbon chain of lysine, and that either choline or glycine betaine furnishes the N-methyl groups. The kinetics of formation of the corresponding demethylated products of both choline and glycine betaine, N,N-demethyl-2-aminoethanol and N,N-dimethylglycine, respectively, were also determined using high-resolution mass spectrometry.

Partial dissolution of ACQ-treated wood in lithium chloride/N-methyl-2-pyrrolidinone: Separation of copper from potential lignocellulosic feedstocks

Treesearch

Thomas L. Eberhardt; Stan Lebow; Karen G. Reed

2012-01-01

A cellulose solvent system based on lithium chloride (LiCl) in N-methyl-2-pyrrolidinone (NMP) was used to assess the merits of partial dissolutions of coarsely ground wood samples. Alkaline Copper Quaternary (ACQ)-treated pine wood was of particular interest for treatment given the potential to generate a copper- rich stream apart from solid and/or liquid...

Oriented antibody immobilization to polystyrene macrocarriers for immunoassay modified with hydrazide derivatives of poly(meth)acrylic acid

PubMed Central

Shmanai, Vadim V; Nikolayeva, Tamara A; Vinokurova, Ludmila G; Litoshka, Anatoli A

2001-01-01

Background Hydrophobic polystyrene is the most common material for solid phase immunoassay. Proteins are immobilized on polystyrene by passive adsorption, which often causes considerable denaturation. Biological macromolecules were found to better retain their functional activity when immobilized on hydrophilic materials. Polyacrylamide is a common material for solid-phase carriers of biological macromolecules, including immunoreagents used in affinity chromatography. New macroformats for immunoassay modified with activated polyacrylamide derivatives seem to be promising. Results New polymeric matrices for immunoassay in the form of 0.63-cm balls which contain hydrazide functional groups on hydrophilic polymer spacer arms at their surface shell are synthesized by modification of aldehyde-containing polystyrene balls with hydrazide derivatives of poly(meth)acrylic acid. The beads contain up to 0.31 μmol/cm2 active hydrazide groups accessible for covalent reaction with periodate-oxidized antibodies. The matrices obtained allow carrying out the oriented antibody immobilization, which increases the functional activity of immunosorbents. Conclusions An efficient site-directed antibody immobilization on a macrosupport is realized. The polymer hydrophilic spacer arms are the most convenient and effective tools for oriented antibody coupling with molded materials. The suggested scheme can be used for the modification of any other solid supports containing electrophilic groups reacting with hydrazides. PMID:11545680

Spectroscopic studies of the reaction between bovine serum amine oxidase (copper-containing) and some hydrazides and hydrazines.

PubMed Central

Morpurgo, L; Befani, O; Sabatini, S; Mondovì, B; Artico, M; Corelli, F; Massa, S; Stefancich, G; Avigliano, L

1988-01-01

The carbonyl cofactor of bovine serum amine oxidase, recently identified as pyrroloquinoline quinone [Ameyama, Hayashi, Matsushita, Shinagawa & Adachi (1984) Agric. Biol. Chem. 48, 561-565; Lobenstein-Verbeek, Jongejan, Frank & Duine (1984) FEBS Lett. 170, 305-309], reacts stoichiometrically and irreversibly with hydrazides of phenylacetic acid and of benzoic acid. With the phenylacetic hydrazides a reversible intermediate step was detected by competition with substrate, carbonylic reagents or phenylhydrazine, a typical inhibitor of the enzyme. All hydrazides form an intense broad band with maximum absorbance in a narrow wavelength range (350-360 nm), irrespective of the acyl group, suggesting that the transition is located on the organic cofactor. A different situation is found with some phenylhydrazines, where extended conjugation can occur between the cofactor and the phenyl pi-electron system via the azo group, as shown by the lower energy and higher intensity of the transition. In this case the transition is sensitive to substituents in the phenyl ring. The c.d. spectrum of the adducts is influenced by the type of hydrazide (derived from phenylacetic acid or benzoic acid), by pH and by NN-diethyldithiocarbamate binding to copper, probably as a result of shifts of equilibria between hydrazone-azo tautomers. PMID:3146976

Mutagenic interactions between X-rays and two promutagens, o-phenylenediamine and N-nitrosodimethylamine, in the stamen hairs of Tradescantia clone BNL 4430.

PubMed

Xiao, L Z; Ichikawa, S

1998-03-16

Mutagenic interactions between X-rays and two promutagens, o-phenylenediamine (PDA) and N-nitrosodimethylamine (DMN), were studied in the stamen hairs of Tradescantia clone BNL 4430, a blue/pink heterozygote. The young inflorescence-bearing shoots with roots of this clone cultivated in a nutrient solution circulating growth chamber were used as tester plants. After determining dose-response curves for X-rays. PDA and DMN, combined treatments with PDA or DMN and X-rays were conducted, exposing acutely to X-rays 20 h before starting, at the midpoint of, or 20 h after completing the PDA or DMN treatments for 4 h. Clear synergistic effects in inducing somatic pink mutations were detected when X-rays were irradiated before the PDA or DMN treatments, resembling those confirmed earlier between maleic hydrazide (MH) and X-rays. On the contrary, clear antagonistic effects were observed when X-rays were given after the PDA or DMN treatments, also resembling those between MH and X-rays. When X-rayed at the midpoint of the PDA or DMN treatments, merely additive and synergistic effects were observed, respectively, differing from the antagonistic effects between MH and X-rays. The mutagenic synergisms detected were considered to be the results of interactions between DNA strand breaks (and the resultant chromosome breaks) induced by X-rays and those by PDA or DMN, whereas the mutagenic antagonisms observed were presumed to be due to X-ray-caused inhibition of the activation of PDA and DMN in the stamen-hair cells. The time periods required for penetrations into floral tissues and/or activations into mutagens seem different among PDA, DMN and MH. Copyright 1998 Elsevier Science B.V.

Expression in mammalian cells of the Escherichia coli O6 alkylguanine-DNA-alkyltransferase gene ogt reduces the toxicity of alkylnitrosoureas.

PubMed Central

Harris, L. C.; Margison, G. P.

1993-01-01

V79 Chinese hamster cells expressing either the O6-alkylguanine-DNA-alkyltransferase (ATase) encoded by the E. coli ogt gene or a truncated version of the E. coli ada gene have been exposed to various alkylnitrosoureas to investigate the contribution of ATase repairable lesions to the toxicity of these compounds. Both ATases are able to repair O6-alkylguanine (O6-AlkG) and O4-alkylthymine (O4-AlkT) but the ogt ATase is more efficient in the repair of O4-methylthymine (O4-MeT) and higher alkyl derivatives of O6-AlkG than is the ada ATase. Expression of the ogt ATase provided greater protection against the toxic effects of the alkylating agents then the ada ATase particularly with N-ethyl-N-nitrosourea (ENU) and N-butyl-N-nitrosourea (BNU) to which the ada ATase expressing cells were as sensitive as parent vector transfected cells. Although ogt was expressed at slightly higher levels than the truncated ada in the transfected cells, this could not account for the differential protection observed. For-N-methyl-N-nitrosourea (MNU) the increased protection in ogt-transfected cells is consistent with O4-MeT acting as a toxic lesion. For the longer chain alkylating agents and chloroethylating agents, the protection afforded by the ogt protein may be a consequence of the more efficient repair of O6-AlkG, O4-AlkT or both of these lesions in comparison with the ada-encoded ATase. Images Figure 2 Figure 3 PMID:8512805

Mice over-expressing human O6 alkylguanine-DNA alkyltransferase selectively reduce O6 methylguanine mediated carcinogenic mutations to threshold levels after N-methyl-N-nitrosourea.

PubMed