Fumonisin FB1 treatment acts synergistically with methyl donor deficiency during rat pregnancy to produce alterations of H3- and H4-histone methylation patterns in fetuses.

Science.gov (United States)

Pellanda, Hélène; Forges, Thierry; Bressenot, Aude; Chango, Abalo; Bronowicki, Jean-Pierre; Guéant, Jean-Louis; Namour, Fares

2012-06-01

Prenatal folate and methyl donor malnutrition lead to epigenetic alterations that could enhance susceptibility to disease. Methyl-deficient diet (MDD) and fumonisin FB1 are risk factors for neural tube defects and cancers. Evidence indicates that FB1 impairs folate metabolism. Folate receptors and four heterochromatin markers were investigated in rat fetuses liver derived from dams exposed to MDD and/or FB1 administered at a dose twice higher than the provisional maximum tolerable daily intake (PMTDI = 2 μg/kg/day). Even though folate receptors transcription seemed up-regulated by methyl depletion regardless of FB1 treatment, combined MDD/FB1 exposure might reverse this up-regulation since folate receptors transcripts were lower in the MDD/FB1 versus MDD group. Methyl depletion decreased H4K20me3. Combined MDD/FB1 decreased H4K20me3 even more and increased H3K9me3. The elevated H3K9me3 can be viewed as a defense mechanism inciting the cell to resist heterochromatin disorganization. H3R2me2 and H4K16Ac varied according to this mechanism even though statistical significance was not consistent. Considering that humans are exposed to FB1 levels above the PMTDI, this study is relevant because it suggests that low doses of FB1 interact with MDD thus contributing to disrupt the epigenetic landscape. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Variations in DNA methylation, acetylated histone H4, and methylated histone H3 during Pinus radiata needle maturation in relation to the loss of in vitro organogenic capability.

Science.gov (United States)

Valledor, Luis; Meijón, Mónica; Hasbún, Rodrigo; Jesús Cañal, Maria; Rodríguez, Roberto

2010-03-15

Needle differentiation is a very complex process associated with the formation of a mature photosynthetic organ. From meristem differentiation to leaf maturation, gene control must play an important role switching required genes on and off to define tissue functions, with the epigenetic code being one of the main regulation mechanisms. In this work, we examined the connections between the variation in the levels of some epigenetic players (DNA methylation, acetylated histone H4 and histone H3 methylation at Lys 4 and Lys 9) at work during needle maturation. Our results indicate that needle maturation, which is associated with a decrease in organogenic capability, is related to an increase in heterochromatin-related epigenetic markers (high DNA methylation and low acetylated histone H4 levels, and the presence of histone H3 methylated at lys 9). Immunohistochemical analyses also showed that the DNA methylation of palisade parenchyma cell layers during the transition from immature to mature scions is associated with the loss of the capacity to induce adventitious organs. Copyright 2009 Elsevier GmbH. All rights reserved.

Arsenic activates the expression of 3β-HSD in mouse Leydig cells through repression of histone H3K9 methylation

DEFF Research Database (Denmark)

Alamdar, Ambreen; Xi, Guochen; Huang, Qingyu

2017-01-01

methylation. The results showed that H3K9me2/3 demethylase (JMJD2A) inhibitor, quercetin (Que) significantly attenuated the decrease of H3K9me2/3 and increase of 3β-HSD expression induced by arsenic. To further elucidate the mechanism for the activation of 3β-HSD, we determined the histone H3K9 methylation......Arsenic exposure has been associated with male reproductive dysfunction by disrupting steroidogenesis; however, the roles of epigenetic drivers, especially histone methylation in arsenic-induced steroidogenic toxicity remain not well documented. In this study, we investigated the role of histone H3...... lysine 9 (H3K9) methylation in steroidogenesis disturbance in mouse Leydig cells (MLTC-1) due to arsenic exposure. Our results indicated that mRNA and protein expression levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) were both significantly up-regulated while the rest of key genes involved...

DOT1L and H3K79 Methylation in Transcription and Genomic Stability.

Science.gov (United States)

Wood, Katherine; Tellier, Michael; Murphy, Shona

2018-02-27

The organization of eukaryotic genomes into chromatin provides challenges for the cell to accomplish basic cellular functions, such as transcription, DNA replication and repair of DNA damage. Accordingly, a range of proteins modify and/or read chromatin states to regulate access to chromosomal DNA. Yeast Dot1 and the mammalian homologue DOT1L are methyltransferases that can add up to three methyl groups to histone H3 lysine 79 (H3K79). H3K79 methylation is implicated in several processes, including transcription elongation by RNA polymerase II, the DNA damage response and cell cycle checkpoint activation. DOT1L is also an important drug target for treatment of mixed lineage leukemia (MLL)-rearranged leukemia where aberrant transcriptional activation is promoted by DOT1L mislocalisation. This review summarizes what is currently known about the role of Dot1/DOT1L and H3K79 methylation in transcription and genomic stability.

DOT1L and H3K79 Methylation in Transcription and Genomic Stability

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Katherine Wood

2018-02-01

Full Text Available The organization of eukaryotic genomes into chromatin provides challenges for the cell to accomplish basic cellular functions, such as transcription, DNA replication and repair of DNA damage. Accordingly, a range of proteins modify and/or read chromatin states to regulate access to chromosomal DNA. Yeast Dot1 and the mammalian homologue DOT1L are methyltransferases that can add up to three methyl groups to histone H3 lysine 79 (H3K79. H3K79 methylation is implicated in several processes, including transcription elongation by RNA polymerase II, the DNA damage response and cell cycle checkpoint activation. DOT1L is also an important drug target for treatment of mixed lineage leukemia (MLL-rearranged leukemia where aberrant transcriptional activation is promoted by DOT1L mislocalisation. This review summarizes what is currently known about the role of Dot1/DOT1L and H3K79 methylation in transcription and genomic stability.

Antagonism between DNA and H3K27 methylation at the imprinted Rasgrf1 locus

DEFF Research Database (Denmark)

Lindroth, Anders M; Park, Yoon Jung; McLean, Chelsea M

2008-01-01

At the imprinted Rasgrf1 locus in mouse, a cis-acting sequence controls DNA methylation at a differentially methylated domain (DMD). While characterizing epigenetic marks over the DMD, we observed that DNA and H3K27 trimethylation are mutually exclusive, with DNA and H3K27 methylation limited...... to the paternal and maternal sequences, respectively. The mutual exclusion arises because one mark prevents placement of the other. We demonstrated this in five ways: using 5-azacytidine treatments and mutations at the endogenous locus that disrupt DNA methylation; using a transgenic model in which the maternal...

Histone H4 Lysine 20 methylation

DEFF Research Database (Denmark)

Jørgensen, Stine; Schotta, Gunnar; Sørensen, Claus Storgaard

2013-01-01

of histones have emerged as key regulators of genomic integrity. Intense research during the past few years has revealed histone H4 lysine 20 methylation (H4K20me) as critically important for the biological processes that ensure genome integrity, such as DNA damage repair, DNA replication and chromatin...... compaction. The distinct H4K20 methylation states are mediated by SET8/PR-Set7 that catalyses monomethylation of H4K20, whereas SUV4-20H1 and SUV4-20H2 enzymes mediate further H4K20 methylation to H4K20me2 and H4K20me3. Disruption of these H4K20-specific histone methyltransferases leads to genomic...

Both H4K20 mono-methylation and H3K56 acetylation mark transcription-dependent histone turnover in fission yeast

International Nuclear Information System (INIS)

Yang, Hanna; Kwon, Chang Seob; Choi, Yoonjung; Lee, Daeyoup

2016-01-01

Nucleosome dynamics facilitated by histone turnover is required for transcription as well as DNA replication and repair. Histone turnover is often associated with various histone modifications such as H3K56 acetylation (H3K56Ac), H3K36 methylation (H3K36me), and H4K20 methylation (H4K20me). In order to correlate histone modifications and transcription-dependent histone turnover, we performed genome wide analyses for euchromatic regions in G2/M-arrested fission yeast. The results show that transcription-dependent histone turnover at 5′ promoter and 3′ termination regions is directly correlated with the occurrence of H3K56Ac and H4K20 mono-methylation (H4K20me1) in actively transcribed genes. Furthermore, the increase of H3K56Ac and H4K20me1 and antisense RNA production was observed in the absence of the histone H3K36 methyltransferase Set2 and histone deacetylase complex (HDAC) that are involved in the suppression of histone turnover within the coding regions. These results together indicate that H4K20me1 as well as H3K56Ac are bona fide marks for transcription-dependent histone turnover in fission yeast.

Both H4K20 mono-methylation and H3K56 acetylation mark transcription-dependent histone turnover in fission yeast

Energy Technology Data Exchange (ETDEWEB)

Yang, Hanna [Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 34141 (Korea, Republic of); Kwon, Chang Seob [Department of Chemistry and Biology, Korea Science Academy of KAIST, Busan, 614-822 (Korea, Republic of); Choi, Yoonjung, E-mail: jjungii@kaist.ac.kr [Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 34141 (Korea, Republic of); Lee, Daeyoup, E-mail: daeyoup@kaist.ac.kr [Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 34141 (Korea, Republic of)

2016-08-05

Nucleosome dynamics facilitated by histone turnover is required for transcription as well as DNA replication and repair. Histone turnover is often associated with various histone modifications such as H3K56 acetylation (H3K56Ac), H3K36 methylation (H3K36me), and H4K20 methylation (H4K20me). In order to correlate histone modifications and transcription-dependent histone turnover, we performed genome wide analyses for euchromatic regions in G2/M-arrested fission yeast. The results show that transcription-dependent histone turnover at 5′ promoter and 3′ termination regions is directly correlated with the occurrence of H3K56Ac and H4K20 mono-methylation (H4K20me1) in actively transcribed genes. Furthermore, the increase of H3K56Ac and H4K20me1 and antisense RNA production was observed in the absence of the histone H3K36 methyltransferase Set2 and histone deacetylase complex (HDAC) that are involved in the suppression of histone turnover within the coding regions. These results together indicate that H4K20me1 as well as H3K56Ac are bona fide marks for transcription-dependent histone turnover in fission yeast.

The neuronal metabolite NAA regulates histone H3 methylation in oligodendrocytes and myelin lipid composition.

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Singhal, N K; Huang, H; Li, S; Clements, R; Gadd, J; Daniels, A; Kooijman, E E; Bannerman, P; Burns, T; Guo, F; Pleasure, D; Freeman, E; Shriver, L; McDonough, J

2017-01-01

The neuronal mitochondrial metabolite N-acetylaspartate (NAA) is decreased in the multiple sclerosis (MS) brain. NAA is synthesized in neurons by the enzyme N-acetyltransferase-8-like (NAT8L) and broken down in oligodendrocytes by aspartoacylase (ASPA) into acetate and aspartate. We have hypothesized that NAA links the metabolism of axons with oligodendrocytes to support myelination. To test this hypothesis, we performed lipidomic analyses using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance thin-layer chromatography (HPTLC) to identify changes in myelin lipid composition in postmortem MS brains and in NAT8L knockout (NAT8L -/- ) mice which do not synthesize NAA. We found reduced levels of sphingomyelin in MS normal appearing white matter that mirrored decreased levels of NAA. We also discovered decreases in the amounts of sphingomyelin and sulfatide lipids in the brains of NAT8L -/- mice compared to controls. Metabolomic analysis of primary cultures of oligodendrocytes treated with NAA revealed increased levels of α-ketoglutarate, which has been reported to regulate histone demethylase activity. Consistent with this, NAA treatment resulted in alterations in the levels of histone H3 methylation, including H3K4me3, H3K9me2, and H3K9me3. The H3K4me3 histone mark regulates cellular energetics, metabolism, and growth, while H3K9me3 has been linked to alterations in transcriptional repression in developing oligodendrocytes. We also noted the NAA treatment was associated with increases in the expression of genes involved in sulfatide and sphingomyelin synthesis in cultured oligodendrocytes. This is the first report demonstrating that neuronal-derived NAA can signal to the oligodendrocyte nucleus. These data suggest that neuronal-derived NAA signals through epigenetic mechanisms in oligodendrocytes to support or maintain myelination.

2-(5-Fluoro-3-isopropylsulfanyl-7-methyl-1-benzofuran-2-ylacetic acid

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Hong Dae Choi

2012-04-01

Full Text Available The title compound, C14H15FO3S, was prepared by alkaline hydrolysis of ethyl 2-(5-fluoro-3-isopropylsulfanyl-7-methyl-1-benzofuran-2-ylacetate. In the crystal, molecules are linked via pairs of O—H...O hydrogen bonds, forming inversion dimers. These dimers are connected by weak C—H...O hydrogen bonds.

Relationship between Gene Body DNA Methylation and Intragenic H3K9me3 and H3K36me3 Chromatin Marks

OpenAIRE

Hahn, Maria A.; Wu, Xiwei; Li, Arthur X.; Hahn, Torsten; Pfeifer, Gerd P.

2011-01-01

To elucidate the relationship between intragenic DNA methylation and chromatin marks, we performed epigenetic profiling of chromosome 19 in human bronchial epithelial cells (HBEC) and in the colorectal cancer cell line HCT116 as well as its counterpart with double knockout of DNMT1 and DNMT3B (HCT116-DKO). Analysis of H3K36me3 profiles indicated that this intragenic mark of active genes is associated with two categories of genes: (i) genes with low CpG density and H3K9me3 in the gene body or ...

Reduced Histone H3 Lysine 9 Methylation Contributes to the Pathogenesis of Latent Autoimmune Diabetes in Adults via Regulation of SUV39H2 and KDM4C

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Xi-yu Liu

2017-01-01

Full Text Available Aims. Latent autoimmune diabetes in adults (LADA is an autoimmune disease of which the mechanism is not clear. Emerging evidence suggests that histone methylation contributes to autoimmunity. Methods. Blood CD4+ T lymphocytes from 26 LADA patients and 26 healthy controls were isolated to detect histone H3 lysine 4 and H3 lysine 9 methylation status. Results. Reduced global H3 lysine 9 methylation was observed in LADA patients’ CD4+ T lymphocytes, compared to healthy controls (P < 0.05. H3 lysine 4 methylation was not statistically different. The reduced H3 lysine 9 methylation was associated with GADA titer but not correlated with glycosylated hemoglobin (HbA1c. When the LADA patient group was divided into those with complication and those without, relatively reduced global H3 lysine 9 methylation was observed in LADA patients with complication (P < 0.05. The expression of histone methyltransferase SUV39H2 for H3 lysine 9 methylation was downregulated in LADA patients, and the expression of histone demethylase KDM4C which made H3 lysine 9 demethylation was upregulated. Conclusion. The reduction of histone H3 lysine 9 methylation which may due to the downregulation of methyltransferase SUV39H2 and the upregulation of demethylase KDM4C was found in CD4+ T lymphocytes of LADA patients.

2-Methyl-3-(2-methylphenyl-7-nitroquinazolin-4(3H-one

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Edward R. T. Tiekink

2012-03-01

Full Text Available In the title methaqualone analogue, C16H13N3O3, the 2-tolyl group is almost orthogonal [dihedral angle = 85.20 (5°] to the fused ring system (r.m.s. deviation of fitted non-H atoms = 0.029 Å. In the crystal, twofold symmetry generates two-molecule aggregates linked by C—H...O and π–π interactions [ring centroid–centroid distance = 3.4967 (6 Å].

Accumulation of histone variant H3.3 with age is associated with profound changes in the histone methylation landscape

DEFF Research Database (Denmark)

Tvardovskiy, Andrey; Schwämmle, Veit; Kempf, Stefan J

2017-01-01

a causal relationship between H3 variant replacement and age-dependent changes in H3 methylation. Furthermore, the H3.3 level is drastically reduced in human hepatocarcinoma cells as compared to nontumoral hepatocytes, suggesting the potential utility of the H3.3 relative abundance as a biomarker...

New Synthesis, Structure and Analgesic Properties of Methyl 1-R-4-Methyl-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxylates

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Liliana Azotla-Cruz

2017-01-01

Full Text Available According to the principles of the methodology of bioisosteric replacements a series of methyl 1-R-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates has been obtained as potential analgesics. In addition, a fundamentally new strategy for the synthesis of compounds of this chemical class involving the introduction of N-alkyl substituent at the final stage in 2,1-benzothiazine nucleus already formed has been proposed. Using nuclear magnetic resonance (NMR spectroscopy, mass spectrometry and X-ray diffraction analysis it has been proven that in the DMSO/K2CO3 system the reaction of methyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate and alkyl halides leads to formation of N-substituted derivatives with good yields regardless of the structure of the alkylating agent. The peculiarities of NMR (1Н and 13С spectra of the compounds synthesized, their mass spectrometric behavior and the spatial structure are discussed. In N-benzyl derivative the ability to form a monosolvate with methanol has been found. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick it has been determined that replacement of 4-ОН-group in methyl 1-R-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates for the methyl group is actually bioisosteric since all methyl 1-R-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates synthesized demonstrated a statistically significant analgesic effect. The majority of the substances can inhibit the thermal pain response much more effective than piroxicam in the same dose. Under the same conditions as an analgesic the N-methyl-substituted analog exceeds not only piroxicam, but more active meloxicam as well. Therefore, it deserves in-depth biological studies on other experimental models.

Role of H3K4 demethylases in complex neurodevelopmental diseases.

Science.gov (United States)

Wynder, Christopher; Stalker, Leanne; Doughty, Martin L

2010-06-01

Significant neurological disorders can result from subtle perturbations of gene regulation that are often linked to epigenetic regulation. Proteins that regulate the methylation of lysine 4 of histone H3 (H3K4) and play a central role in epigenetic regulation, and mutations in genes encoding these enzymes have been identified in both autism and Rett syndrome. The H3K4 demethylases remove methyl groups from lysine 4 leading to loss of RNA polymerase binding and transcriptional repression. When these proteins are mutated, brain development is altered. Currently, little is known regarding how these gene regulators function at the genomic level. In this article, we will discuss findings that link H3K4 demethylases to neurodevelopment and neurological disease.

Crystal structure of 1-ethylpyrazolo[3,4-d]pyrimidine-4(5H-thione

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Mohammed El Fal

2014-09-01

Full Text Available In the title compound, C7H8N4S, the methyl C atom is displaced by 1.232 (7 Å from the mean plane of the pyrazolo[3,4-d]pyrimidine ring system (r.m.s. deviation = 0.007 Å. The N—N—C—Cm (m = methyl torsion angle is −60.3 (6°. In the crystal, molecules are linked by N—H...S hydrogen bonds, generating [010] chains, which are reinforced by C—H...N interactions. The chains are cross-linked by weak C—H...S hydrogen bonds, generating (001 sheets.

1-[3-(2-Methyl-4-phenylquinolin-3-yl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-propane-1-one

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Allaoua Kedjadja

2015-06-01

Full Text Available A novel compound, 1-[3-(2-methyl-4-phenylquinolin-3-yl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-propane-1-one (3 has been synthesized by cyclocondensation of (E-1-(2-methyl-4-phenylquinolin-3-yl-3-phenylprop-2-en-1-one (2 and hydrazine hydrate in propionic acid. The structure of this compound was established by elemental analysis, IR, 1H-NMR, 13C-NMR and MS data.

Dynamic acetylation of all lysine 4-methylated histone H3 in the mouse nucleus: analysis at c-fos and c-jun.

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Catherine A Hazzalin

2005-12-01

Full Text Available A major focus of current research into gene induction relates to chromatin and nucleosomal regulation, especially the significance of multiple histone modifications such as phosphorylation, acetylation, and methylation during this process. We have discovered a novel physiological characteristic of all lysine 4 (K4-methylated histone H3 in the mouse nucleus, distinguishing it from lysine 9-methylated H3. K4-methylated histone H3 is subject to continuous dynamic turnover of acetylation, whereas lysine 9-methylated H3 is not. We have previously reported dynamic histone H3 phosphorylation and acetylation as a key characteristic of the inducible proto-oncogenes c-fos and c-jun. We show here that dynamically acetylated histone H3 at these genes is also K4-methylated. Although all three modifications are proven to co-exist on the same nucleosome at these genes, phosphorylation and acetylation appear transiently during gene induction, whereas K4 methylation remains detectable throughout this process. Finally, we address the functional significance of the turnover of histone acetylation on the process of gene induction. We find that inhibition of turnover, despite causing enhanced histone acetylation at these genes, produces immediate inhibition of gene induction. These data show that all K4-methylated histone H3 is subject to the continuous action of HATs and HDACs, and indicates that at c-fos and c-jun, contrary to the predominant model, turnover and not stably enhanced acetylation is relevant for efficient gene induction.

Crystal structure of 3-methyl-2,6-bis(4-methyl-1,3-thiazol-5-ylpiperidin-4-one

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A. Manimaran

2014-09-01

Full Text Available In the title compound, C14H17N3OS2, the central piperidinone ring adopts a chair conformation and the thiazole rings are inclined to its mean plane by 80.16 (12 and 67.15 (12°. The O atom and methyl group C atom deviate significantly from the mean plane of the central piperidinone ring, by 0.8138 (2 and 0.3175 (2 Å, respectively. The dihedral angle between the thiazole rings is 51.88 (13°. In the crystal, molecules are linked via C—H...O hydrogen bonds, forming zigzag C(10 chains running parallel to [001].

Crystal structure of [(2R,3R,4S)-3,4-bis(acet-yloxy)-5-iodo-3,4-di-hydro-2H-pyran-2-yl]methyl acetate.

Science.gov (United States)

Zukerman-Schpector, Julio; Caracelli, Ignez; Stefani, Hélio A; Shamim, Anwar; Tiekink, Edward R T

2015-01-01

In the title compound, C12H15IO7, the 3,4-di-hydro-2H-pyran ring is in a distorted half-boat conformation with the atom bearing the acet-yloxy group adjacent to the C atom bearing the methyl-acetate group lying 0.633 (6) Å above the plane of the remaining ring atoms (r.m.s. deviation = 0.0907 Å). In the crystal, mol-ecules are linked into a supra-molecular chain along the a axis through two C-H⋯O inter-actions to the same acceptor carbonyl O atom; these chains pack with no specific inter-molecular inter-actions between them.

4-(2,3-Dihydroxybenzylideneamino-3-methyl-1H-1,2,4-triazol-5(4H-one

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Şamil Işık

2009-12-01

Full Text Available All the non-H atoms of the title compound, C10H10N4O3, are almost coplanar, the maximum deviation from planarity being 0.065 (3 Å. The dihedral angle between the aromatic rings is 1.66 (6°. The molecule adopts the enol–imine tautomeric form with an intramolecular hydrogen-bonding interaction between the Schiff base N atom and the hydroxy group. In the crystal, intermolecular N—H...O and O—H...O hydrogen bonds link the molecules into a three-dimensional network.

Links between DNA methylation and nucleosome occupancy in the human genome.

Science.gov (United States)

Collings, Clayton K; Anderson, John N

2017-01-01

DNA methylation is an epigenetic modification that is enriched in heterochromatin but depleted at active promoters and enhancers. However, the debate on whether or not DNA methylation is a reliable indicator of high nucleosome occupancy has not been settled. For example, the methylation levels of DNA flanking CTCF sites are higher in linker DNA than in nucleosomal DNA, while other studies have shown that the nucleosome core is the preferred site of methylation. In this study, we make progress toward understanding these conflicting phenomena by implementing a bioinformatics approach that combines MNase-seq and NOMe-seq data and by comprehensively profiling DNA methylation and nucleosome occupancy throughout the human genome. The results demonstrated that increasing methylated CpG density is correlated with nucleosome occupancy in the total genome and within nearly all subgenomic regions. Features with elevated methylated CpG density such as exons, SINE-Alu sequences, H3K36-trimethylated peaks, and methylated CpG islands are among the highest nucleosome occupied elements in the genome, while some of the lowest occupancies are displayed by unmethylated CpG islands and unmethylated transcription factor binding sites. Additionally, outside of CpG islands, the density of CpGs within nucleosomes was shown to be important for the nucleosomal location of DNA methylation with low CpG frequencies favoring linker methylation and high CpG frequencies favoring core particle methylation. Prominent exceptions to the correlations between methylated CpG density and nucleosome occupancy include CpG islands marked by H3K27me3 and CpG-poor heterochromatin marked by H3K9me3, and these modifications, along with DNA methylation, distinguish the major silencing mechanisms of the human epigenome. Thus, the relationship between DNA methylation and nucleosome occupancy is influenced by the density of methylated CpG dinucleotides and by other epigenomic components in chromatin.

Straightforward Synthesis of N-Methyl-4-(pinB-2(3H-benzothiazol-2-one: A Promising Cross-Coupling Reagent

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Shotaro Izawa

2018-01-01

Full Text Available Cyclo-condensation of N-methyl-2-bromoaniline with chlorocarbonylsulfenyl chloride (CCSC promoted by PhNMe2 and AlCl3, afforded N-methyl-2-bromo-2(3H-benzothiazol-2-one in good yield. Miyaura–Ishiyama cross-coupling of this brominated 2(3H-benzothiazol-2-one with bis(pinacolatodiborone [(pin2B2] produced a novel N-methyl-4-(pinB-2(3H-benzothiazol-2-one (3 using (pin2B2 in the presence of the PdCl2(PPh32 catalyst. The obtained 4-(pinB compound is regarded as a new entry for the library of Suzuki–Miyaura cross-coupling reactions.

Crystal structure of methyl (Z-2-[(Z-3-methyl-2-({(E-1-[(R*-4-methylcyclohex-3-en-1-yl]ethylidene}hydrazinylidene-4-oxothiazolidin-5-ylidene]acetate

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Mourad Fawzi

2017-11-01

Full Text Available The new title 4-thiazolidinone derivative, C16H21N3O3S, was obtained from the cyclization reaction of 4-methyl-3-thiosemicarbazone and dimethyl acetylenedicarboxylate (DMAD. The cyclohexylidene ring has an envelope conformation with the stereogenic centre C atom as the flap. Its mean plane makes a dihedral angle of 56.23 (9° with the thiazolidine ring mean plane. In the crystal, molecules are linked by C—H...O hydrogen bonds forming chains propagating in the [001] direction. Within the chains there are offset π–π interactions between the thiazolidine rings of inversion-related molecules [centroid–centroid distance = 3.703 (1 Å]. The chains are linked by further C—H...O hydrogen bonds, forming slabs parallel to the ac plane.

Reduced Histone H3 Lysine 9 Methylation Contributes to the Pathogenesis of Latent Autoimmune Diabetes in Adults via Regulation of SUV39H2 and KDM4C

OpenAIRE

Liu, Xi-yu; Li, Hong

2017-01-01

Aims. Latent autoimmune diabetes in adults (LADA) is an autoimmune disease of which the mechanism is not clear. Emerging evidence suggests that histone methylation contributes to autoimmunity. Methods. Blood CD4+ T lymphocytes from 26 LADA patients and 26 healthy controls were isolated to detect histone H3 lysine 4 and H3 lysine 9 methylation status. Results. Reduced global H3 lysine 9 methylation was observed in LADA patients’ CD4+ T lymphocytes, compared to healthy controls (P < 0.05). H3 l...

4-[(3-Hydroxyanilino(phenylmethylidene]-3-methyl-1-phenyl-1H-pyrazol-5(4H-one

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Keraghel Saida

2012-06-01

Full Text Available In the title compound, C23H19N3O2, the dihedral angles formed by the pyrazolone ring with the three benzene rings are 30.91 (6, 60.96 (4 and 57.01 (4°. The ligand is in the enamine–keto form and its structure is stabilized by an intramolecular N—H...O hydrogen bond. In the crystal, O—H...N hydrogen bonds link molecules into chains parallel to [01-1].

Regioselectivity in the Thermal Rearrangement of Unsymmetrical 4-Methyl-4H-1,2,4-triazoles to 1-Methyl-1H-1,2,4-triazoles

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Per H.J. Carlsen

2001-11-01

Full Text Available The rearrangement of 4-methyl-3,5-diaryl-4H-1,2,4-triazoles to the corresponding 1-methyl-3,5-diaryl-1H-1,2,4-triazoles showed regioselectivity comparable to that observed for the alkylation of 3,5-diaryl-1H-1,2,4-triazoles. This lends support to a proposed mechanism for the rearrangement that involves consecutive nucleophilic displacements steps.

Synthesis, Molecular Structure and Characterization of Allylic Derivatives of 6-Amino-3-methyl-1,2,4-triazolo[3,4-f][1,2,4]-triazin-8(7H-one

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Gene-Hsiang Lee

2006-06-01

Full Text Available 1-Allyl- (2 and 7-allyl-6-amino-3-methyl-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H-one (3 were obtained via the 18-crown-6-ether catalyzed room temperature reactionof 6-amino-3-methyl-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H-one (1 with potassiumcarbonate and allyl bromide in dry acetone. The structures of these two derivatives wereverified by 2D-NMR measurements, including gHSQC and gHMBC measurements. Theminor compound 2 may possess aromatic character. A single crystal X-ray diffractionexperiment indicated that the major compound 3 crystallizes from dimethyl sulfoxide in themonoclinic space group P21/n and its molecular structure includes an attached dimethylsulfoxide molecule, resulting in the molecular formula C10H16N6O2S. Molecular structuresof 3 are linked by extensive intermolecular N-H···N hydrogen bonding [graph set C 1 (7]. 1Each molecule is attached to the dimethyl sulfoxide oxygen via N-H···O intermolecularhydrogen bonding. The structure is further stabilized by π-π stacking interactions.

Release of /sup 3/H-. cap alpha. -methyl-m-tyramine from rat striatum in vitro

Energy Technology Data Exchange (ETDEWEB)

Dorris, R L [Baylor College of Dentistry, Dallas, Tex. (USA). Dept. of Pharmacology

1976-01-01

Release of /sup 3/H-d-..cap alpha..-methyl-m-tyramine (/sup 3/H-MMTA), a false dopaminergic transmitter from rat striatum was studied in vitro. After its initial uptake, /sup 3/H-MMTA was released by high K/sup +/ and by amphetamine. The release requirements were essentially the same as those known to exist for release of dopamine in vitro. These studies indicate that /sup 3/H-MMTA might serve as a useful tool with which to study dopamine release mechanisms in vitro.

Enzymatic methylation of band 3 anion transporter in intact human erythrocytes

International Nuclear Information System (INIS)

Lou, L.L.; Clarke, S.

1987-01-01

Band 3, the anion transport protein of erythrocyte membranes, is a major methyl-accepting substrate of the intracellular erythrocyte protein carboxyl methyltransferase (S-adenosyl-L-methionine: protein-D-aspartate O-methyltransferase; EC 2.1.1.77). The localization of methylation sites in intact cells by analysis of proteolytic fragments indicated that sites were present in the cytoplasmic N-terminal domain as well as the membranous C-terminal portion of the polypeptide. The amino acid residues that serve as carboxyl methylation sites of the erythrocyte anion transporter were also investigated. 3 H-Methylated band 3 was purified from intact erythrocytes incubated with L-[methyl- 3 H]methionine and from trypsinized and lysed erythrocytes incubated with S-adenosyl-L-[methyl- 3 H]methionine. After proteolytic digestion with carboxypeptidase Y, D-aspartic acid beta-[ 3 H]methyl ester was isolated in low yields (9% and 1%, respectively) from each preparation. The bulk of the radioactivity was recovered as [ 3 H]methanol, and the amino acid residue(s) originally associated with these methyl groups could not be determined. No L-aspartic acid beta-[ 3 H]methyl ester or glutamyl gamma-[ 3 H]methyl ester was detected. The formation of D-aspartic acid beta-[ 3 H]methyl esters in this protein in intact cells resulted from protein carboxyl methyltransferase activity since it was inhibited by adenosine and homocysteine thiolactone, which increases the intracellular concentration of the potent product inhibitor S-adenosylhomocysteine, and cycloleucine, which prevents the formation of the substrate S-adenosyl-L-[methyl- 3 H]methionine

Method of preparing [methyl-3H]thymine and 5-hydroxy[3H]methyluracil mixture of high molar activity

International Nuclear Information System (INIS)

Filip, J.; Bohacek, L.

1981-01-01

Non-active 5-formyluracil dissolved in 0.01 N to 1.0 N of hydrochloric acid is acted upon by gaseous carrier-free tritium at room temperature in the presence of a heterogeneous palladium/carrier catalyst, with advantage palladium on barium sulfate. The described procedure allows the preparation of [methyl- 3 H]thymine on a microscale, with a high molar activity in a single reaction stage with a high chemical (50-70%) and radiochemical (15-25%) yield. (J.P.)

Structure and spectroscopic properties of N,S-coordinating 2-methyl-sulfanyl-N-[(1H-pyrrol-2-yl)methyl-idene]aniline methanol monosolvate.

Science.gov (United States)

Richards, D Douglas; Ang, M Trisha C; McDonald, Robert; Bierenstiel, Matthias

2015-10-01

The reaction of pyrrole-2-carboxaldehyde and 2-(methyl-sulfan-yl)aniline in refluxing methanol gave an olive-green residue in which yellow crystals of the title compound, C12H12N2S·CH3OH, were grown from slow evaporation of methanol at 263 K. In the crystal, hydrogen-bonding inter-actions link the aniline mol-ecule and a nearby methanol solvent mol-ecule. These units are linked by a pair of weak C-H⋯Omethanol interactions, forming inversion dimers consisting of two main molecules and two solvent molecules.

Synthesis and biochemical evaluation of tritium-labeled 1-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-3-carboxa mide, a useful radioligand for 5HT3 receptors

International Nuclear Information System (INIS)

Robertson, D.W.; Bloomquist, W.; Cohen, M.L.; Reid, L.R.; Schenck, K.; Wong, D.T.

1990-01-01

The advent of potent, highly selective 5HT3 receptor antagonists has stimulated considerable interest in 5HT3 receptor mediated physiology and pharmacology. To permit detailed biochemical studies regarding interaction of the indazole class of serotonin (5HT) antagonists with 5HT3 receptors in multiple tissues, we synthesized 1-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole- 3-carboxamide (LY278584, compound 9) in high specific activity, tritium-labeled form. This radioligand was selected as a synthetic target because of its potency as a 5HT3-receptor antagonist, its selectivity for this receptor viz a viz other 5HT-receptor subtypes, and the ability to readily incorporate three tritia via the indazole N-CH3 substituent. Alkylation of N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazole-3-carboxamide (8) with sodium hydride and tritium-labeled iodomethane, followed by HPLC purification, resulted in [3H]-9 with a radiochemical purity of 99% and a specific activity of 80.5 Ci/mmol. This radioligand bound with high affinity to a single class of saturable recognition sites in membranes isolated from cerebral cortex of rat brain. The Kd was 0.69 nM and the Bmax was 16.9 fmol/mg of protein. The specific binding was excellent, and accounted for 83-93% of total binding at concentrations of 2 nM or less. The potencies of known 5HT3-receptor antagonists as inhibitors of [3H]-9 binding correlated well with their pharmacological receptor affinities as antagonists of 5HT-induced decreases in heart rate and contraction of guinea pig ileum, suggesting the central recognition site for this radioligand may be extremely similar to or identical with peripheral 5HT3 receptors

{[2-Methyl-2-(phenoxymethylpropane-1,3-diyl]bis(oxy}dibenzene

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Ziad Moussa

2014-05-01

Full Text Available The title compound, C23H24O3, was obtained in a one-step (60% yield synthesis from 1,1,1-tris(hydroxymethylethane. It features a tripodal ligand capable of complexing metal centres. One of the three conformations involving the methyl group, the central C—C bond and the phenoxy substituents is antiperiplanar while the two others are synclinal [the corresponding C—C—C—O torsion angles are −174.6 (1, −53.2 (2 and −47.3 (2°]. In the crystal, C—H...O interactions link the molecules into [010] chains.

DNA methylation of the IGF2/H19 imprinting control region and adiposity distribution in young adults

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Huang Rae-Chi

2012-11-01

Full Text Available Abstract Background The insulin-like growth factor 2 (IGF2 and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity. DNA methylation in peripheral blood (n = 315 at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs, analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression. Results The principal component of IGF2/H19 ICR DNA methylation (representing mean methylation across all CpG units positively correlated with skin fold thickness (at four CpG units (P-values between 0.04 to 0.001 and subcutaneous adiposity (P = 0.023 at age 17, but not with weight, height, BMI, waist circumference or visceral adiposity. IGF2/H19 methylation did not associate with birth weight, length or HC, but CpG unit 13 to 14 methylation was negatively associated with HC between 1 and 10 years. β-coefficients of four out of five remaining CpG units also estimated lower methylation with increasing childhood HC. Conclusions As greater IGF2/H19 methylation was associated with greater subcutaneous fat measures, but not overall, visceral or central adiposity, we hypothesize that obesogenic pressures in youth result in excess fat being preferentially stored in peripheral fat depots via the IGF2/H19 domain. Secondly, as IGF2/H19 methylation was not associated with birth size but negatively with early childhood HC, we

In silico identification of BIM-1 (2-methyl-1H-indol-3-yl) as a potential ...

African Journals Online (AJOL)

In silico identification of BIM-1 (2-methyl-1H-indol-3-yl) as a potential therapeutic agent against elevated protein kinase C beta associated diseases. U Saeed, N Nawaz, Y Waheed, N Chaudry, HT Bhatti, S Urooj, H Waheed, M Ashraf, UHK Naizi ...

3-Chloro-4-methyl­quinolin-2(1H)-one

Science.gov (United States)

Kassem, Mohamed G.; Ghabbour, Hazem A.; Abdel-Aziz, Hatem A.; Fun, Hoong-Kun; Ooi, Chin Wei

2012-01-01

The title compound, C10H8ClNO, is almost planar (r.m.s. deviation for the 13 non-H atoms = 0.023 Å). In the crystal, inversion dimers linked by pairs of N—H⋯O hydrogen bonds generate R 2 2(8) rings. Weak aromatic π–π stacking inter­actions [centroid–centroid distance = 3.7622 (12) Å] also occur. PMID:22589913

5-Methyl-2-phenyl-2H-pyrazol-3-ol

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Feng Zhi

2008-10-01

Full Text Available The title compound, C10H10N2O, known as Edaravone (MCI-186, was crystallized from methanol. The two independent molecules in the asymmetric unit are linked through an O—H...O hydrogen bond. One molecule adopts a ketone form, while the other adopts an enol form. In the crystal structure, molecules are linked through intermolecular N—H...O hydrogen bonds, forming chains running along the b axis.

Synthesis, Antifungal Activity and Structure-Activity Relationships of Novel 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic Acid Amides.

Science.gov (United States)

Du, Shijie; Tian, Zaimin; Yang, Dongyan; Li, Xiuyun; Li, Hong; Jia, Changqing; Che, Chuanliang; Wang, Mian; Qin, Zhaohai

2015-05-08

A series of novel 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-yl)phenyl)-3-(difluoro-methyl)-1-methyl-1H-pyrazole-4-carboxamide (9m) exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.

Synthesis, Antifungal Activity and Structure-Activity Relationships of Novel 3-(Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic Acid Amides

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Shijie Du

2015-05-01

Full Text Available A series of novel 3-(difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-ylphenyl-3-(difluoro-methyl-1-methyl-1H-pyrazole-4-carboxamide (9m exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.

Alterations of global histone H4K20 methylation during prostate carcinogenesis

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Behbahani Turang E

2012-03-01

Full Text Available Abstract Background Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3 at different stages of prostate cancer (PCA carcinogenesis. Methods Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113, non-malignant prostate disease (n = 27, metastatic hormone-naive PCA (mPCA, n = 30 and castration-resistant PCA (CRPC, n = 34. Immunohistochemistry was performed to assess global levels of H4K20 methylation levels. Results Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy. Conclusions H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.

EPR study of gamma irradiated N-methyl taurine (C 3H 9NO 3S) and sodium hydrogen sulphate monohydrate (NaHSO 3·H 2O) single crystals

Science.gov (United States)

Yıldırım, İlkay; Karabulut, Bünyamin

2011-03-01

EPR study of gamma irradiated C 3H 9NO 3S and NaHSO 3.H 2O single crystals have been carried out at room temperature. There is one site for the radicals in C 3H 9NO 3S and two magnetically distinct sites for the radicals in NaHSO 3. The observed lines in the EPR spectra have been attributed to the species of SO3- and RH radicals for N-methyl taurine, and to the SO3- and OH radicals for sodium hydrogen sulfate monohydrate single crystals. The principal values of the g for SO3-, the hyperfine values of RH and OH proton splitting have been calculated and discussed.

Synthesis and pharmacological properties of new derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones.

Science.gov (United States)

Sladowska, Helena; Sabiniarz, Aleksandra; Sapa, Jacek; Filipek, Barbara

2009-01-01

Synthesis of 2-(2-hydroxy-3-amino)propyl derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (24-35) is described. The chlorides used in the above synthesis exist mainly in the cyclic forms (18, 20-23). Only chloride with benzhydryl substituent at the nitrogen atom of piperazine has the chain structure (19). Among the studied imides the most active analgesics in the "writhing" syndrome test proved to be compounds 30 and 31 (with LD50 > 2000 mg/kg) containing 4-benzylpiperidino group. Furthermore, all imides suppressed significantly spontaneous locomotor activity of mice.

Effects of nickel, chromate, and arsenite on histone 3 lysine methylation

International Nuclear Information System (INIS)

Zhou Xue; Li Qin; Arita, Adriana; Sun Hong; Costa, Max

2009-01-01

Occupational exposure to nickel (Ni), chromium (Cr), and arsenic (As) containing compounds has been associated with lung cancer and other adverse health effects. Their carcinogenic properties may be attributable in part, to activation and/or repression of gene expression induced by changes in the DNA methylation status and histone tail post-translational modifications. Here we show that individual treatment with nickel, chromate, and arsenite all affect the gene activating mark H3K4 methylation. We found that nickel (1 mM), chromate (10 μM), and arsenite (1 μM) significantly increase tri-methyl H3K4 after 24 h exposure in human lung carcinoma A549 cells. Seven days of exposure to lower levels of nickel (50 and 100 μM), chromate (0.5 and 1 μM) or arsenite (0.1, 0.5 and 1 μM) also increased tri-methylated H3K4 in A549 cells. This mark still remained elevated and inherited through cell division 7 days following removal of 1 μM arsenite. We also demonstrate by dual staining immunofluorescence microscopy that both H3K4 tri-methyl and H3K9 di-methyl marks increase globally after 24 h exposure to each metal treatment in A549 cells. However, the tri-methyl H3K4 and di-methyl H3K9 marks localize in different regions in the nucleus of the cell. Thus, our study provides further evidence that a mechanism(s) of carcinogenicity of nickel, chromate, and arsenite metal compounds may involve alterations of various histone tail modifications that may in turn affect the expression of genes that may cause transformation

[6-chloro-3-pyridylmethyl-3H]neonicotinoids as high-affinity radioligands for the nicotinic acetylcholine receptor: preparation using NaB3H4 and LiB3H4

International Nuclear Information System (INIS)

Latli, Bachir; Casida, J.E.

1996-01-01

NaB 3 H 4 and LiB 3 H 4 at 78% and 97% isotopic enrichments, respectively, were used in the synthesis of 3 H-labeled 1-(6-chloro-3-pyridyl)-methyl-2-nitromethyleneimidazolidine (CH-IMI) and N'-[(6-chloro-3-pyridyl)methyl]-n''-cyano-n'-methylacetamidine (acetamiprid) (two very potent insecticides) and of 1-(6-chloro-3-pyridyl)methyl-2-iminoimidazolidine (desnitro-IMI) (a metabolite of the commercial insecticides imidacloprid). 6-Chloronicotinoyl chloride was treated with either NaB 3 H 4 in methanol or LiB 3 H 4 in tetrahydrofuran and the resulting alcohol transformed to 2-chloro-5-chloromethylpyridine, which was then coupled to N-cyano-N'-methylacetamidine to give [ 3 H] acetamiprid (45 Ci/mmol). 2-Chloro-5-chloro[ 3 H]methylpyridine was also reacted with ethylenediamine and the product was either refluxed in absolute ethanol with 1,1-bis(methylthio)-2-nitro-ethylene to provide [ 3 H]CH-IMI or reacted in toluene with a solution of cyanogen bromide to produce [ 3 H] desnitro-IMI (each 55 Ci/mmol. (author)

Crystal structure of 2-amino-4-methyl-pyridin-1-ium (2R,3R)-3-carb-oxy-2,3-di-hydroxy-propano-ate monohydrate.

Science.gov (United States)

Jovita, J V; Sathya, S; Usha, G; Vasanthi, R; Ramanand, A

2014-09-01

The title mol-ecular salt, C6H9N2 (+)·C4H5O6 (-)·H2O, crystallized with two 2-amino-4-methyl-pyridin-1-ium cations, two l-(+)-tartaric acid monoanions [systematic name: (2R,3R)-3-carb-oxy-2,3-di-hydroxy-propano-ate] and two water mol-ecules in the asymmetric unit. In the crystal, the cations, anions and water mol-ecules are linked via a number of O-H⋯O and N-H⋯O hydrogen bonds, and a C-H⋯O hydrogen bond, forming a three-dimensional structure.

6-Bromo-2-(4-chlorophenyl-3-methyl-3H-imidazo[4,5-b]pyridine

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Selma Bourichi

2016-05-01

Full Text Available In the title compound, C13H9BrClN3, the imidazopyridine fused-ring system is almost planar, with r.m.s. deviation of 0.006 (19 Å, and makes a dihedral angle of 29.32 (8° with the mean plane of the 4-chlorophenyl group. In the crystal, C—H...N hydrogen bonds link the molecules into chains propagating in the [100] direction. Weak intermolecular π–π interactions between the five- and six-membered rings of the 3H-imidazo[4,5-b]pyridine moieties of neighbouring molecules [centroid–centroid distance = 3.8648 (12 Å] further consolidate the packing into layers parallel to the ab plane.

Synthesis of new trihalo methylated and non-symmetrical substituted 2-(1H-pyrazolyl)-5-(1H-pyrazolylcarbonyl)pyridines

International Nuclear Information System (INIS)

Bonacorso, Helio G.; Paim, Gisele R.; Guerra, Carolina Z.; Sehnem, Ronan C.; Cechinel, Cleber A.; Porte, Liliane M. F.; Martins, Marcos A. P.; Zanatta, Nilo

2009-01-01

This paper describes the synthesis of a new series of 2-[3-alkyl(aryl/heteroaryl)-5-trifluoro(chloro)methyl-5-hydroxy-4,5-dihydro -1H-pyrazol-1-yl]-5- [3-alkyl(aryl/heteroaryl)-5-trifluoro(chloro)methyl-5-hydroxy= -4,5-dihydro-1H-pyrazol-1-yl-1-carbonyl] pyridines by the cyclocondensation reaction of 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1- trifluoro(chloro) -3-alken- 2-ones [CX 3 C(O)CH=CR 1 OR, where R = Me, Et; R 1 = H, Me, Ph, 4-MeOPh, 4-NO 2 Ph, 4,4'-Biphenyl, 1-Naphthyl, Fur-2-yl, Thien-2-yl and X = F, Cl] with 6-hydrazinonicotinic hydrazide hydrate. Yields of 62 to 97% were obtained when the reactions were performed in ethanol as solvent at 78 deg C for 4 hours. In a subsequent step, the dehydration reactions of 2-(5-hydroxy-1H-pyrazol-1-yl)-5-(5-hydroxy-1H?pyrazol-1-yl-1-carbonyl) pyridines were carried out in pyridine/benzene in the presence of thionyl chloride and led to the isolation of a series of 2- [3-alkyl(aryl/heteroaryl)-5-trifluoro(chloro)methyl-1H-pyrazol-1-yl]-5- [3-alkyl(aryl/heteroaryl)-5 -trifluoro(chloro)methyl-1H-pyrazol-1-yl-1-carbonyl]pyridi= nes, in 64 to 86% yields. (author)

1,4-Dimethyl-3-phenyl-3H-pyrazolo[3,4-c]isoquinolin-5(4H-one

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Giuseppe Daidone

2008-05-01

Full Text Available The title compound, C18H15N3O, is the product of the thermal decomposition of the diazonium salt derived from 2-amino-N-methyl-N-(3-methyl-1-phenyl-1H-pyrazol-5-ylbenzamide. It is characterized by a trans orientation of the methyl groups with respect to the tricyclic ring system. The molecule has a nearly planar phenylpyrazolo[3,4-c]isoquinolin-5-one system, the largest deviation from the mean plane being 0.066 (2 Å for the O atom. The dihedral angle between the phenyl substituent and the heterotricycle is 67 (1°. The packing is stabilized by C—H...N hydrogen-bond interactions, with the formation of molecular chains along the c axis.

1-Methyl-5-nitro-3-phenyl-1H-indazole

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Mohammed Naas

2016-06-01

Full Text Available The title compound, C14H11N3O2, crystallizes with two molecules in the asymmetric unit. The indazole ring system and the nitro group are nearly coplanar, with the largest deviations from the mean plane being 0.070 (4 Å in one molecule and 0.022 (3 Å in the second. The dihedral angle between the mean plane through the phenyl ring and the mean plane of the indazole ring system is of 23.24 (18° in the first molecule and 26.87 (18° in the second. In the crystal, molecules are linked by two C—H...O hydrogen bonds, forming linear zigzag tapes running along the c-axis direction, and by π–π stacking of molecules along the b axis, generating a three-dimensional structure.

Re-patterning of H3K27me3, H3K4me3 and DNA methylation during fibroblast conversion into induced cardiomyocytes

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Ziqing Liu

2016-03-01

Full Text Available Direct conversion of fibroblasts into induced cardiomyocytes (iCMs offers an alternative strategy for cardiac disease modeling and regeneration. During iCM reprogramming, the starting fibroblasts must overcome existing epigenetic barriers to acquire the CM-like chromatin pattern. However, epigenetic dynamics along this reprogramming process have not been studied. Here, we took advantage of our recently generated polycistronic system and determined the dynamics of two critical histone marks, H3K27me3 and H3K4me3, in parallel with gene expression at a set of carefully selected cardiac and fibroblast loci during iCM reprogramming. We observed reduced H3K27me3 and increased H3K4me3 at cardiac promoters as early as day 3, paralleled by a rapid significant increase in their mRNA expression. In contrast, H3K27me3 at loci encoding fibroblast marker genes did not increase until day 10 and H3K4me3 progressively decreased along the reprogramming process; these changes were accompanied by a gradual decrease in the mRNA expression of fibroblast marker genes. Further analyses of fibroblast-enriched transcription factors revealed a similarly late deposition of H3K27me3 and decreased mRNA expression of Sox9, Twist1 and Twist2, three important players in epithelial−mesenchymal transition. Our data suggest early rapid activation of the cardiac program and later progressive suppression of fibroblast fate at both epigenetic and transcriptional levels. Additionally, we determined the DNA methylation states of representative cardiac promoters and found that not every single CpG was equally demethylated during early stages of iCM reprogramming. Rather, there are specific CpGs, whose demethylation states correlated tightly with transcription activation, that we propose are the major contributing CpGs. Our work thus reveals a differential re-patterning of H3K27me3, H3K4me3 at cardiac and fibroblast loci during iCM reprogramming and could provide future genome

Nucleoside-O-Methyl-(H)-Phosphinates: Novel Monomers for the Synthesis of Methylphosphonate Oligonucleotides Using H-Phosphonate Chemistry.

Science.gov (United States)

Kostov, Ondřej; Páv, Ondřej; Rosenberg, Ivan

2017-09-18

This unit comprises the straightforward synthesis of protected 2'-deoxyribonucleoside-O-methyl-(H)-phosphinates in both 3'- and 5'-series. These compounds represent a new class of monomers compatible with the solid-phase synthesis of oligonucleotides using H-phosphonate chemistry and are suitable for the preparation of both 3'- and 5'-O-methylphosphonate oligonucleotides. The synthesis of 4-toluenesulfonyloxymethyl-(H)-phosphinic acid as a new reagent for the preparation of O-methyl-(H)-phosphinic acid derivatives is described. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

2-(7-Methyl-1H-indol-3-ylacetonitrile

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Yu-Hua Ge

2012-01-01

Full Text Available In the title compound, C11H10N2, the carbonitrile group is twisted away from the indole plane [Ccy—Cme—Car—Car = 66.6 (2°; cy = cyanide, me = methylene and ar = aromatic]. In the crystal, N—H...N hydrogen bonds link the molecules into C(7 chains propagating in the [001] direction.

4-Methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic Acid. Peculiarities of Preparation, Structure, and Biological Properties

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Igor V. Ukrainets

2018-03-01

Full Text Available In order to determine the regularities of the structure–analgesic activity relationship, the peculiarities of obtaining, the spatial structure, and biological properties of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid and some of its derivatives have been studied. Using nuclear magnetic resonance (NMR spectroscopy and X-ray diffraction analysis, it has been proven that varying the reaction conditions using alkaline hydrolysis of methyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate makes it possible to successfully synthesize a monohydrate of the target acid, its sodium salt, or 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine. The derivatographic study of the thermal stability of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid monohydrate has been carried out; based on this study, the optimal conditions completely eliminating the possibility of unwanted decomposition have been proposed for obtaining its anhydrous form. It has been shown that 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine is easily formed during the decarboxylation of not only 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid, but also its sodium salt, which is capable of losing СО2 both in rather soft conditions of boiling in an aqueous solution, and in more rigid conditions of dry heating. The NMR spectra of the compounds synthesized are given; their spatial structure is discussed. To study the biological properties of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid and its sodium salt, the experimental model of inflammation caused by subplantar introduction of the carrageenan solution in one of the hind limbs of white rats was used. The anti-inflammatory activity and analgesic effect were assessed by the degree of edema reduction and the ability to affect the pain response compared to the animals of control groups. According to the results of the tests performed, it has been found that after intraperitoneal injection

Facile N-oxygenation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by the flavin-containing monooxygenase. A convenient synthesis of tritiated [methyl-3H]-4-phenyl-2,3-dihydropyridinium species

International Nuclear Information System (INIS)

Cashman, J.R.

1988-01-01

A rapid, efficient procedure useful for the radiosynthesis of [Me- 3 H]-MPDP+ ([methyl- 3 H]-4-phenyl-2,3-dihydropyridinium species) is described. Hog liver microsomes or the highly purified flavin-containing monooxygenase from hog liver quantitatively biotransforms [Me- 3 H]-MPTP to its corresponding radiolabeled N-oxide. For the small-scale synthesis required for radiolabeling procedures, this enzymatic process is superior to H 2 O 2 -mediated N-oxygenation of MPTP. In the presence of 0.5 mM NADPH, 4.5 mM n-octylamine, and 2 microCi [Me- 3 H]-MPTP, the only product detected in extracts from incubations performed with hog liver microsomes or purified hog liver flavin-containing monooxygenase is [Me- 3 H]-MPTP N-oxide. [Me- 3 H]-MPTP N-oxide is almost completely converted to [Me- 3 H]-MPDP+ by the action of trifluoroacetic anhydride. This procedure has the advantage of using a commercially available tritiated starting material, efficient transformations, and easily accomplished purification to afford a rapid synthesis of [Me- 3 H]-MPDP+

5-Methyl-4-oxo-4,6-dihydro-3H-pyridazino[4,5-b]carbazole-1-carbonitrile

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Norbert Haider

2010-02-01

Full Text Available The title compound was prepared in excellent yield from 5-methyl-4-oxo-4,6-dihydro-3H-pyridazino[4,5-b]carbazole-1-carbaldehyde by treatment with hydroxylamine hydrochloride in formic acid without isolation of the intermediate oxime.

Molecular Iodine: A Versatile Catalyst for the Synthesis of 4-Aryl-3-methyl-1-phenyl-1H-benzo[h]pyrazolo[3,4-b]quinoline-5,10-diones in Water

International Nuclear Information System (INIS)

Wu, Liqiang; Yang, Limin; Yan, Fulin; Yang, Chunguang; Fang, Lizhen

2010-01-01

An efficient methodology for the synthesis of 4-aryl-3-methyl-1-phenyl-1H-benzo[h]pyrazolo[3,4-b]quinoline-5,10-diones has been developed. To our best knowledge, this is the first report for the synthesis of these compounds by multicomponent condensation of 3-methyl-1-phenyl-1H-pyrazol-5-amine, aldehydes and 2-hydroxynaphthalene-1,4-dione in the presence of molecular iodine as a catalyst in water. The simple experimental procedure, utilization of an inexpensive and readily available catalyst, and excellent yields are the advantages of the present method. Multicomponent reactions (MCRs) have attracted considerable attention since they are performed without need to isolate any intermediate during their processes; may reduce time and save both energy and raw materials. They have merits over two-component reactions in several aspects including the simplicity of a one-pot procedure, possible structural variations and building up complex molecules

PEG1000-Based Dicationic Acidic Ionic Liquid Catalyzed One-Pot Synthesis of 4-Aryl-3-Methyl-1-Phenyl-1H-Benzo[h]pyrazolo [3,4-b]quinoline-5,10-Diones via Multicomponent Reactions

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Yi-Ming Ren

2015-09-01

Full Text Available A novel and green approach for efficient and rapid synthesis of 4-aryl-3-methyl-1-phenyl-1H-benzo[h]pyrazolo[3,4-b]quinoline-5,10-diones has been accomplished by the one-pot condensation reaction of aromatic aldehydes, 3-methyl-1-phenyl-1H-pyrazol-5-amine and 2-hydroxynaphthalene-1,4-dione using PEG1000-based dicationic acidic ionic liquid (PEG1000-DAIL as a catalyst was reported. Recycling studies have shown that the PEG1000-DAIL can be readily recovered and reused several times without significant loss of activity. The key advantages are the short reaction time, high yields, simple workup, and recovered catalyst.

4-Hydroxy-6-methyl-3-[3-(thiophen-2-ylacryloyl]-2H-pyran-2-one

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Salima Thabti

2013-04-01

Full Text Available The title compound, C13H10O4S, crystallizes with two molecules in the asymmetric unit in which the rings make dihedral angles of 3.9 (1 and 6.0 (1°; this planarity is due in part to the presence of an intramolecular O—H...O hydrogen bond, which generates an S(6 ring in each molecule. Both molecules represent E isomers with respect to the central C=C bond. In the crystal, molecules are linked by C—H...O interactions into a three-dimensional network.

DNA methylation modulates H19 and IGF2 expression in porcine female eye

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Dongxu Wang

2017-03-01

Full Text Available Abstract The sexually dimorphic expression of H19/IGF2 is evolutionarily conserved. To investigate whether the expression of H19/IGF2 in the female porcine eye is sex-dependent, gene expression and methylation status were evaluated using quantitative real-time PCR (qPCR and bisulfite sequencing PCR (BSP. We hypothesized that H19/IGF2 might exhibit a different DNA methylation status in the female eye. In order to evaluate our hypothesis, parthenogenetic (PA cells were used for analysis by qPCR and BSP. Our results showed that H19 and IGF2 were over-expressed in the female eye compared with the male eye (3-fold and 2-fold, respectively. We observed a normal monoallelic methylation pattern for H19 differentially methylated regions (DMRs. Compared with H19 DMRs, IGF2 DMRs showed a different methylation pattern in the eye. Taken together, these results suggest that elevated expression of H19/IGF2 is caused by a specific chromatin structure that is regulated by the DNA methylation status of IGF2 DMRs in the female eye.

DNA methylation modulates H19 and IGF2 expression in porcine female eye

Science.gov (United States)

Wang, Dongxu; Wang, Guodong; Yang, Hao; Liu, Haibo; Li, Cuie; Li, Xiaolan; Lin, Chao; Song, Yuning; Li, Zhanjun; Liu, Dianfeng

2017-01-01

Abstract The sexually dimorphic expression of H19/IGF2 is evolutionarily conserved. To investigate whether the expression of H19/IGF2 in the female porcine eye is sex-dependent, gene expression and methylation status were evaluated using quantitative real-time PCR (qPCR) and bisulfite sequencing PCR (BSP). We hypothesized that H19/IGF2 might exhibit a different DNA methylation status in the female eye. In order to evaluate our hypothesis, parthenogenetic (PA) cells were used for analysis by qPCR and BSP. Our results showed that H19 and IGF2 were over-expressed in the female eye compared with the male eye (3-fold and 2-fold, respectively). We observed a normal monoallelic methylation pattern for H19 differentially methylated regions (DMRs). Compared with H19 DMRs, IGF2 DMRs showed a different methylation pattern in the eye. Taken together, these results suggest that elevated expression of H19/IGF2 is caused by a specific chromatin structure that is regulated by the DNA methylation status of IGF2 DMRs in the female eye. PMID:28266684

Acid-base properties of 1-methyl-1,4-dilhydroborabenzene, CH3BC5H6

International Nuclear Information System (INIS)

Sullivan, S.A.; Sandford, H.; Beauchamp, J.L.; Ashe, A.J. III

1978-01-01

Ion cyclotron resonance techniques are employed to determine the gas-phase Bronsted and Lewis acidities as well as the Bronsted basicity of 1-methyl-1,4-dihydroborabenzene, CH 3 BC 5 H 6 . The ring proton is found to be highly acidic with PA(CH 3 BC 5 H 5 - ) = 337 +- 3 kcal/mol. This acidity results from the formation of 6π electron aromatic anion CH 3 BC 5 H 5 - , which is isoelectronic with toluene. Both the Lewis acidity toward F - as a reference base and the proton basicity of the parent molecule suggest that there is little interaction between the diene π system and the electron-deficient boron. This is further confirmed by the similarity of both negative and positive ion chemistry of the borabenzene to that of aliphatic boranes

An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation.

Science.gov (United States)

Sabbattini, Pierangela; Sjoberg, Marcela; Nikic, Svetlana; Frangini, Alberto; Holmqvist, Per-Henrik; Kunowska, Natalia; Carroll, Tom; Brookes, Emily; Arthur, Simon J; Pombo, Ana; Dillon, Niall

2014-03-01

Methylated histones H3K9 and H3K27 are canonical epigenetic silencing modifications in metazoan organisms, but the relationship between the two modifications has not been well characterized. H3K9me3 coexists with H3K27me3 in pluripotent and differentiated cells. However, we find that the functioning of H3K9me3 is altered by H3S10 phosphorylation in differentiated postmitotic osteoblasts and cycling B cells. Deposition of H3K9me3/S10ph at silent genes is partially mediated by the mitogen- and stress-activated kinases (MSK1/2) and the Aurora B kinase. Acquisition of H3K9me3/S10ph during differentiation correlates with loss of paused S5 phosphorylated RNA polymerase II, which is present on Polycomb-regulated genes in embryonic stem cells. Reduction of the levels of H3K9me3/S10ph by kinase inhibition results in increased binding of RNAPIIS5ph and the H3K27 methyltransferase Ezh1 at silent promoters. Our results provide evidence of a novel developmentally regulated methyl-phospho switch that modulates Polycomb regulation in differentiated cells and stabilizes repressed states.

N-[5-Methyl-2-(2-nitrophenyl-4-oxo-1,3-thiazolidin-3-yl]pyridine-3-carboxamide monohydrate

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Mehmet Akkurt

2011-02-01

Full Text Available In the title compound, C16H14N4O4S·H2O, the benzene and pyridine rings make a dihedral angle of 85.8 (1°. Both enantiomers of the chiral title compound are statistically disordered over the same position in the unit cell. The methyl and carbonyl group attached to the stereogenic center (C5 of the thiazolidine ring were therefore refined with common site-occupation factors of 0.531 (9 and 0.469 (9, respectively, for each stereoisomer. In the crystal, intermolecular N—H...O, O—H...O and O—H...N hydrogen bonds link the molecules, forming a three-dimensional supramolecular network. The crystal structure further shows π–π stacking interactions [centroid–centroid distance = 3.5063 (13 Å] between the pyridine rings.

Drosophila Kismet regulates histone H3 lysine 27 methylation and early elongation by RNA polymerase II.

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Shrividhya Srinivasan

2008-10-01

Full Text Available Polycomb and trithorax group proteins regulate cellular pluripotency and differentiation by maintaining hereditable states of transcription. Many Polycomb and trithorax group proteins have been implicated in the covalent modification or remodeling of chromatin, but how they interact with each other and the general transcription machinery to regulate transcription is not well understood. The trithorax group protein Kismet-L (KIS-L is a member of the CHD subfamily of chromatin-remodeling factors that plays a global role in transcription by RNA polymerase II (Pol II. Mutations in CHD7, the human counterpart of kis, are associated with CHARGE syndrome, a developmental disorder affecting multiple tissues and organs. To clarify how KIS-L activates gene expression and counteracts Polycomb group silencing, we characterized defects resulting from the loss of KIS-L function in Drosophila. These studies revealed that KIS-L acts downstream of P-TEFb recruitment to stimulate elongation by Pol II. The presence of two chromodomains in KIS-L suggested that its recruitment or function might be regulated by the methylation of histone H3 lysine 4 by the trithorax group proteins ASH1 and TRX. Although we observed significant overlap between the distributions of KIS-L, ASH1, and TRX on polytene chromosomes, KIS-L did not bind methylated histone tails in vitro, and loss of TRX or ASH1 function did not alter the association of KIS-L with chromatin. By contrast, loss of kis function led to a dramatic reduction in the levels of TRX and ASH1 associated with chromatin and was accompanied by increased histone H3 lysine 27 methylation-a modification required for Polycomb group repression. A similar increase in H3 lysine 27 methylation was observed in ash1 and trx mutant larvae. Our findings suggest that KIS-L promotes early elongation and counteracts Polycomb group repression by recruiting the ASH1 and TRX histone methyltransferases to chromatin.

A role for repressive complexes and H3K9 di-methylation in PRDM5-associated brittle cornea syndrome

DEFF Research Database (Denmark)

Porter, Louise F; Galli, Giorgio G; Williamson, Sally

2015-01-01

skin fibroblasts and retinal tissue from BCS2 patients, to elucidate the epigenetic role of PRDM5 and mechanisms of its dysregulation in disease.First we report abnormal retinal vascular morphology in the eyes of two cousins with BCS2 (PRDM5 Δ exons 9-14) using immunohistochemistry, and mine data from......, and dysregulated H3K9 di-methylation in skin fibroblasts of three patients (p.Arg590*, p.Glu134* and Δ exons 9-14) by western blotting. These findings suggest that defective interaction of PRDM5 with repressive complexes, and dysregulation of H3K9 di-methylation, play a role in PRDM5-associated disease.......Type 2 brittle cornea syndrome (BCS2) is an inherited connective tissue disease with a devastating ocular phenotype caused by mutations in the transcription factor PRDM5 hypothesised to exert epigenetic effects through histone and DNA methylation. Here we investigate clinical samples, including...

2,4-Diamino-6-methyl-1,3,5-triazin-1-ium hydrogen oxalate

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Bohari M. Yamin

2012-05-01

Full Text Available The title compound, C4H8N5+·C2HO4−, was obtained from the reaction of oxalic acid and 2,4-diamino-6-methyl-1,3,5-triazine. The protonated triazine ring is essentially planar with a maximum deviation of 0.035 (1 Å, but the hydrogen oxalate anion is less planar, with a maximum deviation of 0.131 (1 Å for both carbonyl O atoms. In the crystal, the ions are linked by intermolecular N—H...O, N—H...N, O—H...O and C—H...O hydrogen bonds, forming a three-dimensional network. Weak π–π [centroid–centroid distance = 3.763 Å] and C—O...π interactions [O...centroid = 3.5300 (16 Å, C—O...centroid = 132.19 (10°] are also present.

Exploring the Link between Nucleosome Occupancy and DNA Methylation

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Cecilia Lövkvist

2018-01-01

Full Text Available Near promoters, both nucleosomes and CpG sites form characteristic spatial patterns. Previously, nucleosome depleted regions were observed upstream of transcription start sites and nucleosome occupancy was reported to correlate both with CpG density and the level of CpG methylation. Several studies imply a causal link where CpG methylation might induce nucleosome formation, whereas others argue the opposite, i.e., that nucleosome occupancy might influence CpG methylation. Correlations are indeed evident between nucleosomes, CpG density and CpG methylation—at least near promoter sites. It is however less established whether there is an immediate causal relation between nucleosome occupancy and the presence of CpG sites—or if nucleosome occupancy could be influenced by other factors. In this work, we test for such causality in human genomes by analyzing the three quantities both near and away from promoter sites. For data from the human genome we compare promoter regions with given CpG densities with genomic regions without promoters but of similar CpG densities. We find the observed correlation between nucleosome occupancy and CpG density, respectively CpG methylation, to be specific to promoter regions. In other regions along the genome nucleosome occupancy is statistically independent of the positioning of CpGs or their methylation levels. Anti-correlation between CpG density and methylation level is however similarly strong in both regions. On promoters, nucleosome occupancy is more strongly affected by the level of gene expression than CpG density or CpG methylation—calling into question any direct causal relation between nucleosome occupancy and CpG organization. Rather, our results suggest that for organisms with cytosine methylation nucleosome occupancy might be primarily linked to gene expression, with no strong impact on methylation.

A convenient method to synthesize N-[3H]methyl-N-nitrosocarbamate transfer reagents

International Nuclear Information System (INIS)

Mehta, P.; Gold, B.; Konakahara, T.

1992-01-01

Activated N-alkyl-N-nitrosocarbamates are useful acyl transfer reagents that are employed in the synthesis of N-alkyl-N-nitrosoureas and related N-nitroso compounds. The nitrosourea products are of chemical and biological interest because they provide access to the in situ generation of highly reactive carbonium type intermediates, which, depending on their structure, can be powerful carcinogens or antineoplastic agents. The availability of radiolabeled nitrosoureas greatly facilitates studies on their chemical and biological activities. Generally, the synthesis of activated nitrosocarbamates requires condensation of radiolabeled alkylisocyanates with the appropriate alcohol. Because radiolabeled alkylisocyanates are not commercially available and/or troublesome to synthesize, we have developed an easy and economical method for preparing N-[ 3 H]methyl-N-nitrosocarbamates suitable for use as transfer reagents utilizing 1,2,2,2-tetrachloroethyl chloroformate and [ 3 H]methylamine hydrochloride as starting materials. (author)

Regional Differential Effects of the Novel Histamine H3 Receptor Antagonist 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on Histamine Release in the Central Nervous System of Freely Moving Rats

OpenAIRE

Giannoni, Patrizia; Medhurst, Andrew D.; Passani, Maria Beatrice; Giovannini, Maria Grazia; Ballini, Chiara; Corte, Laura Della; Blandina, Patrizio

2010-01-01

After oral administration, the nonimidazole histamine H3 receptor antagonist, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), increased histamine release from the tuberomammillary nucleus, where all histaminergic somata are localized, and from where their axons project to the entire brain. To further understand functional histaminergic circuitry in the brain, dual-probe microdialysis was used to pharmacologically block H3...

1,1′-{1,4-Phenylene bis[3-(6-chloro-2-methyl-4-phenylquinolin-3-yl-4,5-dihydro-1H-pyrazole-5,1-diyl]}dibutan-1-one

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Allaoua Kedjadja

2015-10-01

Full Text Available A new polycyclic compound, 1,1′-{1,4-phenylene bis[3-(6-chloro-2-methyl-4-phenylquinolin-3-yl-4,5-dihydro-1H-pyrazole-5,1-diyl]}dibutan-1-one (3 has been synthesized by cyclocondensation of (2E,2′E-1,1′-bis(6-chloro-2-methyl-4-phenylquinolin-3-yl-3,3′-(1,4-phenylenediprop-2-en-1-one (2 and hydrazine hydrate in butanoic acid. The structure of this compound was established by elemental analysis, 1H-NMR, 13C-NMR, mass and IR spectroscopy.

Methyl 3-(Quinolin-2-ylindolizine-1-carboxylate

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Roumaissa Belguedj

2015-12-01

Full Text Available A novel compound, methyl 3-(quinolin-2-ylindolizine-1-carboxylate (2 has been synthesized by cycloaddition reaction of 1-(quinolin-2-ylmethylpyridinium ylide (1 with methyl propiolate in presence of sodium hydride in THF. The structure of this compound was established by IR, 1H-NMR, 13C-NMR and MS data

A convenient synthesis of isotopically labelled anthraquinones, chrysophanol, islandicin, and emodin. Incorporation of [methyl-2H3] chrysophanol into tajixanthone in Aspergillus variecolor

International Nuclear Information System (INIS)

Ahmed, S.A.; Bardshiri, E.; Simpson, T.J.

1987-01-01

Cycloaddition reactions of labelled 6-methoxy-3-methyl-2-pyrone (1) with napthoquinones provide the common fungal anthraquinones, chrysophanol (2), islandicin (3), and emodin (4) suitably labelled for biosynthetic studies, as demonstrated by synthesis and incorporation of [methyl- 2 H 3 ]chrysophanol into the xanthone metabolite, tajixanthone (17) in Aspergillus variecolor. (author)

[6-chloro-3-pyridylmethyl-{sup 3}H]neonicotinoids as high-affinity radioligands for the nicotinic acetylcholine receptor: preparation using NaB{sup 3}H{sub 4} and LiB{sup 3}H{sub 4}

Energy Technology Data Exchange (ETDEWEB)

Latli, Bachir; Casida, J.E. [California Univ., Berkeley, CA (United States). Dept. of Environmental Science Policy and Management; Chit Than; Morimoto, Hiromi; Williams, P.G. [Lawrence Berkeley National Lab., CA (United States)

1996-11-01

NaB{sup 3}H{sub 4} and LiB{sup 3}H{sub 4} at 78% and 97% isotopic enrichments, respectively, were used in the synthesis of {sup 3}H-labeled 1-(6-chloro-3-pyridyl)-methyl-2-nitromethyleneimidazolidine (CH-IMI) and N`-[(6-chloro-3-pyridyl)methyl]-n``-cyano-n`-methylacetamidine (acetamiprid) (two very potent insecticides) and of 1-(6-chloro-3-pyridyl)methyl-2-iminoimidazolidine (desnitro-IMI) (a metabolite of the commercial insecticides imidacloprid). 6-Chloronicotinoyl chloride was treated with either NaB{sup 3}H{sub 4} in methanol or LiB{sup 3}H{sub 4} in tetrahydrofuran and the resulting alcohol transformed to 2-chloro-5-chloromethylpyridine, which was then coupled to N-cyano-N`-methylacetamidine to give [{sup 3}H] acetamiprid (45 Ci/mmol). 2-Chloro-5-chloro[{sup 3}H]methylpyridine was also reacted with ethylenediamine and the product was either refluxed in absolute ethanol with 1,1-bis(methylthio)-2-nitro-ethylene to provide [{sup 3}H]CH-IMI or reacted in toluene with a solution of cyanogen bromide to produce [{sup 3}H] desnitro-IMI (each 55 Ci/mmol). (author).

Preparation of H3-labelled methyl ethers of saturated fatty acids by heterogeneous catalytic isotope exchange in solution with gaseous tritium

International Nuclear Information System (INIS)

Shevchenko, V.P.; Myasoedov, N.F.

1980-01-01

A simple method of preparing 3 H-labelled methyl ethers of saturated fatty acids in the dioxane solution using the method of isotopic heterogenous catalytic exchange with gaseous tritium, is suggested. 3 H-labelled natural fatty acids (C 12 -C 18 ) are prepared by alkaline hydrolysis [ru

Investigations on the synthesis and pharmacological properties of 4-alkoxy-2-[2-hydroxy-3-(4-aryl-1-piperazinyl)propyl]-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones.

Science.gov (United States)

Sladowska, Helena; Filipek, Barbara; Szkatuła, Dominika; Sabiniarz, Aleksandra; Kardasz, Małgorzata; Potoczek, Joanna; Sieklucka-Dziuba, Maria; Rajtar, Grazyna; Kleinrok, Zdzisław; Lis, Tadeusz

2002-11-01

Synthesis of 2-[2-hydroxy-3-(4-aryl-1-piperazinyl)propyl] derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (8-12) is described. The chlorides used in the above synthesis can exist in two isomeric forms: chain (18-20) and cyclic (19a, 20a). The compounds 8-12 exhibited potent analgesic activity which was superior than that of acetylsalicylic acid in two different tests. Most of the investigated imides suppressed significantly spontaneous locomotor activity in mice.

2-[3-Furyl(hydroxy)methyl]-2,3-dimethylcyclohexanone.

Science.gov (United States)

García, Esther; Mendoza, Virgilio; Guzmán, José Agustín; Maldonado Graniel, Luis Angel; Hernández-Ortega, Simón

2002-06-01

Contribution No. 1750 of the Instituto de Quimica, UNAM, Mexico. In the molecule of the title compound, C(13)H(18)O(3), there is a syn relationship between the two vicinal methyl groups. The six-membered ring adopts a chair conformation, with one equatorial and two axial groups, and the furyl group is almost parallel to the ketone group. Intermolecular hydrogen bonds [O[bond]H...O[double bond]C 2.814 (3) A] form chains along [100].

Application of machine learning methods to histone methylation ChIP-Seq data reveals H4R3me2 globally represses gene expression

Science.gov (United States)

2010-01-01

Background In the last decade, biochemical studies have revealed that epigenetic modifications including histone modifications, histone variants and DNA methylation form a complex network that regulate the state of chromatin and processes that depend on it including transcription and DNA replication. Currently, a large number of these epigenetic modifications are being mapped in a variety of cell lines at different stages of development using high throughput sequencing by members of the ENCODE consortium, the NIH Roadmap Epigenomics Program and the Human Epigenome Project. An extremely promising and underexplored area of research is the application of machine learning methods, which are designed to construct predictive network models, to these large-scale epigenomic data sets. Results Using a ChIP-Seq data set of 20 histone lysine and arginine methylations and histone variant H2A.Z in human CD4+ T-cells, we built predictive models of gene expression as a function of histone modification/variant levels using Multilinear (ML) Regression and Multivariate Adaptive Regression Splines (MARS). Along with extensive crosstalk among the 20 histone methylations, we found H4R3me2 was the most and second most globally repressive histone methylation among the 20 studied in the ML and MARS models, respectively. In support of our finding, a number of experimental studies show that PRMT5-catalyzed symmetric dimethylation of H4R3 is associated with repression of gene expression. This includes a recent study, which demonstrated that H4R3me2 is required for DNMT3A-mediated DNA methylation--a known global repressor of gene expression. Conclusion In stark contrast to univariate analysis of the relationship between H4R3me2 and gene expression levels, our study showed that the regulatory role of some modifications like H4R3me2 is masked by confounding variables, but can be elucidated by multivariate/systems-level approaches. PMID:20653935

6-Chloro-3-[5-(3-methoxy-8-methyl-4-quinolyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl]-2-methyl-4-phenylquinoline

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Hoong-Kun Fun

2009-11-01

Full Text Available In the title compound, C36H29ClN4O, the dihydropyrazole ring adopts an envelope conformation. The two quinoline ring systems (r.m.s. deviations = 0.029 and 0.018 Å are oriented at a dihedral angle of 71.43 (4°. One of the quinoline rings makes a dihedral angle of 65.40 (7° with the phenyl substituent. In the crystal, molecules are linked into chains along the b axis by intermolecular C—H...N hydrogen bonds. In addition, C—H...π and π–π [centroid–centroid distance = 3.7325 (8 Å] interactions are observed.

A comparison of N-methyl-D-aspartate-evoked release of adenosine and [3H]norepinephrine from rat cortical slices

International Nuclear Information System (INIS)

Hoehn, K.; Craig, C.G.; White, T.D.

1990-01-01

Tetrodotoxin reduced N-methyl-D-aspartate (NMDA)-evoked release of adenosine by 35% but virtually abolished [3H]norepinephrine release. Although [3H]norepinephrine release from rat cortical slices evoked by 500 microM NMDA was abolished by 1.2 mM Mg++, which produces a voltage-sensitive, uncompetitive block of NMDA-channels, adenosine release was increased in the presence of Mg++. Partial depolarization with 12 mM K+ relieved the Mg++ block of 500 microM NMDA-evoked [3H]norepinephrine release but did not affect adenosine release, indicating that a Mg++ requirement for the adenosine release process per se cannot account for this discrepancy. NMDA was 33 times more potent in releasing adenosine than [3H]norepinephrine. At submaximal concentrations of NMDA (10 and 20 microM), adenosine release was augmented in Mg+(+)-free medium. Although a high concentration of the uncompetitive NMDA antagonist MK-801 [(+)-5-methyl-10,11,dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine maleate] (3 microM) blocked NMDA-evoked release of [3H]norepinephrine and adenosine, a lower concentration (300 nM) decreased NMDA-evoked [3H]norepinephrine release by 66% without affecting adenosine release. These findings suggest that maximal adenosine release occurs when relatively few NMDA receptors are activated, raising the possibility that spare receptors exist for NMDA-evoked adenosine release. Rather than acting as a protectant against excessive NMDA excitation, released adenosine might provide an inhibitory threshold which must be overcome for NMDA-mediated neurotransmission to proceed

Crystal structure of 1-methyl-4-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine

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Mohammed El Fal

2014-12-01

Full Text Available In the title compound, C7H8N4S, the non-H atoms of the pyrazolo[3,4-d]pyrimidine ring system and the methylsulfanyl group lie on a crystallographic mirror plane. In the crystal, molecules are linked via a number of π–π interactions [centroid–centroid distances vary from 3.452 (7 to 3.6062 (8 Å], forming a three-dimensional structure.

Repression of Middle Sporulation Genes in Saccharomyces cerevisiae by the Sum1-Rfm1-Hst1 Complex Is Maintained by Set1 and H3K4 Methylation

Science.gov (United States)

Jaiswal, Deepika; Jezek, Meagan; Quijote, Jeremiah; Lum, Joanna; Choi, Grace; Kulkarni, Rushmie; Park, DoHwan; Green, Erin M.

2017-01-01

The conserved yeast histone methyltransferase Set1 targets H3 lysine 4 (H3K4) for mono, di, and trimethylation and is linked to active transcription due to the euchromatic distribution of these methyl marks and the recruitment of Set1 during transcription. However, loss of Set1 results in increased expression of multiple classes of genes, including genes adjacent to telomeres and middle sporulation genes, which are repressed under normal growth conditions because they function in meiotic progression and spore formation. The mechanisms underlying Set1-mediated gene repression are varied, and still unclear in some cases, although repression has been linked to both direct and indirect action of Set1, associated with noncoding transcription, and is often dependent on the H3K4me2 mark. We show that Set1, and particularly the H3K4me2 mark, are implicated in repression of a subset of middle sporulation genes during vegetative growth. In the absence of Set1, there is loss of the DNA-binding transcriptional regulator Sum1 and the associated histone deacetylase Hst1 from chromatin in a locus-specific manner. This is linked to increased H4K5ac at these loci and aberrant middle gene expression. These data indicate that, in addition to DNA sequence, histone modification status also contributes to proper localization of Sum1. Our results also show that the role for Set1 in middle gene expression control diverges as cells receive signals to undergo meiosis. Overall, this work dissects an unexplored role for Set1 in gene-specific repression, and provides important insights into a new mechanism associated with the control of gene expression linked to meiotic differentiation. PMID:29066473

Radiosynthesis of 3-{l_brace}[4-(4-[{sup 18}F]fluorobenzyl)]piperazin-1-yl{r_brace}methyl-1H-pyrrolo[2,3-b]pyridine: A potential dopamine D{sub 4} receptor imaging agent

Energy Technology Data Exchange (ETDEWEB)

Haibin Tian; Duanzhi Yin; Junling Li; Lan Zhang; Cunfu Zhang; Yongxian Wang; Wei Zhou [Radiopharmaceutical Research Center, Shanghai Inst. of Nuclear Research, The Chinese Academy of Sciences, Shanghai, SH (China)

2003-07-01

The dopamine D{sub 4} receptor (D{sub 4}R) is expressed in low density in various extrastriatal brain regions. This receptor subtype is discussed in relation to the pathophysiology and treatment of schizophrenia but to date no selective positron emission tomography (PET) ligand is available to study its distribution in vivo. The 7-azaindole derivative 3-([4-(4-iodophenyl)piperazin-1-yl]-methyl)-1H-pyrrolo [2,3-b]pyridine (L-750,667) is a novel, high-affinity (K{sub i}=0.51nM) and selective D{sub 4}R ligand. L-750,667 analogue 3-[4-(4-[{sup 18}F]fluorobenzyl)]piperazin-1-yl methyl-1H-pyrrolo[2,3-b]-pyridine was prepared by reacting 3-(piperazin-1-yl)-methyl-1H-pyrrolo[2,3-b]pyridine with 4-[ 18F]fluorobenzaldehyde, which was labeled with no carrier added [ 18F]fluoride. The radiochemical yield of 3-[4-(4-[{sup 18}F]fluorobenzyl)]piperazin-1-yl methyl-1H-pyrrolo[2,3-b]pyridine was 12.0% at end of synthesis (EOS), and the synthesis time was 73min. The labeled benzaldehydes may be useful precursors for the radiosyntheses of other complex radiotracers for PET.

6-Hydroxy-5-[(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl(4-nitrophenylmethyl]-1,3-dimethylpyrimidine-2,4(1H,3H-dione

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N. Sureshbabu

2013-11-01

Full Text Available In the title compound, C21H23N3O7, the pyrimidinedione ring adopts a screw-boat conformation, whereas the cyclohexenone ring adopts an envelope conformation, with the C atom bearing the methyl groups as the flap atom. The dihedral angle between the mean planes of the pyrimidinedione and cyclohexenone rings is 58.78 (2°. The pyrimidinedione and cyclohexenone rings form dihedral angles of 59.94 (3 and 54.73 (2°, respectively, with the 4-nitrophenyl ring. Relatively strong intramolecular O—H...O hydrogen bonds are observed. In the crystal, molecules are linked by C—H...O hydrogen bonds, forming a chain along the c-axis direction.

A convenient method to synthesize N-[[sup 3]H]methyl-N-nitrosocarbamate transfer reagents

Energy Technology Data Exchange (ETDEWEB)

Mehta, P.; Gold, B. (Nebraska Univ., Omaha, NE (United States). Eppley Inst. for Research in Cancer); Konakahara, T. (Science Univiversity of Tokyo, Noda, Chiba (Japan). Faculty of Science and Technology)

1992-11-01

Activated N-alkyl-N-nitrosocarbamates are useful acyl transfer reagents that are employed in the synthesis of N-alkyl-N-nitrosoureas and related N-nitroso compounds. The nitrosourea products are of chemical and biological interest because they provide access to the in situ generation of highly reactive carbonium type intermediates, which, depending on their structure, can be powerful carcinogens or antineoplastic agents. The availability of radiolabeled nitrosoureas greatly facilitates studies on their chemical and biological activities. Generally, the synthesis of activated nitrosocarbamates requires condensation of radiolabeled alkylisocyanates with the appropriate alcohol. Because radiolabeled alkylisocyanates are not commercially available and/or troublesome to synthesize, we have developed an easy and economical method for preparing N-[[sup 3]H]methyl-N-nitrosocarbamates suitable for use as transfer reagents utilizing 1,2,2,2-tetrachloroethyl chloroformate and [[sup 3]H]methylamine hydrochloride as starting materials. (author).

4-Methyl-5-phenyl-1H-pyrazol-3-ol

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Tara Shahani

2010-07-01

Full Text Available The title compound, C10H10N2O, crystallizes with two independent molecules in the asymmetric unit, having closely comparable geometries. The dihedral angles between the 1H-pyrazole and benzene rings in the two molecules are 39.57 (14 and 41.95 (13°. The two molecules are each connected to neighbouring molecules by pairs of intermolecular O—H...N hydrogen bonds, forming dimers with R22(8 ring motifs. These dimers are further linked into R44(10 ring motifs by intermolecular N—H...O hydrogen bonds, forming chains along [101]. The crystal structure is further stabilized by a C—H...π interaction.

(E-4-Hydroxy-6-methyl-3-[1-(2-phenylhydrazinylideneethyl]-2H-pyran-2-one

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Samra Rahmouni

2016-05-01

Full Text Available The title compound, C14H14N2O3, crystallized with three crystallographically independent molecules (A, B and C in the asymmetric unit. The three molecules each have an E conformation about the C=N bond but differ in the orientation of the phenyl and pyran rings. The dihedral angles between the phenyl and pyran ring planes are 14.30 (1, 28.38 (1 and 25.58 (1° in molecules A, B and C, respectively. There is an intramolecular O—H...N hydrogen bond in each molecule with an S(6 ring motif. In the crystal, molecules are linked by N—H...O and C—H...O hydrogen bonds, forming layers parallel to (001, enclosing R22(8 and R33(21 ring motifs. The layers are linked via C—H...π interactions, forming bilayers, which are joined by a further C—H...π interaction, forming a three-dimensional structure.

The histone H3K9 methylation and RNAi pathways regulate normalnucleolar and repeated DNA organization by inhibiting formation ofextrachromosomal DNAs

Energy Technology Data Exchange (ETDEWEB)

Peng, Jamy C.; Karpen, Gary H.

2006-06-15

In order to identify regulators of nuclear organization, Drosophila mutants in the Su(var)3-9 histone H3K9 methyltransferase, RNAi pathway components, and other regulators of heterochromatin-mediated gene silencing were examined for altered nucleoli and positioning of repeated DNAs. Animals lacking components of the H3K9 methylation and RNAi pathways contained disorganized nucleoli, ribosomal DNA (rDNA) and satellite DNAs. The levels of H3K9 dimethylation (H3K9me2) in chromatin associated with repeated DNAs decreased dramatically in Su(var)3-9 and dcr-2 (dicer-2) mutant tissues compared to wild type. We also observed a substantial increase in extrachromosomal repeated DNAs in mutant tissues. The disorganized nucleolus phenotype depends on the presence of Ligase 4 (Lig4), and ecc DNA formation is not induced by removal of cohesin. We conclude that H3K9 methylation of rDNA and satellites, maintained by Su(var)3-9, HP1, and the RNAi pathway, is necessary for the structural stability of repeated DNAs, which is mediated through suppression of non-homologous end joining (NHEJ). These results suggest a mechanism for how local chromatin structure can regulate genome stability, and the organization of chromosomal elements and nuclear organelles.

Biosynthesis, purification and receptor binding properties of high specific radioactivity 1α,24(R), 25-trihydroxy-[26,27-methyl-3H]-vitamin D3

International Nuclear Information System (INIS)

Chandler, J.S.; Pike, J.W.; Haussler, M.R.

1982-01-01

A procedure for the biosynthesis and purification of 1α,24(R),25-trihydroxy[26,27-methyl- 3 H]-vitamin D 3 (1,24,25-(OH) 3 [ 3 H]D 3 ) is reported. A kidney homogenate from chicks receiving a high calcium diet (3%) and oral supplements of 1α,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) was used for C-24-hydroxylation of 1α,25-dihydroxy[26,27-methyl- 3 H]-vitamin D 3 (1,25-(OH) 2 [ 3 H]D 3 ), in vitro. Extraction and purification of the homogenate lipid fraction by Sephadex LH-20 and high performance liquid chromatography yielded radiochemically pure 1,24,25-(OH) 3 [ 3 H]D 3 with a specific radioactivity equivalent to the initial substrate (166 Ci/mmol). The authenticity of the generated metabolite was assessed by co-migration with synthetic 1,24,25-(OH) 3 D 3 on high performance liquid chromatography and by equimolar competition with authentic radioinert 1,24,25-(OH) 3 D 3 for binding to a purified receptor protein from rat kidney. Binding studies indicate the trihydroxylated metabolite competes 40-50% as effectively as 1,25-(OH) 2 D 3 for hormone binding sites. Further analysis of 1,24,25-(OH) 3 D 3 -receptor interaction reveals a high-affinity, saturable binding with an apparent Ksub(d) of 2.2 x 10 -9 M. These studies demonstrate that although slightly less active than 1,25-(OH) 2 D 3 , 1,24,25-(OH) 3 D 3 is capable of hormone-like interactions, in vitro. The availability of this high specific radioactivity sterol should allow for clarification of its potential physiologic significance. (author)

Evidence for methyl group transfer between the methyl-accepting chemotaxis proteins in Bacillus subtilis

International Nuclear Information System (INIS)

Bedale, W.A.; Nettleton, D.O.; Sopata, C.S.; Thoelke, M.S.; Ordal, G.W.

1988-01-01

The authors present evidence for methyl (as methyl or methoxy) transfer from the methyl-accepting chemotaxis proteins H1 and possibly H3 of Bacillus subtilis to the methyl-accepting chemotaxis protein H2. This methyl transfer, which has been observed in vitro was strongly stimulated by the chemoattractant aspartate and thus may plan an important role in the sensory processing system of this organism. Although radiolabeling of H1 and H3 began at once after the addition of [ 3 H] methionine, radiolabeling of H2 showed a lag. Furthermore, the addition of excess nonradioactive methionine caused immediate exponential delabeling of H1 and H3 while labeling of H2 continued to increase. Methylation of H2 required the chemotactic methyltransferase, probably to first methylate H1 and H3. Aspartate caused increased labeling of H2 and strongly decreased labeling of H1 and H3 after the addition of nonradioactive methionine. Without the addition of nonradioactive methionine, aspartate caused demethylation of H1 and to a lesser extent H3, with an approximately equal increase of methylation of H2

The synthesis of [[sup 2]H],[[sup 3]H], and [[sup 14]C]-labeled 8[beta]-[(methylthio)methyl]-6-propylergoline mesylate (pergolide mesylate), a potent, long-acting dopamine agonist

Energy Technology Data Exchange (ETDEWEB)

Wheeler, W.J.; Kau, D.L.K.; Bach, N.J. (Lilly (Eli) and Co., Indianapolis, IN (United States). Lilly Research Labs.)

1990-03-01

The [[sup 3]H]- and two[[sup 14]C]-isopomers of 8[beta]-[(methylthio)methyl]-6-propylergoline mesylate (pergolide mesylate) have been synthesized. The [[sup 3]H]-derivative was synthesized by the palladium catalyzed tritiation of the corresponding 6-allyl derivative. Reaction of 8[beta]-[(methylthio)methyl]-ergoline with 1-[[sup 14]C]-1-propyl bromide yielded pergolide labeled in the 6-propyl group. Alternatively, reaction of 8[beta]-mesyloxy-6-propylergoline with [[sup 14]C]-sodium cyanide, followed by base hydrolysis, yielded 8 [beta]-carboxy-6-propylergoline-[[sup 14]C], which was subsequently converted to pergolide mesylate radiolabeled in the 17-position via a four step sequence. (Author).

Identification of metabolites in urine and feces from rats dosed with the heterocyclic amine, 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C)

DEFF Research Database (Denmark)

Frederiksen, H; Frandsen, H

2004-01-01

2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C) is a proximate mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking. In model systems, MeA alpha C can be formed by pyrolyses of either tryptophan or proteins of animal or vegetable origin. In the present study, the in ......2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C) is a proximate mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking. In model systems, MeA alpha C can be formed by pyrolyses of either tryptophan or proteins of animal or vegetable origin. In the present study...

tert-Butyl 3-(8-bromo-4H,10H-1,2-oxazolo[4,3-c][1]benzoxepin-10-yl-2-methyl-1H-indole-1-carboxylate

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Ankur Trigunait

2010-08-01

Full Text Available In the title compound, C25H23BrN2O4, the seven-membered ring adopts a twisted-boat conformation. The indole ring system is planar within 0.021 (2 Å and the ester group [–C(=O—O—C–] is almost coplanar with it [dihedral angle = 3.0 (2°]. The conformation of the ester group is influenced by intramolecular C—H...O interactions. In the crystal structure, molecules are linked into chains along the b axis by C—H...N hydrogen bonds.

Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition?

International Nuclear Information System (INIS)

Roon, Eddy HJ van; Hes, Frederik J; Tops, Carli MJ; Wezel, Tom van; Boer, Judith M; Morreau, Hans; Puijenbroek, Marjo van; Middeldorp, Anneke; Eijk, Ronald van; Meijer, Emile J de; Erasmus, Dianhdra; Wouters, Kim AD; Engeland, Manon van; Oosting, Jan

2010-01-01

To investigate the etiology of MLH1 promoter methylation in mismatch repair (MMR) mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high ages, young patients bearing this type of malignancy are rare and could provide additional insight into the etiology of sporadic MSI-H colon cancer. We studied a set of 46 MSI-H colon tumors cases with MLH1 promoter methylation which was enriched for patients with an age of onset below 50 years (n = 13). Tumors were tested for CIMP marker methylation and mutations linked to methylation: BRAF, KRAS, GADD45A and the MLH1 -93G>A polymorphism. When available, normal colon and leukocyte DNA was tested for GADD45A mutations and germline MLH1 methylation. SNP array analysis was performed on a subset of tumors. We identified two cases (33 and 60 years) with MLH1 germline promoter methylation. BRAF mutations were less frequent in colon cancer patients below 50 years relative to patients above 50 years (p-value: 0.044). CIMP-high was infrequent and related to BRAF mutations in patients below 50 years. In comparison with published controls the G>A polymorphism was associated with our cohort. Although similar distribution of the pathogenic A allele was observed in the patients with an age of onset above and below 50 years, the significance for the association was lost for the group under 50 years. GADD45A sequencing yielded an unclassified variant. Tumors from both age groups showed infrequent copy number changes and loss-of-heterozygosity. Somatic or germline GADD45A mutations did not explain sporadic MSI-H colon cancer. Although germline MLH1 methylation was found in two individuals, locus-specific somatic MLH1 hypermethylation explained the majority of sporadic early onset MSI-H colon cancer cases. Our data do not suggest an intrinsic tendency for CpG island hypermethylation in these early onset MSI-H tumors other than through somatic mutation of BRAF

Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition?

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Hes Frederik J

2010-05-01

Full Text Available Abstract Background To investigate the etiology of MLH1 promoter methylation in mismatch repair (MMR mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high ages, young patients bearing this type of malignancy are rare and could provide additional insight into the etiology of sporadic MSI-H colon cancer. Methods We studied a set of 46 MSI-H colon tumors cases with MLH1 promoter methylation which was enriched for patients with an age of onset below 50 years (n = 13. Tumors were tested for CIMP marker methylation and mutations linked to methylation: BRAF, KRAS, GADD45A and the MLH1 -93G>A polymorphism. When available, normal colon and leukocyte DNA was tested for GADD45A mutations and germline MLH1 methylation. SNP array analysis was performed on a subset of tumors. Results We identified two cases (33 and 60 years with MLH1 germline promoter methylation. BRAF mutations were less frequent in colon cancer patients below 50 years relative to patients above 50 years (p-value: 0.044. CIMP-high was infrequent and related to BRAF mutations in patients below 50 years. In comparison with published controls the G>A polymorphism was associated with our cohort. Although similar distribution of the pathogenic A allele was observed in the patients with an age of onset above and below 50 years, the significance for the association was lost for the group under 50 years. GADD45A sequencing yielded an unclassified variant. Tumors from both age groups showed infrequent copy number changes and loss-of-heterozygosity. Conclusion Somatic or germline GADD45A mutations did not explain sporadic MSI-H colon cancer. Although germline MLH1 methylation was found in two individuals, locus-specific somatic MLH1 hypermethylation explained the majority of sporadic early onset MSI-H colon cancer cases. Our data do not suggest an intrinsic tendency for CpG island hypermethylation in these early onset MSI-H tumors other than through

Crystal structures of 2-methoxyisoindoline-1,3-dione, 1,3-dioxoisoindolin-2-yl methyl carbonate and 1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-2-yl methyl carbonate: three anticonvulsant compounds

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Fortune Ezemobi

2014-12-01

Full Text Available The title compounds, C9H7NO3, (1, C10H7NO5, (2, and C14H9NO5, (3, are three potentially anticonvulsant compounds. Compounds (1 and (2 are isoindoline derivatives and (3 is an isoquinoline derivative. Compounds (2 and (3 crystallize with two independent molecules (A and B in their asymmetric units. In all three cases, the isoindoline and benzoisoquinoline moieties are planar [r.m.s. deviations are 0.021 Å for (1, 0.04 and 0.018 Å for (2, and 0.033 and 0.041 Å for (3]. The substituents attached to the N atom are almost perpendicular to the mean planes of the heterocycles, with dihedral angles of 89.7 (3° for the N—O—Cmethyl group in (1, 71.01 (4 and 80.00 (4° for the N—O—C(=OO—Cmethyl groups in (2, and 75.62 (14 and 74.13 (4° for the same groups in (3. In the crystal of (1, there are unusual intermolecular C=O...C contacts of 2.794 (1 and 2.873 (1 Å present in molecules A and B, respectively. There are also C—H...O hydrogen bonds and π–π interactions [inter-centroid distance = 3.407 (3 Å] present, forming slabs lying parallel to (001. In the crystal of (2, the A and B molecules are linked by C—H...O hydrogen bonds, forming slabs parallel to (10-1, which are in turn linked via a number of π–π interactions [the most significant centroid–centroid distances are 3.4202 (7 and 3.5445 (7 Å], forming a three-dimensional structure. In the crystal of (3, the A and B molecules are linked via C—H...O hydrogen bonds, forming a three-dimensional structure, which is consolidated by π–π interactions [the most significant inter-centroid distances are 3.575 (3 and 3.578 (3 Å].

Synthesis of N-methyl-N-nitrosourea linked to a methidium chloride analogue and its reactions with 32P-end-labeled DNA

International Nuclear Information System (INIS)

Konakahara, T.; Wurdeman, R.L.; Gold, B.

1988-01-01

The synthesis and characterization of an N-methyl-N-nitrosourea (MNU) analogue that is covalently linked to methidium nucleus (9) is described. At 37/degrees/C in pH 8.0 buffer 9 hydrolyzes via pseudo-first-order kinetics, with a calculated t/sub 1/2/ = 77 min. By use of polyacrylamide sequencing gels the formation of piperidine-labile N 7 -methylguanine adducts from the reaction of 9 and MNU with 5'- 32 P-end-labeled DNA restriction fragments is reported. DNA methylation by 9 in 10 mM Tris buffer is enhanced with increasing ionic strength (50-200 mM NaCl), which contrasts to the inhibition of MNU-induced cleavage with increasing salt. In addition, 9 methylates all G sites equally, while MNU shows a clear preference for d(G)/sub n/ (n ≥ 3) runs and an asymmetrical methylation pattern within these G-rich regions. The results are discussed in terms of the delivery of the MNU moiety to the DNA target by a non-sequence-specific intercalation process and the subsequent hydrolytic generation of a nondiffusible alkylating intermediate

Synthesis, spectral, thermal and biological studies of transition metal complexes of 4-hydroxy-3-[3-(4-hydroxyphenyl-acryloyl]-6-methyl-2H-pyran-2-one

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BALASAHEB R. ARBAD

2011-09-01

Full Text Available The solid complexes of Mn(II, Fe(III, Co(II, Ni(II, and Cu(II with 4-hydroxy-3-[(2E-3-(4-hydroxyphenylprop-2-enoyl]-6-methyl-2H-pyran-2-one, derived from 3-acetyl-6-methyl-2H-pyran-2,4(3H-dione (dehydroacetic acid and 4-hydroxybenzaldehyde, were synthesized and characterized by elemental analysis, conductometry, thermal analysis, magnetic measurements, IR, 1H-NMR and UV–Vis spectroscopy and a biological study. From the analytical and spectral data, the stoichiometry of the complexes was found to be 1:2 (metal:ligand. The physico–chemical data suggest a distorted octahedral geometry for the Cu(II complexes and an octahedral geometry for all the other complexes. The thermal decomposition of all the complexes was studied by the TG–DTA method. The synthesized ligand and its metal complexes were screened for their in vitro antibacterial activity against Gram-negative (Escherichia coli and Gram-positive (Staphylococcus aureus bacterial strains and for in vitro antifungal activity against Aspergillus flavus, Curvularia lunata and Penicillium notatum. The results of these studies showed the metal complexes to be more antibacterial/antifungal against one or more species as compared with the non-complexed ligand.

Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes

OpenAIRE

Jufvas, ?sa; Sj?din, Simon; Lundqvist, Kim; Amin, Risul; Vener, Alexander V; Str?lfors, Peter

2013-01-01

BACKGROUND: Epidemiological evidence indicates yet unknown epigenetic mechanisms underlying a propensity for overweight and type 2 diabetes. We analyzed the extent of methylation at lysine 4 and lysine 9 of histone H3 in primary human adipocytes from 43 subjects using modification-specific antibodies. RESULTS: The level of lysine 9 dimethylation was stable, while adipocytes from type 2 diabetic and non-diabetic overweight subjects exhibited about 40% lower levels of lysine 4 dimethylation com...

Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers.

Science.gov (United States)

DeVries, Avery; Wlasiuk, Gabriela; Miller, Susan J; Bosco, Anthony; Stern, Debra A; Lohman, I Carla; Rothers, Janet; Jones, Anya C; Nicodemus-Johnson, Jessie; Vasquez, Monica M; Curtin, John A; Simpson, Angela; Custovic, Adnan; Jackson, Daniel J; Gern, James E; Lemanske, Robert F; Guerra, Stefano; Wright, Anne L; Ober, Carole; Halonen, Marilyn; Vercelli, Donata

2017-08-01

The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception. We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study [n = 30] and the Childhood Origins of Asthma Study [n = 28]) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell-derived IL-1β levels were measured by means of ELISA. Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3, the most connected node within the network of asthma-associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator. The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

The crystal structure of zwitterionic 2-{[(4-iminiumyl-3-methyl-1,4-dihydropyridin-1-ylmethyl]carbamoyl}benzoate hemihydrate

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C. S. Chidan Kumar

2017-07-01

Full Text Available The asymmetric unit of the title compound, C15H15N3O3·0.5H2O, comprises two 2-{[(4-iminiumyl-3-methyl-1,4-dihydropyridin-1-ylmethyl]carbamoyl}benzoate zwitterions (A and B and a water molecule. The dihedral angles between the pyridine and phenyl rings in the zwitterions are 53.69 (10 and 73.56 (11° in A and B, respectively. In the crystal, molecules are linked by N—H...O, O—H...O, C—H...O and C—H...π(ring hydrogen bonds into a three-dimensional network. The crystal structure also features π–π interactions involving the centroids of the pyridine and phenyl rings [centroid–centroid distances = 3.5618 (12 Å in A and 3.8182 (14 Å in B].

Non-Covalent Interactions in the Crystal Structure of Methyl 4-Hydroxy-3-Nitrobenzoate

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Jim Simpson

2012-06-01

Full Text Available Methyl 4-hydroxy-3-nitrobenzoate, (I, C8H7NO5, crystallizes with two unique molecules, A and B, in the asymmetric unit of the triclinic unit cell. The space group was assigned as P-1, with lattice parameters a = 0.72831(15, b = 1.0522(2, c = 1.1410(2 nm, α = 83.38(3, β = 80.83(3, γ = 82.02(3°, Z = 4, V = 0.8510(3 nm3, Mr = 197.15, Dc = 1.539 g/m3, µ= 0.131 mm−1, F(000 = 408, R = 0.1002 and wR = 0.2519. In the crystal structure, 12 hydrogen bonding and two p-stacking interactions link the molecules into infinite stacked sheets parallel to (101.

X-ray investigations of sulfur-containing fungicides. IV. 4'-[[Benzoyl(4-chlorophenylhydrazono)methyl]sulfonyl]acetanilide and 4'-[[benzoyl(4-methoxyphenylhydrazono)methyl]sulfonyl]acetanilide.

Science.gov (United States)

Wolf, W M

2001-09-01

The conformations of the two approximately isomorphous structures 4'-[[benzoyl(4-chlorophenylhydrazono)methyl]sulfonyl]acetanilide, C(22)H(18)ClN(3)O(4)S, and 4'-[[benzoyl(4-methoxyphenylhydrazono)methyl]sulfonyl]acetanilide, C(23)H(21)N(3)O(5)S, are stabilized by resonance-assisted intramolecular hydrogen bonds linking the hydrazone moieties and sulfonyl groups. The stronger bond is observed in the former compound. The difference in electronic properties between the Cl atom and the methoxy group is too small to significantly alter the non-bonding interactions of the sulfonyl and beta-carbonyl groups.

1H-indol-3-yl-methyl

African Journals Online (AJOL)

Methods: 2-(1H-indol-3-yl)acetic acid (1) was reacted with absolute ethanol and catalytic amount of ... dehydration in the same pot with CBr4 and Ph3P. [6]. ... and used after distillation. ... distilled water or by solvent extraction depending.

Mass spectrometry analysis of the variants of histone H3 and H4 of soybean and their post-translational modifications

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Lam Hon-Ming

2009-07-01

Full Text Available Abstract Background Histone modifications and histone variants are of importance in many biological processes. To understand the biological functions of the global dynamics of histone modifications and histone variants in higher plants, we elucidated the variants and post-translational modifications of histones in soybean, a legume plant with a much bigger genome than that of Arabidopsis thaliana. Results In soybean leaves, mono-, di- and tri-methylation at Lysine 4, Lysine 27 and Lysine 36, and acetylation at Lysine 14, 18 and 23 were detected in HISTONE H3. Lysine 27 was prone to being mono-methylated, while tri-methylation was predominant at Lysine 36. We also observed that Lysine 27 methylation and Lysine 36 methylation usually excluded each other in HISTONE H3. Although methylation at HISTONE H3 Lysine 79 was not reported in A. thaliana, mono- and di-methylated HISTONE H3 Lysine 79 were detected in soybean. Besides, acetylation at Lysine 8 and 12 of HISTONE H4 in soybean were identified. Using a combination of mass spectrometry and nano-liquid chromatography, two variants of HISTONE H3 were detected and their modifications were determined. They were different at positions of A31F41S87S90 (HISTONE variant H3.1 and T31Y41H87L90 (HISTONE variant H3.2, respectively. The methylation patterns in these two HISTONE H3 variants also exhibited differences. Lysine 4 and Lysine 36 methylation were only detected in HISTONE H3.2, suggesting that HISTONE variant H3.2 might be associated with actively transcribing genes. In addition, two variants of histone H4 (H4.1 and H4.2 were also detected, which were missing in other organisms. In the histone variant H4.1 and H4.2, the amino acid 60 was isoleucine and valine, respectively. Conclusion This work revealed several distinct variants of soybean histone and their modifications that were different from A. thaliana, thus providing important biological information toward further understanding of the histone

(3R,4R,4aS,7aR,12bS-3-Cyclopropylmethyl-4a,9-dihydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-3-ium bromide

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Xiangfeng Chen

2012-02-01

Full Text Available The title compound, C21H26NO4+·Br−, also known as R-methylnaltrexone (MNTX bromide, is a selective peripherally acting μ-opioid receptor antagonist with a oroxymorphone skeleton, synthesized by hydroxyl protection, N-methylation, deprotection and anion exchange of naltrexone. It comprises a five-ring system A/B/C/D/E. Rings C and E adopt distorted chair conformations, whereas ring D is in half-chair conformation. The C/E ring junctions are trans fused. The dihedral angle between rings D and E is 82.3 (1°, while the dihedral angles between the planes of rings C and A, and rings D and E are respectively 81.7 (1, 75.9 (1 and 12.2 (1°. In the crystal, molecules are linked by O—H...Br hydrogen bonds.

Photolabeling of tonoplast from sugar beet cell suspensions by [3H]5-(N-methyl-N-isobutyl)-amiloride, an inhibitor of the vacuolar Na+/H+ antiport

International Nuclear Information System (INIS)

Barkla, B.J.; Charuk, J.H.M.; Blumwald, E.; Cragoe, E.J. Jr.

1990-01-01

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 ΔpH-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

DNMT3AR882H mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice

DEFF Research Database (Denmark)

Scourzic, L; Couronné, L; Pedersen, Marianne Terndrup

2016-01-01

malignancies with one mouse developing an AITL-like disease, two mice presenting acute myeloid leukemia (AML)-like and two others T-cell acute lymphoblastic leukemia (T-ALL)-like diseases within 6 months following transplantation. Serial transplantations of DNMT3A(R882H) Tet2(-/-) progenitors led...... to a differentiation bias toward the T-cell compartment, eventually leading to AITL-like disease in 9/12 serially transplanted recipients. Expression profiling suggested that DNMT3A(R882H) Tet2(-/-) T-ALLs resemble those of NOTCH1 mutant. Methylation analysis of DNMT3A(R882H) Tet2(-/-) T-ALLs showed a global increase...... in DNA methylation affecting tumor suppressor genes and local hypomethylation affecting genes involved in the Notch pathway. Our data confirm the transformation potential of DNMT3A(R882H) Tet2(-/-) progenitors and represent the first cooperative model in mice involving Tet2 inactivation driving lymphoid...

N-(3-Chloro-4-ethoxy-1-methyl-1H-indazol-5-yl-4-methoxybenzenesulfonamide

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Hakima Chicha

2014-06-01

Full Text Available The indazole ring system of the title compound, C17H18ClN3O4S, is almost planar (r.m.s. deviation = 0.0113 Å and forms dihedral angles of 32.22 (8 and 57.5 (3° with the benzene ring and the mean plane through the 4-ethoxy group, respectively. In the crystal, molecules are connected by pairs of N—H...O hydrogen bonds into inversion dimers, which are further linked by π–π interactions between the diazole rings [intercentroid distance = 3.4946 (11 Å], forming chains parallel to [101].

Blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentration in dystonia cases vs. controls.

Science.gov (United States)

Louis, Elan D; Factor-Litvak, Pam; Michalec, Monika; Jiang, Wendy; Zheng, Wei

2014-09-01

Harmane (1-methyl-9H-pyrido[3,4-b]indole) (HA) is a potent neurotoxin that has been linked to two neurological diseases, essential tremor and Parkinson's disease. Blood harmane concentrations [HA] are elevated in patients with both diseases. An important question is whether HA is specifically linked with these diseases or alternatively, is a non-specific marker of neurological illness. We assessed whether blood [HA] was elevated in patients with a third neurological disease, dystonia, comparing them to controls. Blood [HA] was quantified by high performance liquid chromatography. Subjects comprised 104 dystonia cases and 107 controls. Mean log blood [HA] in dystonia cases was similar to that of controls (0.41±0.51g(-10)/ml vs. 0.38±0.61g(-10)/ml, t=0.42, p=0.68). In unadjusted and adjusted logistic regression analyses, log blood [HA] was not associated with the outcome (diagnosis of dystonia vs. control): odds ratio (OR)unadjusted=1.11, 95% confidence interval (CI)=0.69-1.79, p=0.68; ORadjusted=1.07, 95% CI=0.58-1.97, p=0.84. In contrast to the elevated blood [HA] that has been reported in patients with essential tremor and Parkinson's disease, our data demonstrate that blood [HA] was similar in patients with dystonia and controls. These findings provide the first support for the notion that an elevated blood [HA] is not a broad feature of neurological disease, and may be a specific feature of certain tremor disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Indirect [3H]methyl exchange as a general method for labeling methionine residues: application to calcitonin.

Science.gov (United States)

Barling, P M; Preston, J R; Bibby, N J; Wilson, T

1985-02-01

Native porcine calcitonin from Armour is known to contain two components. It is shown that these can be separated by cation-exchange chromatography in 8 M urea. The technique of [3H]methyl exchange on the methionine residue was used to prepare each of these in a tritiated form. The reduced components formed by demethylation were found to readily reoxidize at neutral pH, to regenerate the disulfide bridge. Evidence is provided to show that the two forms were partially interconverted during these steps. The reoxidized 3H-labeled products were found to be indistinguishable in chemical, immunological, and biological properties from the equivalent components in native porcine calcitonin and had specific activities of approximately 20 Ci/mmol. It is concluded that this labeling method can be conveniently applied to peptides containing one or more disulfide bridges, to give products of high specific activity in acceptable yield, provided appropriate conditions are used to ensure correct reoxidation occurs.

Spatial and temporal variations in bacterial macromolecule labeling with [methyl-3H]thymidine in a hypertrophic lake

International Nuclear Information System (INIS)

Robarts, R.D.; Wicks, R.J.; Sephton, L.M.

1986-01-01

The incorporation of [methyl- 3 H]thymidine into three macromolecular fractions, designated as DNA, RNA, and protein, by bacteria from Hartbeespoort Dam, South Africa, was measured over 1 year by acid-base hydrolysis procedures. Samples were collected at 10 m, which was at least 5 m beneath the euphotic zone. On four occasions, samples were concurrently collected at the surface. Approximately 80% of the label was incorporated into bacterial DNA in surface samples. At 10 m, total incorporation of label into bacterial macromolecules was correlated to bacterial utilization of glucose. The labeling of DNA, which ranged between 0 and 78% of total macromolecule incorporation, was inversely related to glucose uptake, total thymidine incorporation, and euphotic zone algal production. With decreased DNA labeling, increasing proportions of label were found in the RNA fraction and proteins. Enzymatic digestion followed by chromatographic separation of macromolecule fragments indicated that DNA and proteins were labeled while RNA was not. The RNA fraction may represent labeled lipids or other macromolecules or both. The data demonstrated a close coupling between phytoplankton production and heterotrophic bacterial activity in this hypertrophic lake but also confirmed the need for the routine extraction and purification of DNA during [methyl- 3 H]thymidine studies of aquatic bacterial production

Isoproterenol potentiation of methyl mercury effects in vivo cardiac ATPasees and 3H-dopamine uptake

International Nuclear Information System (INIS)

Ahammad-Sahib, K.I.; Moorthy, K.S.; Cameron, J.A.; Desaiah, D.

1988-01-01

Isoproterenol, a potent B-adrenergic receptor agonist, has been known to produce infarct-like myocardial lesions in rats characterized by swelling of endoplasmic reticulum. The swelling of this system is interpreted as an influx of large amount of extracellular fluid into myocardial cells by disturbances of the electrolyte metabolism. Isoproterenol is employed clinically as a bronchodilator in respiratory disorders and as a stimulant in heart block and cardiogenic shocks. In spite of its clinical use, possible drug-chemical interactions leading to adverse health effects are obvious when individuals on a regular isoproterenol treatment are exposed to an environmental contaminant such as methyl mercury. Consumption of fish and fish products is by far the most significant route of exposure to environmental mercury. In spite of such a possibility, little is know about isoproterenol-methyl mercury interaction. The present study forms the first of this kind to report such interactions and their effects on cardiac membrane bound enzymes such as Na + -K + and Ca 2+ -ATPases. Since Na + -K + ATPase has been implicated in uptake and release processes of catecholamines, the effects were also studied on 3 H-dopamine uptake by sarcoplasmic reticulum. As a prelude to these proposed long-term chronic studies with non-lethal doses in the present report only single and sub-lethal doses were used for a shorter (48h) duration

Zeolite H-USY for the production of lactic acid and methyl lactate from C-3-sugars

DEFF Research Database (Denmark)

West, R.M.; Holm, Martin Spangsberg; Shunmugavel, Saravanamurugan

2010-01-01

and dihydroxyacetone directly to methyl lactate and lactic acid catalyzed by inexpensive commercially available zeolites is presented. One particular zeolite, H-USY (Si/Al = 6) is shown to be quite active with near quantitative yields for this isomerization. Deactivation of the H-USY-zeolite was studied by correlating...

Crystal structure of 2-methyl-1H-imidazol-3-ium aquatrichlorido(oxalato-κ2O,O′stannate(IV

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Mouhamadou Birame Diop

2015-05-01

Full Text Available The tin(IV atom in the complex anion of the title salt, (C4H7N2[Sn(C2O4Cl3(H2O], is in a distorted octahedral coordination environment defined by three chlorido ligands, an oxygen atom from a water molecule and two oxygen atoms from a chelating oxalate anion. The organic cation is linked through a bifurcated N—H...O hydrogen bond to the free oxygen atoms of the oxalate ligand of the complex [Sn(H2OCl3(C2O4]− anion. Neighbouring stannate(IV anions are linked through O—H...O hydrogen bonds involving the water molecule and the two non-coordinating oxalate oxygen atoms. In combination with additional N—H...Cl hydrogen bonds between cations and anions, a three-dimensional network is spanned.

Quantum molecular dynamics of methyl rotors in peptide links

International Nuclear Information System (INIS)

Del-Mar, Jon

2002-01-01

A particles wavefunction extends beyond the classically accessible regions of the potential energy surface. Quantum mechanical tunnelling is the result of this partial delocalisation, which enables the surpassing of classically inaccessible potential barriers. A particles mass is an important aspect, reflecting the tunnelling probability; a consequence of this is that a proton is ideally suited to this behaviour. Symmetrical molecular rotors such as Ch 3 provide a clear example of quantum mechanical tunnelling, seen in their motional spectrum. The advantage of the methyl rotor is that it's found in a wide range of organic compounds, giving a wide range in hindering potentials. It is effectively a proton rotor, and is easily observed using techniques such as Nuclear Magnetic Resonance (NMR), and Inelastic Neutron Scattering (INS). Both NMR and INS techniques are sensitive to molecular motion, and as they measure the tunnel frequencies in different energy windows, are complementary. Of central importance to many biological processes and structures is the peptide unit, -CONH-. Of particular significance are the intermolecular networks that are often formed by the NHO hydrogen bonds, the peptide links. The molecules were chosen for the research in this thesis to form a tractable model for polypeptides and alpha-helix proteins. Methyl rotor tunnelling frequencies have been used, which are very sensitive to the potential energy surface, as a probe of the electronic and molecular structure associated with the peptide links. Quantum chemistry calculations were then utilized to connect experiments to theory to learn about the hydrogen bond. (author)

2,2-Dimethyl-2,3-dihydro-1H-perimidine

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Sarah Maloney

2013-02-01

Full Text Available The title compound, C13H14N2, was obtained from reaction of diaminonaphthalene with acetone. In both independent molecules in the asymmetric unit, the tricyclic perimidine consists of a planar (r.m.s. deviations = 0.0125 and 0.0181 Å naphthalene ring system and an envelope conformation C4N2 ringwith the NCN group hinged with respect to the naphthalene backbone by 36.9 (2 and 41.3 (2° in the two independent molecules. The methyl substituents are arranged approximately axial and equatorial on the apical C atom. In the crystal, one of the N—H groups of one independent molecule is involved in classical N—H...N hydrogen bonding. Short intermolecular (C/N—H...π(arene interactions, near the short T-shaped limit, link molecules in the absence of strong acceptors.

Ornithine decarboxylase antizyme induces hypomethylation of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2 in human oral cancer cell line.

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Daisuke Yamamoto

2010-09-01

Full Text Available Methylation of CpG islands of genome DNA and lysine residues of histone H3 and H4 tails regulates gene transcription. Inhibition of polyamine synthesis by ornithine decarboxylase antizyme-1 (OAZ in human oral cancer cell line resulted in accumulation of decarboxylated S-adenosylmethionine (dcSAM, which acts as a competitive inhibitor of methylation reactions. We anticipated that accumulation of dcSAM impaired methylation reactions and resulted in hypomethylation of genome DNA and histone tails.Global methylation state of genome DNA and lysine residues of histone H3 and H4 tails were assayed by Methylation by Isoschizomers (MIAMI method and western blotting, respectively, in the presence or absence of OAZ expression. Ectopic expression of OAZ mediated hypomethylation of CpG islands of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2. Protein level of DNA methyltransferase 3B (DNMT3B and histone H3K9me specific methyltransferase G9a were down-regulated in OAZ transfectant.OAZ induced hypomethylation of CpG islands of global genome DNA and H3K9me2 by down-regulating DNMT3B and G9a protein level. Hypomethylation of CpG islands of genome DNA and histone H3K9me2 is a potent mechanism of induction of the genes related to tumor suppression and DNA double strand break repair.

Overexpression of Human-Derived DNMT3A Induced Intergenerational Inheritance of Active DNA Methylation Changes in Rat Sperm

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Xiaoguo Zheng

2017-12-01

Full Text Available DNA methylation is the major focus of studies on paternal epigenetic inheritance in mammals, but most previous studies about inheritable DNA methylation changes are passively induced by environmental factors. However, it is unclear whether the active changes mediated by variations in DNA methyltransferase activity are heritable. Here, we established human-derived DNMT3A (hDNMT3A transgenic rats to study the effect of hDNMT3A overexpression on the DNA methylation pattern of rat sperm and to investigate whether this actively altered DNA methylation status is inheritable. Our results revealed that hDNMT3A was overexpressed in the testis of transgenic rats and induced genome-wide alterations in the DNA methylation pattern of rat sperm. Among 5438 reliable loci identified with 64 primer-pair combinations using a methylation-sensitive amplification polymorphism method, 28.01% showed altered amplified band types. Among these amplicons altered loci, 68.42% showed an altered DNA methylation status in the offspring of transgenic rats compared with wild-type rats. Further analysis based on loci which had identical DNA methylation status in all three biological replicates revealed that overexpression of hDNMT3A in paternal testis induced hypermethylation in sperm of both genotype-negative and genotype-positive offspring. Among the differentially methylated loci, 34.26% occurred in both positive and negative offspring of transgenic rats, indicating intergenerational inheritance of active DNA methylation changes in the absence of hDNM3A transmission. Furthermore, 75.07% of the inheritable loci were hyper-methylated while the remaining were hypomethylated. Distribution analysis revealed that the DNA methylation variations mainly occurred in introns and intergenic regions. Functional analysis revealed that genes related to differentially methylated loci were involved in a wide range of functions. Finally, this study demonstrated that active DNA methylation

Synthesis and characterization of Ru(II) complexes with polyfunctional quinazoline-(3H)-4-ones

International Nuclear Information System (INIS)

Prabhakar, B.; Lingaiah, P.; Laxma Reddy, K.

1991-01-01

Few Ru(II) complexes of the type Ru(O-N-O) 2 with tridentate O-N-O donors and of the type RuCl 2 (O-N) 2 with bidentate O-O and O-N donors have been synthesized and characterized on the basis of analytical, conductivity, thermal, magnetic, IR, electronic and PMR spectral data. The IR and PMR spectral data of the metal complexes indicate that the lignads like 2-methyl/phenyl-3-(2'-hydroxybenzalamino) quinazoline-(3H)-4-one(MHBQ/PHBQ) act as uninegative tridentate, 2-methyl/phenyl-3-(carboxymethyl) quinazoline(3H)-4-one (MCMQ/PCMQ) as uninegative bidentate and 2-methyl/phenyl-3-(furfuralamino) quinazoline-(3H)-4-one (MFQ/PFQ), 2-methyl/phenyl-3-(acetamino) quinazoline-(3H)-4-one (MAQ/PAQ), 2-methyl/phenyl3-(uramino)quinazoline-(3H)-4-one (MUQ/PUQ) and 2-methyl/phenyl-3-thiouramino)quinazoline-(3H)-4-one-(MTUQ/PTUQ) as neutral bidentate ligands. The electronic spectral data of the complexes indicate that the arrangement around Ru(II) is octahedral. (author). 25 refs., 2 tabs

Improving the Performances of Poly(vinylphosphonic acid) by Compositing or Copolymerization with Poly(4-(α-methyl)vinyl-1H-1,2,3-triazole)

International Nuclear Information System (INIS)

Han, Shuaiyuan; Yue, Baohua; Yan, Liuming

2014-01-01

Graphical abstract: - Highlights: • Poly(4-(α-methyl)vinyl-1H-1,2,3-triazole) is synthesized • PVPA/PMVTri polymeric composite proton conducting membranes are prepared • The proton conductivity of PVPA is improved by compositing with PMVTri • The water resistance of PVPA is improved by compositing with PMVTri • The oxidative stability is greatly improved - Abstract: The poly(vinylphosphonic acid) (PVPA), poly(4-(α-methyl)vinyl-1H-1,2,3-triazole) (PMVTri), and poly(VPA-co-MVTri) were synthesized, and proton exchange membranes were prepared based on the acid-base polymeric composite of PVPA and PMVTri, and acid-base amphoteric copolymer of poly(VPA-co-MVTri). The overall performances of PVPA, proton conductivity, thermal and oxidative stability, and water resistance, are greatly improved by compositing of PMVTri or copolymerization with 4-(α-methyl)vinyl-1H-1,2,3-triazole (MVTri). About four or eight folds improvement in maximum proton conductivity was observed in the polymeric composite of PVPA/PMVTri or acid-base amphoteric copolymer poly(VPA-co-MVTri) because of the redistribution of ions in the heterostructures of PVPA and PMVTri, respectively, compared with the pristine PVPA. At the same time, the oxidative stability and the water resistance of PVPA were also greatly improved attributing to the absent of α-H in the main chain of PMVTri and the acid-base interaction between the phosphonic acid groups and the triazolyl groups, respectively

Synthesis of a new selective borotritide: [3H]lithium 9-boratabicyclo[3.3.1]nonane. Some applications to the preparation of secondary and primary [3H] alcohols

International Nuclear Information System (INIS)

Rasset, C.; Rousseau, B.

1994-01-01

[ 3 H]lithium 9-boratabicyclo[3.3.1]nonane, at specific activity of 52-55 Ci/mmol, was synthesized by reduction of B-OMe-9-BBN with lithium tritide. Its reducing characteristics were illustrated by the synthesis of [17- 3 H] estradiol, [2- 3 H] dihydrotetrabenazine and 1-(hydroxy[ 3 H]methyl)naphtalene, with good radiochemical yields and high specific activities. (Author)

N-[5-Methyl-2-(2-nitro-phen-yl)-4-oxo-1,3-thia-zolidin-3-yl]pyridine-3-carboxamide monohydrate.

Science.gov (United States)

Akkurt, Mehmet; Celik, Ismail; Demir, Hale; Ozkırımlı, Sumru; Büyükgüngör, Orhan

2011-01-08

In the title compound, C(16)H(14)N(4)O(4)S·H(2)O, the benzene and pyridine rings make a dihedral angle of 85.8 (1)°. Both enanti-omers of the chiral title compound are statistically disordered over the same position in the unit cell. The methyl and carbonyl group attached to the stereogenic center (C(5) of the thia-zolidine ring) were therefore refined with common site-occupation factors of 0.531 (9) and 0.469 (9), respectively, for each stereoisomer. In the crystal, inter-molecular N-H⋯O, O-H⋯O and O-H⋯N hydrogen bonds link the mol-ecules, forming a three-dimensional supra-molecular network. The crystal structure further shows π-π stacking inter-actions [centroid-centroid distance = 3.5063 (13) Å] between the pyridine rings.

Methyl 2-Benzamido-2-(1H-benzimidazol-1-ylmethoxyacetate

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Alami Anouar

2012-09-01

Full Text Available The heterocyclic carboxylic α-aminoester methyl 2-benzamido-2-(1H-benzimidazol-1-ylmethoxyacetate is obtained by O-alkylation of methyl α-azido glycinate N-benzoylated with 1H-benzimidazol-1-ylmethanol.

Crystal structure of (Z-ethyl 3-[2-(5-methyl-7-nitro-1H-indole-2-carbonylhydrazinylidene]butanoate

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Amal Errossafi

2015-09-01

Full Text Available The reaction of 5-methyl-7-nitro-1H-indole-2-carbohydrazide with ethyl acetoacetate yielded the title molecule, C16H18N4O5, in which the indole ring is almost planar, with the greatest deviation from the mean plane being 0.006 (2 Å. The nine atoms of the indole ring are almost perpendicular to the mean plane through the ethyl acetate group, as indicated by the dihedral angle of 87.02 (4° between them. In the crystal, centrosymmetric supramolecular dimers are formed via N—H...O hydrogen bonds and eight-membered amide {...HNCO}2 synthons. These are consolidated into a three-dimensional architecture by C—H...O contacts, and by π–π interactions between six-membered rings [inter-centroid distance = 3.499 (2 Å].

Gadolinium(III Ion-Selective Electrode Based on 3-Methyl-1H-1,2,4-triazole-5-thiol

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Hassan Ali Zamani

2012-01-01

Full Text Available The 3-methyl-1H-1,2,4-triazole-5-thiol (MTH was used as a suitable ionophore for fabrication of a new gadolinium(III ion selective potentiometric sensor. Nitrobenzene (NB was used as plasticizing solvent mediator and sodium tetraphenyl borate (NaTPB as an anion excluder. It displays a Nernstian response (19.8± 0.4 mV/decade in the concentration range of 1.0×10-7 to 1.0×10-2 M with the detection limit of 7.3×10-8 M. The sensor has a very short response time (<10s and can be used the pH range of 2.9-8.4. electrode was successfully applied as an indicator for gadolinium determination in titration with EDTA.

Lysine methyltransferase G9a is not required for DNMT3A/3B anchoring to methylated nucleosomes and maintenance of DNA methylation in somatic cells

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Sharma Shikhar

2012-01-01

Full Text Available Abstract Background DNA methylation, histone modifications and nucleosome occupancy act in concert for regulation of gene expression patterns in mammalian cells. Recently, G9a, a H3K9 methyltransferase, has been shown to play a role in establishment of DNA methylation at embryonic gene targets in ES cells through recruitment of de novo DNMT3A/3B enzymes. However, whether G9a plays a similar role in maintenance of DNA methylation in somatic cells is still unclear. Results Here we show that G9a is not essential for maintenance of DNA methylation in somatic cells. Knockdown of G9a has no measurable effect on DNA methylation levels at G9a-target loci. DNMT3A/3B remain stably anchored to nucleosomes containing methylated DNA even in the absence of G9a, ensuring faithful propagation of methylated states in cooperation with DNMT1 through somatic divisions. Moreover, G9a also associates with nucleosomes in a DNMT3A/3B and DNA methylation-independent manner. However, G9a knockdown synergizes with pharmacologic inhibition of DNMTs resulting in increased hypomethylation and inhibition of cell proliferation. Conclusions Taken together, these data suggest that G9a is not involved in maintenance of DNA methylation in somatic cells but might play a role in re-initiation of de novo methylation after treatment with hypomethylating drugs, thus serving as a potential target for combinatorial treatments strategies involving DNMTs inhibitors.

Kinetics of the reactions H+C2H4->C2H5, H+C2H5->2CH3 and CH3+C2H5->products studies by pulse radiolysis combined with infrared diode laser spectroscopy

DEFF Research Database (Denmark)

Sillesen, A.; Ratajczak, E.; Pagsberg, P.

1993-01-01

Formation of methyl radicals via the consecutive reactions H+C2H4+M-->C2H5+M (1) and H+C2H5-->CH3+CH3 (2a) was initiated by pulse radiolysis of 10-100 mbar H-2 in the presence of ethylene. The kinetics of CH3 Were studied by monitoring the transient infrared absorption at the Q(3, 3) line of the ...

Quantitative mass spectrometry of histones H3.2 and H3.3 in Suz12-deficient mouse embryonic stem cells reveals distinct, dynamic post-translational modifications at Lys-27 and Lys-36

DEFF Research Database (Denmark)

Jung, Hye Ryung; Pasini, Diego; Helin, Kristian

2010-01-01

distinct coexisting modifications. In certain cases, high mass accuracy LTQ-Orbitrap MS/MS allowed precise localization of near isobaric coexisting PTMs such as trimethylation and acetylation within individual peptides. ETD MS/MS facilitated sequencing and annotation of phosphorylated histone peptides....... The combined use of ETD and CID MS/MS increased the total number of identified modified peptides. Comparative quantitative analysis of histones from wild type and Suz12-deficient ESCs using stable isotope labeling with amino acids in cell culture and LC-MS/MS revealed a dramatic reduction of H3K27me2 and H3K27......me3 and an increase of H3K27ac, thereby uncovering an antagonistic methyl/acetyl switch at H3K27. The reduction in H3K27 methylation and increase in H3K27 acetylation was accompanied by H3K36 acetylation and methylation. Estimation of the global isoform percentage of unmodified and modified histone...

Methyl 3-[3',4'-(methylenedioxy)phenyl]-2-methyl glycidate: an ecstasy precursor seized in Sydney, Australia.

Science.gov (United States)

Collins, Michael; Heagney, Aaron; Cordaro, Frank; Odgers, David; Tarrant, Gregory; Stewart, Samantha

2007-07-01

Five 44 gallon drums labeled as glycidyl methacrylate were seized by the Australian Customs Service and the Australian Federal Police at Port Botany, Sydney, Australia, in December 2004. Each drum contained a white, semisolid substance that was initially suspected to be 3,4-methylenedioxymethylamphetamine (MDMA). Gas chromatography-mass spectroscopy (GC/MS) analysis demonstrated that the material was neither glycidyl methacrylate nor MDMA. Because intelligence sources employed by federal agents indicated that this material was in some way connected to MDMA production, suspicion fell on the various MDMA precursor chemicals. Using a number of techniques including proton nuclear magnetic resonance spectroscopy ((1)H NMR), carbon nuclear magnetic resonance spectroscopy ((13)C NMR), GC/MS, infrared spectroscopy, and total synthesis, the unknown substance was eventually identified as methyl 3-[3',4'(methylenedioxy)phenyl]-2-methyl glycidate. The substance was also subjected to a published hydrolysis and decarboxylation procedure and gave a high yield of the MDMA precursor chemical, 3,4-methylenedioxyphenyl-2-propanone, thereby establishing this material as a "precursor to a precursor."

Lymphocytes From Patients With Type 1 Diabetes Display a Distinct Profile of Chromatin Histone H3 Lysine 9 Dimethylation

Science.gov (United States)

Miao, Feng; Smith, David D.; Zhang, Lingxiao; Min, Andrew; Feng, Wei; Natarajan, Rama

2008-01-01

OBJECTIVE—The complexity of interactions between genes and the environment is a major challenge for type 1 diabetes studies. Nuclear chromatin is the interface between genetics and environment and the principal carrier of epigenetic information. Because histone tail modifications in chromatin are linked to gene transcription, we hypothesized that histone methylation patterns in cells from type 1 diabetic patients can provide novel epigenetic insights into type 1 diabetes and its complications. RESEARCH DESIGN AND METHODS—We used chromatin immunoprecipitation (ChIP) linked to microarray (ChIP-chip) approach to compare genome-wide histone H3 lysine 9 dimethylation (H3K9me2) patterns in blood lymphocytes and monocytes from type 1 diabetic patients versus healthy control subjects. Bioinformatics evaluation of methylated candidates was performed by Ingenuity Pathway Analysis (IPA) tools. RESULTS—A subset of genes in the type 1 diabetic cohort showed significant increase in H3K9me2 in lymphocytes but not in monocytes. CLTA4, a type 1 diabetes susceptibility gene, was one of the candidates displaying increased promoter H3K9me2 in type 1 diabetes. IPA identified two high-scoring networks that encompassed genes showing altered H3K9me2. Many of them were associated with autoimmune and inflammation-related pathways, such as transforming growth factor-β, nuclear factor-κB, p38 mitogen-activated protein kinase, toll-like receptor, and interleukin-6. IPA also revealed biological relationships between these networks and known type 1 diabetes candidate genes. CONCLUSIONS—The concerted and synergistic alteration of histone methylation within the identified network in lymphocytes might have an effect on the etiology of type 1 diabetes and its complications. These studies provide evidence of a novel association between type 1 diabetes and altered histone methylation of key genes that are components of type 1 diabetes–related biological pathways and also a new

Three dimensional analysis of histone methylation patterns in normal and tumor cell nuclei

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M Cremer

2009-06-01

Full Text Available Histone modifications represent an important epigenetic mechanism for the organization of higher order chromatin structure and gene regulation. Methylation of position-specific lysine residues in the histone H3 and H4 amino termini has been linked with the formation of constitutive and facultative heterochromatin as well as with specifically repressed single gene loci. Using an antibody, directed against dimethylated lysine 9 of histone H3 and several other lysine methylation sites, we visualized the nuclear distribution pattern of chromatin flagged by these methylated lysines in 3D preserved nuclei of normal and malignant cell types. Optical confocal serial sections were used for a quantitative evaluation. We demonstrate distinct differences of these histone methylation patterns among nuclei of different cell types after exit of the cell cycle. Changes in the pattern formation were also observed during the cell cycle. Our data suggest an important role of methylated histones in the reestablishment of higher order chromatin arrangements during telophase/early G1. Cell type specific histone methylation patterns are possibly causally involved in the formation of cell type specific heterochromatin compartments, composed of (pericentromeric regions and chromosomal subregions from neighboring chromosome territories, which contain silent genes.

Synthesis of 3-Methyl-1-morpholin-4-ylmethyl-2,6-diphenylpiperidin-4-one

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Bathey R. Venkatraman

2009-09-01

Full Text Available This paper describes the synthesis of 3-methyl-1-morpholin-4-ylmethyl-2,6-diphenylpiperidin-4-one from 3-methyl-2,6-diphenylpiperidin-4-one. The synthesized compound was characterized by FT-IR, 1H NMR, EI-MS and elemental analysis.

The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas

Science.gov (United States)

Fang, Dong; Gan, Haiyun; Lee, Jeong-Heon; Han, Jing; Wang, Zhiquan; Riester, Scott M.; Jin, Long; Chen, Jianji; Zhou, Hui; Wang, Jinglong; Zhang, Honglian; Yang, Na; Bradley, Elizabeth W.; Ho, Thai H.; Rubin, Brian P.; Bridge, Julia A.; Thibodeau, Stephen N; Ordog, Tamas; Chen, Yue; van Wijnen, Andre J.; Oliveira, Andre M.; Xu, Rui-Ming; Westendorf, Jennifer J.; Zhang, Zhiguo

2016-01-01

Over 90% of chondroblastomas contain a heterozygous mutation replacing lysine 36 with methionine (K36M) in the histone H3 variant H3.3. Here, we show that H3K36 methylation is reduced globally in chondroblastomas and in chondrocytes harboring the same genetic mutation due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and trimethylation in H3.3K36M cells are enriched in cancer pathways. In addition, H3.3K36M chondrocytes exhibit several hallmarks of cancer cells including increased ability to form colonies, resistance to apoptosis and defects in differentiation. Thus, H3.3K36M proteins reprogram H3K36 methylation landscape and contribute to tumorigenesis in part through altering the expression of cancer-associated genes. PMID:27229140

SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis.

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Martinelli, G; Mancini, M; De Benedittis, C; Rondoni, M; Papayannidis, C; Manfrini, M; Meggendorfer, M; Calogero, R; Guadagnuolo, V; Fontana, M C; Bavaro, L; Padella, A; Zago, E; Pagano, L; Zanotti, R; Scaffidi, L; Specchia, G; Albano, F; Merante, S; Elena, C; Savini, P; Gangemi, D; Tosi, P; Ciceri, F; Poletti, G; Riccioni, L; Morigi, F; Delledonne, M; Haferlach, T; Cavo, M; Valent, P; Soverini, S

2018-01-01

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.

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

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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

Synthesis and properties of 4-alkoxy-2-[2-hydroxy-3-(4-o,m,p-halogenoaryl-1 -piperazinyl)propyl]-6-methyl-1H-pyrrolo-[3,4-c]pyridine-1,3(2H)-diones with analgesic and sedative activities.

Science.gov (United States)

Sladowska, Helena; Sabiniarz, Aleksandra; Szkatuła, Dominika; Filipek, Barbara; Sapa, Jacek

2006-01-01

Synthesis of N-substituted derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (17-26) is described. The chlorides, containing OH group, used in the above synthesis can exist in two isomeric forms: chain (12, 14-16) and cyclic (12a, 14a-16a). All final imides studied exhibited analgesic activity in the "writhing syndrome" test which was superior than that of acetylsalicylic acid. In the "hot plate" test only two compounds (19, 20) were active as antinociceptive agents. Furthermore, all compounds tested significantly suppressed the spontaneous locomotor activity of mice.

Delineation of G-Quadruplex Alkylation Sites Mediated by 3,6-Bis(1-methyl-4-vinylpyridinium iodide)carbazole-Aniline Mustard Conjugates.

Science.gov (United States)

Chen, Chien-Han; Hu, Tsung-Hao; Huang, Tzu-Chiao; Chen, Ying-Lan; Chen, Yet-Ran; Cheng, Chien-Chung; Chen, Chao-Tsen

2015-11-23

A new G-quadruplex (G-4)-directing alkylating agent BMVC-C3M was designed and synthesized to integrate 3,6-bis(1-methyl-4-vinylpyridinium iodide)carbazole (BMVC) with aniline mustard. Various telomeric G-4 structures (hybrid-2 type and antiparallel) and an oncogene promoter, c-MYC (parallel), were constructed to react with BMVC-C3M, yielding 35 % alkylation yield toward G-4 DNA over other DNA categories (alkylation adducts by electrospray ionization mass spectroscopy (ESI-MS) revealed the stepwise DNA alkylation mechanism of aniline mustard for the first time. Furthermore, the monoalkylation sites and intrastrand cross-linking sites were determined and found to be dependent on G-4 topology based on the results of footprinting analysis in combination with mass spectroscopic techniques and in silico modeling. The results indicated that BMVC-C3M preferentially alkylated at A15 (H26), G12 (H24), and G2 (c-MYC), respectively, as monoalkylated adducts and formed A15-C3M-A21 (H26), G12-C3M-G4 (H24), and G2-C3M-G4/G17 (c-MYC), respectively, as cross-linked dialkylated adducts. Collectively, the stability and site-selective cross-linking capacity of BMVC-C3M provides a credible tool for the structural and functional characterization of G-4 DNAs in biological systems. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and crystal structures of 2-methyl-4-aryl-5-oxo-5H-indeno [1,2-b] pyridine carboxylate derivatives

DEFF Research Database (Denmark)

Pandian, Ramesh; Naushad, Edayadulla; Vijayakumar, Vinodhkumar

2014-01-01

pyridine derivatives through oxidation. Consequently, the interest in this aromatization reaction, investigation of a wide range of 1, 4-DHPs continues to attract the attention of researchers. Herein, we report the preparation of pyridine derivatives and the crystal structures determined by X......-ray crystallographic methods.Results: The crystal structures and conformational studies of two organic compounds, namely ethyl 2-methyl-4-phenyl-5-oxo-5H-indeno [1,2-b] pyridine-3-carboxylate (I) and ethyl 2-methyl-4-(4 chlorophenyl)-5-oxo-5H-indeno [1,2-b] pyridine-3-carboxylate (II) are reported. The terminal ethyl......) dimer running along 011 direction.Conclusion: The crystal structures ethyl 2-methyl-4-phenyl-5-oxo-5H-indeno [1,2-b] pyridine-3-carboxylate and ethyl 2-methyl-4-(4 chlorophenyl)-5-oxo-5H-indeno [1,2-b] pyridine-3-carboxylate have been investigated in detail. The terminal ethyl group of compound I...

Photolabeling of Tonoplast from Sugar Beet Cell Suspensions by [3H]5-(N-Methyl-N-Isobutyl)-Amiloride, an Inhibitor of the Vacuolar Na+/H+ Antiport 1

Science.gov (United States)

Barkla, Bronwyn J.; Charuk, Jeffrey H. M.; Cragoe, Edward J.; Blumwald, Eduardo

1990-01-01

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 Ki of 2.5 and 5.9 micromolar for ΔpH-dependent 22Na+ influx in tonoplast vesicles and Na+-dependent H+ efflux in intact vacuoles, respectively. Scatchard analysis of the binding of [3H]MIA to tonoplast membranes revealed a high affinity binding component with a Kd 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 [3H]MIA revealed two sets of polypeptides with a different affinity to amiloride and its analog. Images Figure 7 PMID:16667602

Syntheses of DNA adducts of two heterocyclic amines, 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C) and 2-amino-9H-pyrido[2,3-b]indole (A alpha C) and identification of DNA adducts in organs from rats dosed with MeA alpha C

DEFF Research Database (Denmark)

Frederiksen, Hanne; Frandsen, Henrik Lauritz; Pfau, W.

2004-01-01

2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (AalphaC) are mutagenic and carcinogenic heterocyclic amines formed during ordinary cooking. MeAalphaC and AalphaC are activated to mutagenic metabolites by cytochrome P450-mediated N-oxidation...... by reaction of the parent amines with acetylated guanine N3-oxide. N-2-OH-MeAalphaC and N-2-OH-AalphaC reacted with calf thymus DNA after addition of acetic anhydride. P-32-postlabelling analysis of modified DNA showed one major adduct co-migrating with N-2-(3',5'-diphospho-2'-deoxyguanosin-8-yl...

CpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer.

Science.gov (United States)

Stefansson, Olafur Andri; Hermanowicz, Stefan; van der Horst, Jasper; Hilmarsdottir, Holmfridur; Staszczak, Zuzanna; Jonasson, Jon Gunnlaugur; Tryggvadottir, Laufey; Gudjonsson, Thorkell; Sigurdsson, Stefan

2017-07-05

DNA repair of alkylation damage is defective in various cancers. This occurs through somatically acquired inactivation of the MGMT gene in various cancer types, including breast cancers. In addition to MGMT, the two E. coli AlkB homologs ALKBH2 and ALKBH3 have also been linked to direct reversal of alkylation damage. However, it is currently unknown whether ALKBH2 or ALKBH3 are found inactivated in cancer. Methylome datasets (GSE52865, GSE20713, GSE69914), available through Omnibus, were used to determine whether ALKBH2 or ALKBH3 are found inactivated by CpG promoter methylation. TCGA dataset enabled us to then assess the impact of CpG promoter methylation on mRNA expression for both ALKBH2 and ALKBH3. DNA methylation analysis for the ALKBH3 promoter region was carried out by pyrosequencing (PyroMark Q24) in 265 primary breast tumours and 30 proximal normal breast tissue samples along with 8 breast-derived cell lines. ALKBH3 mRNA and protein expression were analysed in cell lines using RT-PCR and Western blotting, respectively. DNA alkylation damage assay was carried out in cell lines based on immunofluorescence and confocal imaging. Data on clinical parameters and survival outcomes in patients were obtained and assessed in relation to ALKBH3 promoter methylation. The ALKBH3 gene, but not ALKBH2, undergoes CpG promoter methylation and transcriptional silencing in breast cancer. We developed a quantitative alkylation DNA damage assay based on immunofluorescence and confocal imaging revealing higher levels of alkylation damage in association with epigenetic inactivation of the ALKBH3 gene (P = 0.029). In our cohort of 265 primary breast cancer, we found 72 cases showing aberrantly high CpG promoter methylation over the ALKBH3 promoter (27%; 72 out of 265). We further show that increasingly higher degree of ALKBH3 promoter methylation is associated with reduced breast-cancer specific survival times in patients. In this analysis, ALKBH3 promoter methylation at >20

The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue

DEFF Research Database (Denmark)

Clausen, Rasmus Prætorius; Naur, Peter; Kristensen, Anders Skov

2009-01-01

The design, synthesis, and pharmacological characterization of a highly potent and selective glutamate GluR5 agonist is reported. (S)-2-Amino-3-((RS)-3-hydroxy-8-methyl-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (5) is the 8-methyl analogue of (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H......-cyclohepta[d]isoxazol-4-yl)propionic acid ((S)-4-AHCP, 4). Compound 5 displays an improved selectivity profile compared to 4. A versatile stereoselective synthetic route for this class of compounds is presented along with the characterization of the binding affinity of 5 to ionotropic glutamate receptors (i......GluRs). Functional characterization of 5 at cloned iGluRs using a calcium imaging assay and voltage-clamp recordings show a different activation of GluR5 compared to (S)-glutamic acid (Glu), kainic acid (KA, 1), and (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid ((S)-ATPA, 3) as previously...

Covalent Modifications of Histone H3K9 Promote Binding of CHD3

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Adam H. Tencer

2017-10-01

Full Text Available Chromatin remodeling is required for genome function and is facilitated by ATP-dependent complexes, such as nucleosome remodeling and deacetylase (NuRD. Among its core components is the chromodomain helicase DNA binding protein 3 (CHD3 whose functional significance is not well established. Here, we show that CHD3 co-localizes with the other NuRD subunits, including HDAC1, near the H3K9ac-enriched promoters of the NuRD target genes. The tandem PHD fingers of CHD3 bind histone H3 tails and posttranslational modifications that increase hydrophobicity of H3K9—methylation or acetylation (H3K9me3 or H3K9ac—enhance this interaction. Binding of CHD3 PHDs promotes H3K9Cme3-nucleosome unwrapping in vitro and perturbs the pericentric heterochromatin structure in vivo. Methylation or acetylation of H3K9 uniquely alleviates the intra-nucleosomal interaction of histone H3 tails, increasing H3K9 accessibility. Collectively, our data suggest that the targeting of covalently modified H3K9 by CHD3 might be essential in diverse functions of NuRD.

Theoretical study of the regioselectivity of the interaction of 3-methyl-4-pyrimidone and 1-methyl-2-pyrimidone with Lewis acids.

Science.gov (United States)

Kasende, Okuma Emile; Muya, Jules Tshishimbi; Broeckaert, Lies; Maes, Guido; Geerlings, Paul

2012-08-23

A density functional theory (DFT) study is performed to determine the stability of the complexes formed between either the N or O site of 3-methyl-4-pyrimidone and 1-methyl-2-pyrimidone molecules and different ligands. The studied ligands are boron and alkali Lewis acids, namely, B(CH(3))(3), HB(CH(3))(2), H(2)B(CH(3)), BH(3), H(2)BF, HBF(2), BF(3), Li(+), Na(+), and K(+). The acids are divided into two groups according to their hardness. The reactivity predictions, according to the molecular electrostatic potential (MEP) map and the natural bond orbital (NBO) analysis, are in agreement with the calculated relative stabilities. Our findings reveal a strong regioselectivity with borane and its derivatives preferring the nitrogen site in both pyrimidone isomers, while a preference for oxygen is observed for the alkali acids in the 3-methyl-4-pyrimidone molecule. The complexation of 1-methyl-2-pyrimidone with these hard alkali acids does not show any discrimination between the two sites due to the presence of a continuous delocalized density region between the nitrogen and the oxygen atoms. The preference of boron Lewis acids toward the N site is due to the stronger B-N bond as compared to the B-O bond. The influence of fluorine or methyl substitution on the boron atom is discussed through natural orbital analysis (NBO) concentrating on the overlap of the boron empty p-orbital with the F lone pairs and methyl hyperconjugation, respectively. The electrophilicity of the boron acids gives a good overall picture of the interaction capabilities with the Lewis base.

Crystal structure of N′-[(E-(1S,3R-(3-isopropyl-1-methyl-2-oxocyclopentylmethylidene]-4-methylbenzenesulfonohydrazide

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David Tymann

2015-12-01

Full Text Available 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.

2-Acetyl-amino-1,3,4,6-tetra-O-(tri-methyl-silyl)-2-de-oxy-α-d-gluco-pyran-ose.

Science.gov (United States)

Cheng, Zhao-Dong; Cui, Yan-Li; Mao, Jian-Wei

2013-06-01

The title compound, C20H47NO6Si4, was synthesized by per-O-tri-methyl-silylation of N-acetyl-d-glucosa-mine using chloro-tri-methyl-silane in the presence of hexa-methyl-disiloxane. The tri-methyl-silyl group and acetamido group are located on the same side of the pyran ring, showing an α-configuration glycoside. One of the tri-methyl-silyl groups is disordered over two orientations, with site-occupancy factors of 0.625 (9) and 0.375 (9). In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into supra-molecular chains along the a-axis direction.

5-(4-Methoxyphenyl-4-methyl-1-phenyl-3-p-tolyl-1H-pyrazole

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Yahya Ben Soumane

2017-11-01

Full Text Available The title compound, C24H22N2O, crystallizes with two independent molecules (A and B in the asymmetric unit. The phenyl, p-tolyl and p-methoxyphenyl rings are inclined to the pyrazole ring by 42.5 (2, 17.68 (19 and 52.20 (19°, respectively, in molecule A, and by 39.5 (2, 40.77 (19 and 59.76 (18°, respectively, in molecule B. In the asymmetric unit, the pyrarole ring of molecule A makes a dihedral angle of 3.7 (2° with that of molecule B. In the crystal, the two independent molecules are linked to each other by a C—H...O hydrogen bond.

Epigenetic regulation of facultative heterochromatinisation in Planococcus citri via the Me(3)K9H3-HP1-Me(3)K20H4 pathway.

Science.gov (United States)

Bongiorni, Silvia; Pasqualini, Barbara; Taranta, Monia; Singh, Prim B; Prantera, Giorgio

2007-03-15

Using RNA interference (RNAi) we have conducted a functional analysis of the HP1-like chromobox gene pchet2 during embryogenesis of the mealybug Planococcus citri. Knocking down pchet2 expression results in decondensation of the male-specific chromocenter that normally arises from the developmentally-regulated facultative heterochromatinisation of the paternal chromosome complement. Together with the disappearance of the chromocenter the staining levels of two associated histone modifications, tri-methylated lysine 9 of histone H3 [Me(3)K9H3] and tri-methylated lysine 20 of histone H4 [Me(3)K20H4], are reduced to undetectable levels. Embryos treated with double-stranded RNA (dsRNA) targeting pchet2 also exhibit chromosome abnormalities, such as aberrant chromosome condensation, and also the presence of metaphases that contain 'lagging' chromosomes. We conclude that PCHET2 regulates chromosome behavior during metaphase and is a crucial component of a Me(3)K9H3-HP1-Me(3)K20H4 pathway involved in the facultative heterochromatinisation of the (imprinted) paternal chromosome set.

Structural study of ethyl 3-methyl-9-oxo-3-azabicyclo63.3.19nonane-1-carboxylate by two-dimensional NMR spectroscopy

Science.gov (United States)

Arias-Pérez, M. S.; Alejo, A.; Gálvez, E.; Pérez, S. M.; Santos, M. J.

1995-04-01

Ethyl 3-methyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylate has been studied by 1H, 13C and 2D NMR spectroscopy in order to establish its conformational behaviour. The combined use of COSY and 1H- 13C correlation spectra helped in the unambiguous and complete assignment of the bicyclic carbon and proton resonances. It is found that the piperidone ring displays a slightly fattened chair conformation with the N-methyl group in the equatorial position, while a twist-chair form seems to be favoured for the cyclohexanone one. Two preferred orientations migth be proposed for the ethoxycarbonyl moiety.

Stereoselective synthesis of 5-alkoxycarbonyl-4 alkyl-2-anino-3-cyano-6-methyl-4H-pyranes 3 via asymmetric Michael addition to aceptors-gamma-stereogenics; Sintesis esteroselective de 5-alcoxicarbonil-4-alquil-2-amino-3-ciano-6-metil-4H-piranos via adicion Michael sobre aceptores-gama-esterogenicos

Energy Technology Data Exchange (ETDEWEB)

Martinez-Grau, A.; Jimenez, B.; Martin, N.; Seoane, C.; Marco, J.L. [Departamento de Quimica Organica, Facultad de Quimica, Universidad Complutense, Madrid (Spain)

1994-12-31

The stereoselective synthesis of 5-alkoxycarbonyl-4-alkyl-2-amino-3-cyano-6-methyl-4H-pyrans 3 via asymmetric Michael addition of malononitrile to gamma-stereogenic alpha-acetylacrylates 2 obtained by Knoevenagel reaction of acetylacetates to quiral alpha-hydroxyaldehydes 1 is described. The resulting 2-amino-4H-pyrans 3 have been obtained in moderate yield and good diastereoselectivity. 15 refs.

MET-2-Dependent H3K9 Methylation Suppresses Transgenerational Small RNA Inheritance.

Science.gov (United States)

Lev, Itamar; Seroussi, Uri; Gingold, Hila; Bril, Roberta; Anava, Sarit; Rechavi, Oded

2017-04-24

In C. elegans, alterations to chromatin produce transgenerational effects, such as inherited increase in lifespan and gradual loss of fertility. Inheritance of histone modifications can be induced by double-stranded RNA-derived heritable small RNAs. Here, we show that the mortal germline phenotype, which is typical of met-2 mutants, defective in H3K9 methylation, depends on HRDE-1, an argonaute that carries small RNAs across generations, and is accompanied by accumulated transgenerational misexpression of heritable small RNAs. We discovered that MET-2 inhibits small RNA inheritance, and, as a consequence, induction of RNAi in met-2 mutants leads to permanent RNAi responses that do not terminate even after more than 30 generations. We found that potentiation of heritable RNAi in met-2 animals results from global hyperactivation of the small RNA inheritance machinery. Thus, changes in histone modifications can give rise to drastic transgenerational epigenetic effects, by controlling the overall potency of small RNA inheritance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Syntheses and biological evaluation of {sup 18}F-labeled 3-(1-benzyl-piperidin-4-yl)-1-(1-methyl-1H-indol-3-yl)propan-1-ones for in vivo mapping of acetylcholinesterase

Energy Technology Data Exchange (ETDEWEB)

Choe, Y.-S. E-mail: yschoe@samsung.co.kr; Oh, S.-J.; Shim, Insop; Naruto, Shunji; Chi, Dae Yoon; Kim, Sang Eun; Lee, Kyung-Han; Choi, Yong; Kim, B.-T

2000-04-01

We synthesized novel {sup 18}F-labeled acetylcholinesterase (AChE) inhibitors, 3-[1-(3- and 4-[{sup 18}F]fluoromethylbenzyl)piperidin-4-yl]-1-(1-methyl-1H-indol-3-yl)propan- 1-ones ([{sup 18}F]1 and [{sup 18}F]2) and 3-[1-(4-[{sup 18}F]fluorobenzyl)piperidin-4-yl]-1-(1-methyl-1H-indol-3-yl)propan- 1-one ([{sup 18}F]3) in high yields (decay-corrected, 25%-40%) and with high effective specific activities (>37 GBq/{mu}mol). Tissue distribution studies of the [{sup 18}F]1 and the [{sup 18}F]3 in mice showed the nonspecific bindings in brain regions, with metabolic defluorination of the [{sup 18}F]1. The result suggests that these radioligands may not be suitable agents for in vivo mapping of AChE, despite their potent in vitro anti-AChE activities.

Synthesis of New Silicon-linked Lanthanocene Complexes and Their High Catalytic Activity for Methyl Methacrylate Polymerization with Nanometric Sodium Hydride as Co-catalyst

Institute of Scientific and Technical Information of China (English)

谢小敏; 黄吉玲

2005-01-01

The synthesis and characterization of four new silicon-linked lanthanocene complexes with pendant phenyl groups on cyclopentadiene were reported. Based on the data of elemental analyses, MS and IR, the complexes were presumed to be unsolvated and dimeric complexes [Me2Si(C5H3CMe2C6H5)2LnC1]2 [Ln=Er (1), Gd (2), Sm (3), Dy (4)]. In conjunction with AlEt3 or sodium hydride as the co-catalyst, these complexes could efficiently catalyze the polymerization of methyl methacrylate (MMA). When the nanometric sodium hydride was used as a co-catalyst, the complexes were highly effective for the polymerization of MMA. At low temperature and in short time, in [MeESi(C5H3CMe2C6H5)2LnC1]2/NaH (nanometric) system, the polymer was obtained in more than 80% yield and the molecular weight was greater than 105. The activity reached that of organolanthanide hydride as a single-component catalyst. In ]MeESi(C5H3CMe2C6H5)2ErC1]2/Nail (nanometric) system, the effects of the molar ratio of MMA/catalyst and catalyst/co-catalyst, and the temperature on polymerization were studied.

Naturally Abundance Vanillin as Starting Material to Synthesizing 4-(4-Hydroxy-3-methoxyphenyl-6-methyl-3,4-dihydropyrimidin-2(1H-one

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Masruri MASRURI

2015-12-01

Full Text Available Indonesia is the second biggest producer of natural vanillin. Traditionally it was isolated from the bean of vanilla (Vanilla planifolia Andrews. This paper reports on applying vanillin as starting material for synthesizing a biologically important chemical structure 3,4-dihydropyrimidinone. The reaction was undertaken in one step following multi component reaction (MCR. Products determination was undergone using FTIR and UV-Vis spectrophotometry, and also liquid chromatography-mass spectrometry (LCMS. After purification under flash column chromatography in ethyl acetate-hexane, it was found a white solid of 4-(4-hydroxy-3-methoxyphenyl-6-methyl-3,4-dihydropyrimidin-2(1H-one in 67% yield with a few amount of an unreacted vanillin.

Transcriptome and H3K27 tri-methylation profiling of Ezh2-deficient lung epithelium

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Aliaksei Z. Holik

2015-09-01

Full Text Available The adaptation of the lungs to air breathing at birth requires the fine orchestration of different processes to control lung morphogenesis and progenitor cell differentiation. However, there is little understanding of the role that epigenetic modifiers play in the control of lung development. We found that the histone methyl transferase Ezh2 plays a critical role in lung lineage specification and survival at birth. We performed a genome-wide transcriptome study combined with a genome-wide analysis of the distribution of H3K27 tri-methylation marks to interrogate the role of Ezh2 in lung epithelial cells. Lung cells isolated from Ezh2-deficient and control mice at embryonic day E16.5 were sorted into epithelial and mesenchymal populations based on EpCAM expression. This enabled us to dissect the transcriptional and epigenetic changes induced by the loss of Ezh2 specifically in the lung epithelium. Here we provide a detailed description of the analysis of the RNA-seq and ChIP-seq data, including quality control, read mapping, differential expression and differential binding analyses, as well as visualisation methods used to present the data. These data can be accessed from the Gene Expression Omnibus database (super-series accession number GSE57393.

Methyl 2-(4a,8-Dimethyl-7-oxodecahydronaphthalen-2-ylacrylate

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Mohamed Tebbaa

2012-08-01

Full Text Available The title compound, C16H24O3, was isolated from the aerial part of Inula Viscosa (L Aiton [or Dittrichia Viscosa (L Greuter]. The molecule contains two fused (trans six-membered rings which both exibit a chair conformation. In the crystal, molecules are linked into chains along [100] by weak C—H...O hydrogen bonds involving the methyl and carbonyl groups.

DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation.

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Castillo-Fernandez, Juan E; Loke, Yuk Jing; Bass-Stringer, Sebastian; Gao, Fei; Xia, Yudong; Wu, Honglong; Lu, Hanlin; Liu, Yuan; Wang, Jun; Spector, Tim D; Saffery, Richard; Craig, Jeffrey M; Bell, Jordana T

2017-03-24

The association of in vitro fertilisation (IVF) and DNA methylation has been studied predominantly at regulatory regions of imprinted genes and at just thousands of the ~28 million CpG sites in the human genome. We investigated the links between IVF and DNA methylation patterns in whole cord blood cells (n = 98) and cord blood mononuclear cells (n = 82) from newborn twins using genome-wide methylated DNA immunoprecipitation coupled with deep sequencing. At a false discovery rate (FDR) of 5%, we identified one significant whole blood DNA methylation change linked to conception via IVF, which was located ~3 kb upstream of TNP1, a gene previously linked to male infertility. The 46 most strongly associated signals (FDR of 25%) included a second region in a gene also previously linked to infertility, C9orf3, suggesting that our findings may in part capture the effect of parental subfertility. Using twin modelling, we observed that individual-specific environmental factors appear to be the main overall contributors of methylation variability at the FDR 25% IVF-associated differentially methylated regions, although evidence for methylation heritability was also obtained at several of these regions. We replicated previous findings of differential methylation associated with IVF at the H19/IGF2 region in cord blood mononuclear cells, and we validated the signal at C9orf3 in monozygotic twins. We also explored the impact of intracytoplasmic sperm injection on the FDR 25% signals for potential effects specific to male or female infertility factors. To our knowledge, this is the most comprehensive study of DNA methylation profiles at birth and IVF conception to date, and our results show evidence for epigenetic modifications that may in part reflect parental subfertility.

(E-2-Methyl-6-{[(5-methylpyridin-2-ylimino]methyl}phenol

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Md. Azharul Arafath

2017-01-01

Full Text Available In the title compound, C14H14N2O, the dihedral angle between the aromatic rings is 5.54 (9°. The conformation is reinforced by an intramolecular O—H...N hydrogen bond, which closes an S(6 ring. The pyridine N atom and methyl group lie to opposite sides of the molecule. In the crystal, the molecules are linked into a zigzag chain propagating in [0-11] by weak C—H...O hydrogen bonds.

Synthesis of Poly(N-vinyl-2-pyrrolidone-co-methyl methacrylate by Maghnite-H+ a Non-toxic Catalyst

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Mohamed Benadda

2014-10-01

Full Text Available In the present work poly (N-vinyl-2-pyrrolidone-co-methyl methacrylate copolymers were prepared successfully and cleanly by a one step process via cationic copolymerization of N-vinyl-2-pyrrolidone (NVP with methyl methacrylate (MMA, in heterogeneous phase using “Maghnite-H+” (Mag-H+ as catalyst in bulk, Maghnite is a montmorillonite sheet silicate clay exchanged with protons to produce Maghnite-H+. Temperature is varied between 20 and 80 °C. The effects of reaction temperature, amount of Mag-H+ on the yield and the intrinsic viscosity (η were investigated. A typical reaction product of poly (NVP-co- MMA was analyzed by infra red spectroscopy (FTIR and 1H-NMR, 13C-NMR spectroscopy as well as by viscosimetry. © 2014 BCREC UNDIP. All rights reservedReceived: 24th November 2013; Revised: 30th June 2014; Accepted: 8th July 2014How to Cite: Benadda, M., Ferrahi, M.I., Belbachir, M. (2014. Synthesis of Poly(N-vinyl-2-pyrrolidone-co-methyl methacrylate by Maghnite-H+ a Non-toxic Catalyst. Bulletin of Chemical Reaction Engineering & Catalysis, 9 (3: 201-206. (doi: 10.9767/bcrec.9.3.5743.201-206Permalink/DOI: http://dx.doi.org/10.9767/bcrec.9.3.5743.201-206

2,3-Di­phenyl­male­imide 1-methyl­pyrrol­idin-2-one monosolvate

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Bulatov, Evgeny; Boyarskaya, Dina; Chulkova, Tatiana; Haukka, Matti

2014-01-01

In the title compound, C16H11NO2·C5H9NO, the dihedral angles between the male­imide and phenyl rings are 34.7 (2) and 64.8 (2)°. In the crystal, the 2,3-di­phenyl­male­imide and 1-methyl­pyrrolidin-2-one mol­ecules form centrosymmetrical dimers via pairs of strong N—H⋯O hydrogen bonds and π–π stacking inter­actions between the two neighboring male­imide rings [centroid–centroid distance = 3.495 (2) Å]. The dimers are further linked by weak C—H⋯O and C—H⋯π hydrogen bonds into a three-dimensional framework. PMID:24764976

In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level

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Park, Insun; Hwang, Yu Jin; Kim, TaeHun; Viswanath, Ambily Nath Indu; Londhe, Ashwini M.; Jung, Seo Yun; Sim, Kyoung Mi; Min, Sun-Joon; Lee, Ji Eun; Seong, Jihye; Kim, Yun Kyung; No, Kyoung Tai; Ryu, Hoon; Pae, Ae Nim

2017-10-01

ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a histone lysine methyltransferase (HKMT) and it preferentially tri-methylates lysine 9 of histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington's disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide-competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico-in vitro approach. A ligand-based pharmacophore model was built and employed for the virtual screening of ChemDiv and Asinex database. Also, a human SETDB1/ESET homology model was constructed to supplement the data further. Biological evaluation of the selected 21 candidates singled out 5 compounds exhibiting a notable reduction of the H3K9me3 level via inhibitory potential of SETDB1/ESET activity in SETDB1/ESET-inducible cell line and HD striatal cells. Later on, we identified two compounds as final hits that appear to have neuronal effects without cytotoxicity based on the result from MTT assay. These compounds hold the calibre to become the future lead compounds and can provide structural insights into more SETDB1/ESET-focused drug discovery research. Moreover, these SETDB1/ESET inhibitors may be applicable for the preclinical study to ameliorate neurodegenerative disorders via epigenetic regulation.

In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level.

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Park, Insun; Hwang, Yu Jin; Kim, TaeHun; Viswanath, Ambily Nath Indu; Londhe, Ashwini M; Jung, Seo Yun; Sim, Kyoung Mi; Min, Sun-Joon; Lee, Ji Eun; Seong, Jihye; Kim, Yun Kyung; No, Kyoung Tai; Ryu, Hoon; Pae, Ae Nim

2017-10-01

ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a histone lysine methyltransferase (HKMT) and it preferentially tri-methylates lysine 9 of histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington's disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide-competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico-in vitro approach. A ligand-based pharmacophore model was built and employed for the virtual screening of ChemDiv and Asinex database. Also, a human SETDB1/ESET homology model was constructed to supplement the data further. Biological evaluation of the selected 21 candidates singled out 5 compounds exhibiting a notable reduction of the H3K9me3 level via inhibitory potential of SETDB1/ESET activity in SETDB1/ESET-inducible cell line and HD striatal cells. Later on, we identified two compounds as final hits that appear to have neuronal effects without cytotoxicity based on the result from MTT assay. These compounds hold the calibre to become the future lead compounds and can provide structural insights into more SETDB1/ESET-focused drug discovery research. Moreover, these SETDB1/ESET inhibitors may be applicable for the preclinical study to ameliorate neurodegenerative disorders via epigenetic regulation.

Identification of metabolites in urine and feces from rats dosed with the heterocyclic amine, 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C)

DEFF Research Database (Denmark)

Frederiksen, H.; Frandsen, Henrik Lauritz

2004-01-01

2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC) is a proximate mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking. In model systems, MeAalphaC can be formed by pyrolyses of either tryptophan or proteins of animal or vegetable origin. In the present study, the in vivo...

Cardioprotective Activity of N′′,N′′′-Bis[5-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]carbonohydrazide Derivative against Doxorubicin Induced Cardiotoxicity in Rats

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Salma Tabassum

2014-01-01

Full Text Available The present study was aimed at evaluating the cardioprotective effect of novel synthetic N′′,N′′′-bis[5-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]carbonohydrazide derivative, by estimating the various biomarkers like creatine kinase-myoglobin (CK-MB, lactate dehydrogenase (LDH, aspartate aminotransferase (AST, and triglycerides (TG in plasma and antioxidants like catalase, superoxide dismutase in heart tissue homogenate, and histopathological examination of heart tissues. The results showed the significant (P<0.05 dose dependent decrease in elevated cardiotoxic biomarkers CK-MB, LDH, AST, and TG levels. The histopathological studies of heart tissues showed mild degeneration of muscle bundles and less interstitial edematous changes. The results showed the significant (P<0.05 dose dependent increase in antioxidant enzymes catalase and superoxide dismutase in heart tissue homogenates. These observations enable us to conclude that N′′,N′′′-bis[5-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]carbonohydrazide has cardioprotective activity against doxorubicin induced cardiotoxicity.

Synthesis and evaluation of alpha-[[(2-haloethyl)amino]methyl]-2- nitro-1H-imidazole-1-ethanols as prodrugs of alpha-[(1-aziridinyl)methyl]-2- nitro-1H-imidazole-1-ethanol (RSU-1069) and its analogues which are radiosensitizers and bioreductively activated cytotoxins

International Nuclear Information System (INIS)

Jenkins, T.C.; Naylor, M.A.; O'Neill, P.; Threadgill, M.D.; Cole, S.; Stratford, I.J.; Adams, G.E.; Fielden, E.M.; Suto, M.J.; Stier, M.A.

1990-01-01

alpha-[(1-Aziridinyl)methyl]-2-nitro-1H-imidazole-1-ethanols, of general formula ImCH2CH(OH)CH2NCR1R2CR3R4, where Im = 2-nitroimidazole and R1, R2, R3, R4 = H, Me, are radiosensitizers and selective bioreductively activated cytotoxins toward hypoxic tumor cells in vitro and in vivo. Treatment of the aziridines with hydrogen halide in acetone or aqueous acetone gave the corresponding 2-haloethylamines of general formula ImCH2CH(OH)CH2(+)-NH2CR1R2CR3R4X X-, where R1, R2, R3, R4 = H, Me, and X = F, Cl, Br, I. These 2-haloethylamines were evaluated as prodrugs of the parent aziridines. The rates of ring closure in aqueous solution at pH approximately 6 were found to increase with increasing methyl substitution and to depend on the nature of the leaving group (I approximately Br greater than Cl much greater than F). A competing reaction of ImCH2CH(OH)CH2+NH2CH2CH2X X- (X = Cl, Br) with aqueous HCO3- ions gives 3-[2-hyroxy-3-(2-nitro-1H-imidazol-1-yl)propyl]-2-oxazolidinone. The activities of these prodrugs as radiosensitizers or as bioreductively activated cytotoxins were consistent with the proportion converted to the parent aziridine during the course of the experiment. alpha-[[(2-Bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1- ethanol (RB 6145, 10), the prodrug of alpha-[(1-aziridinyl)methyl]-2-nitro-1H-imidazole-1-ethanol (RSU-1069, 3), is identified as the most useful compound in terms of biological activity and rate of ring closure under physiological conditions

Molecular and polymeric uranyl and thorium hybrid materials featuring methyl substituted pyrazole dicarboxylates and heterocyclic 1,3-diketones

Science.gov (United States)

Carter, Korey P.; Kerr, Andrew T.; Taydakov, Ilya V.; Cahill, Christopher L.

2018-02-01

A series of seven novel f-element bearing hybrid materials have been prepared from either methyl substituted 3,4 and 4,5-pyrazoledicarboxylic acids, or heterocyclic 1,3- diketonate ligands using hydrothermal conditions. Compounds 1, [UO2(C6H4N2O4)2(H2O)], and 3, [Th(C6H4N2O4)4(H2O)5]·H2O feature 1-Methyl-1H-pyrazole-3,4-dicarboxylate ligands (SVI-COOH 3,4), whereas 2, [UO2(C6H4N2O4)2(H2O)], and 4, [Th(C6H5N2O4)(OH)(H2O)6]2·2(C6H5N2O4)·3H2O feature 1-Methyl-1H-pyrazole-4,5-dicarboxylate moieties (SVI-COOH 4,5). Compounds 5, [UO2(C13H15N4O2)2(H2O)]·2H2O and 6, [UO2(C11H11N4O2)2(H2O)]·4.5H2O feature 1,3-bis(4-N1-methyl-pyrazolyl)propane-1,3-dione and 1,3-bis(4-N1,3-dimethyl-pyrazolyl)propane-1,3-dione respectively, whereas the heterometallic 7, [UO2(C11H11N4O2)2(CuCl2)(H2O)]·2H2O is formed by using 6 as a metalloligand starting material. Single crystal X-ray diffraction indicates that all coordination to either [UO2]2+ or Th(IV) metal centers is through O-donation as anticipated. Room temperature, solid-state luminescence studies indicate characteristic uranyl emissive behavior for 1 and 2, whereas those for 5 and 6 are weak and poorly resolved.

Bis(2-methyl-1H-imidazol-3-ium naphthalene-1,5-disulfonate dihydrate

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Yu-feng Wang

2012-06-01

Full Text Available The asymmetric unit of the title organic salt, 2C4H7N2+·C10H6O6S22−·2H2O, consists of a 2-methylimidazolium cation, a half of a naphthalene-1,5-disulfonate anion, which lies about a center of symmetry, and a water molecule. In the crystal, N—H...O and O—H...O hydrogen bonds link the cations, anions and water molecules into the layers parallel to (111.

1-13C; methyl-2H3 methionine kinetics in humans: Methionine conservation and cystine sparing

International Nuclear Information System (INIS)

Storch, K.J.; Wagner, D.A.; Burke, J.F.; Young, V.R.

1990-01-01

Methionine (Met) conservation in healthy young adult men (4/diet group) was explored by supplying one of the following three L-amino acid based diets: (1) adequate Met but no cystine; (2) neither Met nor cystine; or (3) no Met but cystine supplementation. After 5 days, subjects received a continuous intravenous infusion of L-[1-13C; methyl-2H3]Met for 5 h while the diet was given as small isocaloric isonitrogenous meals. Estimates were made of rates of Met incorporation into protein synthesis (S) and release from body proteins (B), transmethylation (TM), remethylation of homocysteine (RM), and transsulfuration (TS). For the adequate Met diet, the rates were S = 24 +/- 2, B = 18 +/- 1, TM = 12.4 +/- 1.7, RM = 4.7 +/- 1.1, and TS = 7.6 +/- 0.6 (SE) mumol.kg-1.h-1. The sulfur amino acid-devoid diet significantly (P less than 0.05) reduced S, TM, RM, and TS. Supplementation of this diet with cystine reduced Met oxidation (P = 0.05). Therefore, two loci are quantitatively important regulatory points in Met conservation in vivo: (1) the distribution of Met between the pathways of protein anabolism and TM (Met locus) and (2) the distribution of homocysteine between RM and TS (homocysteine locus)

Certain and progressive methylation of histone H4 at lysine 20 during the cell cycle.

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Pesavento, James J; Yang, Hongbo; Kelleher, Neil L; Mizzen, Craig A

2008-01-01

Methylation of histone H4 at lysine 20 (K20) has been implicated in transcriptional activation, gene silencing, heterochromatin formation, mitosis, and DNA repair. However, little is known about how this modification is regulated or how it contributes to these diverse processes. Metabolic labeling and top-down mass spectrometry reveal that newly synthesized H4 is progressively methylated at K20 during the G(2), M, and G(1) phases of the cell cycle in a process that is largely inescapable and irreversible. Approximately 98% of new H4 becomes dimethylated within two to three cell cycles, and K20 methylation turnover in vivo is undetectable. New H4 is methylated regardless of prior acetylation, and acetylation occurs predominantly on K20-dimethylated H4, refuting the hypothesis that K20 methylation antagonizes H4 acetylation and represses transcription epigenetically. Despite suggestions that it is required for normal mitosis and cell cycle progression, K20 methylation proceeds normally during colchicine treatment. Moreover, delays in PR-Set7 synthesis and K20 methylation which accompany altered cell cycle progression during sodium butyrate treatment appear to be secondary to histone hyperacetylation or other effects of butyrate since depletion of PR-Set7 did not affect cell cycle progression. Together, our data provide an unbiased perspective of the regulation and function of K20 methylation.

Facile synthesis of (4S)-(-)-[9-3H]limonene

International Nuclear Information System (INIS)

Hiraga, Yoshikazu; Danjo, Hiroshi; Ito, Takatoshi; Suga, Takayuki

1993-01-01

[ 3 H]-1-Methyl-4-(1'-methylethenyl)cyclohexene [ 3 H] limonene) was synthesized from: -2-(4'-methylcyclohex-3'-enyl)propanal -(-)-1-ρ-menthen-9-al) via a convenient route in a high yield with improved enantiomeric purity. (Author)

Hydroxylation of methylated DNA by TET1 in chondrocyte differentiation of C3H10T1/2 cells

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Ryo Ito

2016-03-01

Full Text Available DNA methylation is closely involved in the regulation of cellular differentiation, including chondrogenic differentiation of mesenchymal stem cells. Recent studies showed that Ten–eleven translocation (TET family proteins converted 5-methylcytosine (5mC to 5-hydroxymethylcytosine, 5-formylcytosine and 5carboxylcytosine by oxidation. These reactions constitute potential mechanisms for active demethylation of methylated DNA. However, the relationship between the DNA methylation patterns and the effects of TET family proteins in chondrocyte differentiation is still unclear. In this study, we showed that DNA hydroxylation of 5mC was increased during chondrocytic differentiation of C3H10T1/2 cells and that the expression of Tet1 was particularly enhanced. Moreover, knockdown experiments revealed that the downregulation of Tet1 expression caused decreases in chondrogenesis markers such as type 2 and type 10 collagens. Furthermore, we found that TET proteins had a site preference for hydroxylation of 5mC on the Insulin-like growth factor 1 (Igf1 promoter in chondrocytes. Taken together, we showed that the expression of Tet1 was specifically facilitated in chondrocyte differentiation and Tet1 can regulate chondrocyte marker gene expression presumably through its hydroxylation activity for DNA.

(Carbonyl-1κC)bis-[2,3(η)-cyclo-penta-dien-yl][μ(3)-(S-methyl trithio-carbonato)methylidyne-1:2:3κC,S'':C:C](triphenyl-phosphine-1κP)(μ(3)-sulfido-1:2:3κS)dicobalt(II)iron(II) trifluoro-methane-sulfonate.

Science.gov (United States)

Manning, Anthony R; McAdam, C John; Palmer, Anthony J; Simpson, Jim

2008-04-10

The asymmetric unit of the title compound, [FeCo(2)(C(5)H(5))(2)(C(3)H(3)S(3))S(C(18)H(15)P)(CO)]CF(3)SO(3), consists of a triangular irondicobalt cluster cation and a trifluoro-methane-sulfonate anion. In the cation, the FeCo(2) triangle is symmetrically capped on one face by an S atom and on the other by a C atom linked to a methyl trithio-carbonate residue that bridges the Fe-C bond. Each Co atom carries a cyclo-penta-dienyl ligand while the Fe atom coordinates to one carbonyl and one triphenyl-phosphine ligand. In the crystal structure, the cation is linked to the anion by a number of weak non-classical C-H⋯O and C-H⋯F hydrogen bonds and weak S⋯O (3.317 Å) and S⋯F (3.198 Å) inter-actions. The structure is further stabilized by additional inter-molecular C-H⋯O, C-H⋯F and O⋯O (2.942 Å) contacts, together with an unusual S⋯π(Cp) inter-action (S⋯centroid distance = 3.385 Å), generating an extended network.

Prenatal famine and genetic variation are independently and additively associated with DNA methylation at regulatory loci within IGF2/H19.

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Elmar W Tobi

Full Text Available Both the early environment and genetic variation may affect DNA methylation, which is one of the major molecular marks of the epigenome. The combined effect of these factors on a well-defined locus has not been studied to date. We evaluated the association of periconceptional exposure to the Dutch Famine of 1944-45, as an example of an early environmental exposure, and single nucleotide polymorphisms covering the genetic variation (tagging SNPs with DNA methylation at the imprinted IGF2/H19 region, a model for an epigenetically regulated genomic region. DNA methylation was measured at five differentially methylated regions (DMRs that regulate the imprinted status of the IGF2/H19 region. Small but consistent differences in DNA methylation were observed comparing 60 individuals with periconceptional famine exposure with unexposed same-sex siblings at all IGF2 DMRs (P(BH<0.05 after adjustment for multiple testing, but not at the H19 DMR. IGF2 DMR0 methylation was associated with IGF2 SNP rs2239681 (P(BH = 0.027 and INS promoter methylation with INS SNPs, including rs689, which tags the INS VNTR, suggesting a mechanism for the reported effect of the VNTR on INS expression (P(BH = 3.4 × 10(-3. Prenatal famine and genetic variation showed similar associations with IGF2/H19 methylation and their contributions were additive. They were small in absolute terms (<3%, but on average 0.5 standard deviations relative to the variation in the population. Our analyses suggest that environmental and genetic factors could have independent and additive similarly sized effects on DNA methylation at the same regulatory site.

Crystal structure of N′-diphenylmethylidene-5-methyl-1H-pyrazole-3-carbohydrazide

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Khalid Karrouchi

2015-11-01

Full Text Available In the title compound, C18H16N4O, the planes of the phenyl rings are approximately perpendicular to each other [dihedral angle = 78.07 (8°] and form dihedral angles of 56.43 (8 and 24.59 (8° with the pyrazole ring. In the crystal, molecules are linked by N—H...O hydrogen bonds to form one-dimensional chains parallel to the [010] direction.

Bioactivation of the heterocyclic aromatic amine 2-amino-3-methyl-9H-pyrido [2,3-b]indole (MeA alpha C) in recombinant test systems expressing human xenobiotic-metabolizing enzymes

DEFF Research Database (Denmark)

Glatt, H.; Pabel, U.; Meinl, W.

2004-01-01

2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC) and some metabolites were investigated for mutagenicity in mammalian cell lines and bacterial strains engineered for the expression of human enzymes. MeAalphaC induced gene mutations (studied at the hprt locus) in Chinese hamster V79-derived cel...

4-Methyl-N-(2-methylbenzoylbenzenesulfonamide

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B. Thimme Gowda

2010-06-01

Full Text Available In the title compound, C15H15NO3S, the conformation of the N—H bond in the C—SO2—NH—C(O segment is anti to the C=O bond. Further, the conformation of the C=O bond is syn to the ortho-methyl group in the benzoyl ring. The dihedral angle between the sulfonyl benzene ring and the —SO2—NH—C—O segment is 87.1 (1° and that between the sulfonyl and the benzoyl benzene rings is 58.2 (1°. In the crystal structure, molecules are linked by pairs of N—H...O(S hydrogen bonds, forming inversion dimers.

Substituent effects on the photolysis of methyl 2-carboxylate substituted aliphatic 2 H-azirines

Science.gov (United States)

Gómez-Zavaglia, Andrea; Kaczor, Agnieszka; Cardoso, Ana L.; Pinho e Melo, Teresa M. V. D.; Fausto, Rui

2007-05-01

In this study, the UV induced photochemical reactions of two 2 H-azirines - methyl 2-chloro-3-methyl-2 H-azirine-2-carboxylate (MCMAC) and methyl 3-methyl-2 H-azirine-2-carboxylate (MMAC) - isolated in argon matrices are compared. For both compounds, irradiation with λ > 235 nm led to observation of two primary photoprocesses: (a) C sbnd C bond cleavage, with production of nitrile ylides (P1-type products), and (b) C sbnd N bond cleavage, with production of methylated ketene imines (P2-type products). However, subsequent photoprocesses were found to be different in the two cases. In MCMAC, both primary photoproducts were shown to undergo further reactions: P1-type products decarboxylate, giving [(1-chloroethylidene)imino]ethanide, which bears a C dbnd N +dbnd C - group (P3-type product); P2-type products decarbonylate, yielding a substituted ylidene methanamine (P4-type product). In MMAC, only P2-type primary photoproducts appeared to react, undergoing decarbonylation or decarboxylation (both reactions leading to P4-type products), whereas P1-type products were found to be non-reactive. The non-observation of any secondary photoproduct resulting from photolysis of P1-MMAC revealed the higher photostability of this species when compared with the corresponding photoproduct obtained from MCMAC. The C sbnd N photochemical cleavage is an unusual process in aliphatic 2 H-azirines. In the studied compounds, its preference over the commonly observed C sbnd C azirine-ring bond photocleavage is attributed to the presence of electron withdrawing substituents (methylcarboxy group in both azirines and also the chlorine atom in MCMAC), which accelerates intersystem crossing towards the triplet state from where the cleavage of the C sbnd N bond takes place. The lack of the chlorine atom in MMAC may be partially compensated by the significantly higher stabilization of the P2-type photoproduct derived from this molecule ( ca. -52 kJ mol -1) relatively to the reactant, when

Fibrillarin methylates H2A in RNA polymerase I trans-active promoters in Brassica oleracea

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lloyd eLoza-Muller

2015-11-01

Full Text Available Fibrillarin is a well conserved methyltransferase involved in several if not all of the more than 100 methylations sites in rRNA which are essential for proper ribosome function. It is mainly localized in the nucleoli and Cajal bodies inside the cell nucleus where it exerts most of its functions. In plants, fibrillarin binds directly the guide RNA together with Nop56, Nop58 and 15.5ka proteins to form a snoRNP complex that selects the sites to be methylated in pre-processing of ribosomal RNA. Recently, the yeast counterpart NOP1 was found to methylate histone H2A in the nucleolar regions. Here we show that plant fibrillarin can also methylate histone H2A. In Brassica floral meristem cells the methylated histone H2A is mainly localized in the nucleolus but unlike yeast or human cells it also localize in the periphery of the nucleus. In specialized transport cells the pattern is altered and it exhibits a more diffuse staining in the nucleus for methylated histone H2A as well as for fibrillarin. Here we also show that plant fibrillarin is capable of interacting with H2A and carry out its methylation in the rDNA promoter.

Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density

DEFF Research Database (Denmark)

Barres, Romain; Osler, Megan E; Yan, Jie

2009-01-01

-CpG nucleotides. Non-CpG methylation was acutely increased in human myotubes by exposure to tumor necrosis factor-alpha (TNF-alpha) or free fatty acids, but not insulin or glucose. Selective silencing of the DNA methyltransferase 3B (DNMT3B), but not DNMT1 or DNMT3A, prevented palmitate-induced non......-CpG methylation of PGC-1alpha and decreased mtDNA and PGC-1alpha mRNA. We provide evidence for PGC-1alpha hypermethylation, concomitant with reduced mitochondrial content in type 2 diabetic patients, and link DNMT3B to the acute fatty-acid-induced non-CpG methylation of PGC-1alpha promoter....

[Central muscle relaxant activities of 2-methyl-3-aminopropiophenone derivatives].

Science.gov (United States)

Kontani, H; Mano, A; Koshiura, R; Yamazaki, M; Shimada, Y; Oshita, M; Morikawa, K; Kato, H; Ito, Y

1987-02-01

In this experiment, we synthetized new 2-methyl-3-aminopropiophenone (MP) derivatives, whose structure is known to have central muscle relaxant activities, and quinolizidine and indan . tetralin derivatives derived from MP by cyclization, and we investigated the central muscle relaxant activity. Among the quinolizidine derivatives, there was a very strong central depressant agent, trans (3H, 9aH)-3-(p-chloro) benzoyl-quinolizidine (HSR-740), and among the indan . tetralin derivatives, there was an excitant agents, trans (1H, 2H)-5-methoxy-3, 3-dimethyl-2-piperidinomethyl indan-1-ol (HSR-719). From the results, these derivatives were not considered to be adequate for central muscle relaxant. Among the MP derivatives, (4'-chloro-2'-methoxy-3-piperidino) propiophenone HCl (HSR-733) and (4'-ethyl-2-methyl-3-pyrrolidino) propiophenone HCl (HSR-770) strongly inhibited the cooperative movement in the rotating rod method using mice, and it exerted almost the same depressant activity on the cross extensor reflex using alpha-chloralose anesthetized rats. However, the inhibitory effects of HSR-733 on the anemic decerebrate rigidity and the rigidity induced by intracollicular decerebration in rats were weaker than those of HSR-770 and eperisone. In spinal cats, at a low dose (5 mg/kg, i.v.), HSR-733 depressed monosynaptic and dorsal root reflex potentials as compared with polysynaptic reflex potentials, and inhibitory effects of HSR-733 on these three reflex potentials were more potent than those of eperisone and HSR-770. Although HSR-770 acts on the spinal cord and supraspinal level on which eperisone has been reported to act, HSR-733 may mainly act on the spinal cord. These results indicate that the MP derivative with a 2-methyl group may be suitable as a central muscle relaxant. HSR-770, which has equipotent muscle relaxant activity to eperisone, exerted strong inhibitory effects on oxotremorine-induced tremor and weak inhibitory effects on spontaneous motor activity in the

Synthesis of 14C- and 2H-labeled 1,3 dihydro-3, 3-dimethyl-5-(1,4,5,6,- tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one (LY195115), an orally effective positive inotrope

International Nuclear Information System (INIS)

Robertson, D.W.; Krushinski, J.H.; Kau, D.

1986-01-01

The synthesis of 14 C- and 2 H-labeled 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol -2-one (LY195115), an extremely potent, orally-effective cardiotonic with inotropic and vasodilator activities is described. The 14 C-label was introduced in the antepenultimate step by reaction of a β-chloroketone precursor with Na 14 CN; acid-catalyzed hydrolysis and cyclization with hydrazine provided the tetrahydropyridazinone bearing the 14 C-label in the oxo-carbon. 1,3-Dihydro-3,3-di(methyl-d 3 ) -2H-indol-2-one was prepared by exhaustive methylation of 1-acetyl-1,3-dihydro-2H-indol-2-one with sodium hydride and iodomethane-d 3 , followed by removal of the nitrogen protecting group. This labeled material was converted in two steps to [ 2 H 6 ]-LY195115. (author)

Synthesis of novel nitroso acetal derivatives via tandem 6π-electrocyclization/ [3+2]-cycloaddition of 1-nitro-2-methyl-1,3 butadiene

OpenAIRE

Esra Koc

2017-01-01

Novel nitroso acetal derivatives (4-methyl-2,3,3a,6-tetrahydroisoxazolo[2,3-b][1,2]oxazine) were synthesized through 6π-electrocyclization/[3+2]-cycloaddition reaction of several dionophiles with 1-nitro-2-methyl-1,3-butadiene. Structures of the synthesized compounds were determined by 1H-NMR, 13C-NMR, IR and GC-MS analyses.

Vinclozolin: 3-(3,5-dichlorophenyl-5-ethenyl-5-methyl-1,3-oxazolidine-2,4-dione

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Seonghwa Cho

2014-07-01

Full Text Available In the title compound, C12H9Cl2NO3, which is the fungicide vinclozolin, the dihedral angle between the oxazolidine ring mean plane [r.m.s. deviation = 0.029 Å] and the benzene ring is 77.55 (8°. In the crystal, molecules are linked via C—H...O hydrogen bonds, forming chains along [010]. The chains are linked by short Cl...Cl contacts [3.4439 (3 and 3.5798 (3 Å], resulting in a three-dimensional architecture.

Hexakis(1-methyl-1H-imidazole-κN3cobalt(II dibromide dihydrate

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Rufu Yao

2009-02-01

Full Text Available The asymmetric unit of the title compound, [Co(C4H6N26]Br2·2H2O, contains one-half of the centrosymmetric cation, one Br atom and one water molecule. The CoII atom, lying on an inversion center, has a distorted octahedral geometry, defined by six N atoms from six 1-methylimidazole ligands. In the crystal structure, intra- and intermolecular O—H...Br hydrogen bonds link pairs of uncoordinated water molecules and bromide anions.

Protein methylation in pea chloroplasts

International Nuclear Information System (INIS)

Niemi, K.J.; Adler, J.; Selman, B.R.

1990-01-01

The methylation of chloroplast proteins has been investigated by incubating intact pea (Pisum sativum) chloroplasts with [ 3 H-methyl]-S-adenosylmethionine. Incubation in the light increases the amount of methylation in both the thylakoid and stromal fractions. Numerous thylakoid proteins serve as substrates for the methyltransfer reactions. Three of these thylakoid proteins are methylated to a significantly greater extent in the light than in the dark. The primary stromal polypeptide methylated is the large subunit of ribulose bisphosphate carboxylase/oxygenase. One other stromal polypeptide is also methylated much more in the light than in the dark. Two distinct types of protein methylation occur. One methylinkage is stable to basic conditions whereas a second type is base labile. The base-stable linkage is indicative of N-methylation of amino acid residues while base-lability is suggestive of carboxymethylation of amino acid residues. Labeling in the light increases the percentage of methylation that is base labile in the thylakoid fraction while no difference is observed in the amount of base-labile methylations in light-labeled and dark-labeled stromal proteins. Also suggestive of carboxymethylation is the detection of volatile [ 3 H]methyl radioactivity which increases during the labeling period and is greater in chloroplasts labeled in the light as opposed to being labeled in the dark; this implies in vivo turnover of the [ 3 H]methyl group

Synthesis of [14α, 15α-3H]-norgestrel

International Nuclear Information System (INIS)

Wagner, H.

1988-01-01

The preparation of the well-known gestogen norgestrel in a tritium labelled form is described. Starting material was 18-methyl-3-methoxy-estra-1,3,5(10),8,14-pentaen-17β-o1 acetate. In a four step synthesis 17α-ethinyl-17β-hydroxy-18-methyl-[14α,15α- 3 H]-estr-4-en-3-one was obtained with a specific activity of 52 Ci/mmol and a radiochemical purity > 99%. (author)

GAS PHASE STRUCTURE AND STABILITY OF COMPLEX FORMED BY H2O, NH3, H2S AND THEIR METHYL DERIVATIVES WITH THE CATION CO2+

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Cahyorini Kusumawardani

2010-06-01

Full Text Available Ab initio molecular orbital calculations at the Hartree-Fock-Self Consistent Field (HF-SCF have been performed in order to determine the structure and gas phase energies of complex formed by the Lewis bases of H2O, NH3, H2S and their methyl derivatives with the cation Co2+. The relative basicities of the base studied depend on both the substituent. The gas-phase interaction energies computed by the SCF method including electron correlation Møller-Plesset 2 (MP2 dan Configuration Iteration (CI were comparable in accuracy. The binding energies computed by these two methods reach the targeted chemical accuracy.   Keywords: ab initio calculation, cobalt complex, structure stability

4-[(5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-ylphenylmethyl]-5-methyl-2-phenyl-1H-pyrazol-3(2H-one ethanol hemisolvate

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Hoong-Kun Fun

2009-01-01

Full Text Available The asymmetric unit of the title compound, C27H24N4O2·0.5C2H6O, comprises two crystallographically independent molecules (A and B with slightly different conformations, and one ethanol molecule of crystallization. Intramolecular C—H...O and O—H...O hydrogen bonds generate six- and eight-membered rings, producing S(6 and S(8 ring motifs, respectively. In molecule A, one of the benzene rings is disordered over two positions, with site-occupancy factors of 0.542 (11 and 0.458 (11. The dihedral angles between the central benzene ring and the two outer benzene rings are 73.88 (9 and 82.6 (2/88.9 (2° in molecule A, and 80.81 (8 and 79.38 (8° in molecule B. In the crystal structure, molecules form infinite one-dimensional chains in the (101 plane. The crystal structure is stabilized by intermolecular O—H...N, N—H...N, N—H...O and C—H...O hydrogen bonds, weak C—H...π and π–π [centroid–centroid = 3.5496 (1 Å] interactions.

Synthesis of specifically 2H-labeled reserpines, 3,4,5-trimethoxybenzoic acids, and syringic acid

International Nuclear Information System (INIS)

Roth, R.W.; Fischer, D.L.; Pachta, J.M.; Althaus, J.F.

1982-01-01

3,4,5-Trimethoxy- 2 H 9 -, 4-methoxy-3,5-dimethoxy- 2 H 6 , and 4-hydroxyl-3,5-dimethoxy- 2 H 6 -benzoic acids were prepared from n-propyl 3,4,5-trihydroxybenzoate (n-propyl gallate) by means of appropriate alkylation-hydrolysis sequences employing iodomethane- 2 H 3 or dimethyl- 2 H 6 -sulfate as the deuterium source. 4-Methoxy- 2 H 3 -3,5-dimethoxybenzoic acid was similarly prepared from ethyl 4-hydroxy-3,5-dimethoxybenzoate. The labeled trimethoxybenzoic acids were converted to the corresponding 2 H-labeled reserpines by condensation of the acid chlorides with methyl reserpate in pyridine according to the classical procedure. The labeled reserpine analog methyl 18-0-(4-hydroxy-3,5-dimethoxy- 2 H 6 )benzoyl reserpate was likewise prepared from 4-hydroxy-3,5-dimethoxy- 2 H 6 -benzoic acid via the intermediate methyl 18-0-(4-ethoxycarbonyloxy-3,5-dimethoxy- 2 H 6 -benzoyl)reserpate (syrosingopine- 2 H 6 ). The isotopic purity of each compound exceeded 99 atom percent 2 H. (author)

(/sup 3/H)MK-801 labels a site on the N-methyl-D-aspartate receptor channel complex in rat brain membranes

Energy Technology Data Exchange (ETDEWEB)

Wong, E H; Knight, A R; Woodruff, G N

1988-01-01

The potent noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (/sup 3/H)MK-801 bound with nanomolar affinity to rat brain membranes in a reversible, saturable, and stereospecific manner. The affinity of (/sup 3/H)MK-801 was considerably higher in 5 mM Tris-HCl (pH 7.4) than in previous studies using Krebs-Henseleit buffer. (/sup 3/H)MK-801 labels a homogeneous population of sites in rat cerebral cortical membranes with KD of 6.3 nM and Bmax of 2.37 pmol/mg of protein. This binding was unevenly distributed among brain regions, with hippocampus greater than cortex greater than olfactory bulb = striatum greater than medulla-pons, and the cerebellum failing to show significant binding. Detailed pharmacological characterization indicated (/sup 3/H)MK-801 binding to a site which was competitively and potently inhibited by known noncompetitive NMDA receptor antagonists, such as phencyclidine, thienylcyclohexylpiperidine (TCP), ketamine, N-allylnormetazocine (SKF 10,047), cyclazocine, and etoxadrol, a specificity similar to sites labelled by (/sup 3/H)TCP. These sites were distinct from the high-affinity sites labelled by the sigma receptor ligand (+)-(/sup 3/H)SKF 10,047. (/sup 3/H)MK-801 binding was allosterically modulated by the endogenous NMDA receptor antagonist Mg2+ and by other active divalent cations. These data suggest that (/sup 3/H)MK-801 labels a high-affinity site on the NMDA receptor channel complex, distinct from the NMDA recognition site, which is responsible for the blocking action of MK-801 and other noncompetitive NMDA receptor antagonists.

9-Ethyl-2,3-dihydro-9H-carbazol-4(1H-one

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S. Sriman Narayanan

2008-09-01

Full Text Available In the title compound, C28H30N2O2, the cyclohexene ring system adopts a sofa conformation. The crystal structure is stabilized by C—H...O interactions between methyl H atoms of the ethyl substituents and the O atoms of carbonyl groups of adjacent molecules, and by an intermolecular carbonyl–carbonyl interactions [3.207 (2 Å

Methyl-Donor and Cofactor Nutrient Intakes in the First 2–3 Years and Global DNA Methylation at Age 4: A Prospective Cohort Study

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Rachael M. Taylor

2018-02-01

Full Text Available Background: During the early postnatal period, the impact of nutrition on DNA methylation has not been well studied in humans. The aim was to quantify the relationship between one-carbon metabolism nutrient intake during the first three years of life and global DNA methylation levels at four years. Design: Childhood dietary intake was assessed using infant feeding questionnaires, food frequency questionnaires, 4-day weighed food records and 24-h food records. The dietary records were used to estimate the intake of methionine, folate, vitamins B2, B6 and B12 and choline. The accumulative nutrient intake specific rank from three months to three years of age was used for analysis. Global DNA methylation (%5-methyl cytosines (%5-mC was measured in buccal cells at four years of age, using an enzyme-linked immunosorbent assay (ELISA commercial kit. Linear regression models were used to quantify the statistical relationships. Results: Data were collected from 73 children recruited from the Women and their Children’s Health (WATCH study. No association was found between one-carbon metabolism nutrient intake and global DNA methylation levels (P > 0.05. Global DNA methylation levels in males were significantly higher than in females (median %5-mC: 1.82 vs. 1.03, males and females respectively, (P < 0.05. Conclusion: No association was found between the intake of one-carbon metabolism nutrients during the early postnatal period and global DNA methylation levels at age four years. Higher global DNA methylation levels in males warrants further investigation.

Methyl-Donor and Cofactor Nutrient Intakes in the First 2–3 Years and Global DNA Methylation at Age 4: A Prospective Cohort Study

Science.gov (United States)

Taylor, Rachael M.; Smith, Roger; Collins, Clare E.; Mossman, David; Wong-Brown, Michelle W.; Chan, Eng-Cheng; Evans, Tiffany-Jane; Attia, John R.; Smith, Tenele; Butler, Trent

2018-01-01

Background: During the early postnatal period, the impact of nutrition on DNA methylation has not been well studied in humans. The aim was to quantify the relationship between one-carbon metabolism nutrient intake during the first three years of life and global DNA methylation levels at four years. Design: Childhood dietary intake was assessed using infant feeding questionnaires, food frequency questionnaires, 4-day weighed food records and 24-h food records. The dietary records were used to estimate the intake of methionine, folate, vitamins B2, B6 and B12 and choline. The accumulative nutrient intake specific rank from three months to three years of age was used for analysis. Global DNA methylation (%5-methyl cytosines (%5-mC)) was measured in buccal cells at four years of age, using an enzyme-linked immunosorbent assay (ELISA) commercial kit. Linear regression models were used to quantify the statistical relationships. Results: Data were collected from 73 children recruited from the Women and their Children’s Health (WATCH) study. No association was found between one-carbon metabolism nutrient intake and global DNA methylation levels (P 0.05). Global DNA methylation levels in males were significantly higher than in females (median %5-mC: 1.82 vs. 1.03, males and females respectively, (P 0.05)). Conclusion: No association was found between the intake of one-carbon metabolism nutrients during the early postnatal period and global DNA methylation levels at age four years. Higher global DNA methylation levels in males warrants further investigation. PMID:29495543

5-Chloro-2-methyl-3-phenylsulfonyl-1-benzofuran

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Hong Dae Choi

2008-07-01

Full Text Available The title compound, C15H11ClO3S, was prepared by the oxidation of 5-chloro-2-methyl-3-phenylsulfanyl-1-benzofuran with 3-chloroperoxybenzoic acid. There are two symmetry-independent molecules in the asymmetric unit. The dihedral angles formed by the phenyl ring and the plane of the benzofuran system are 77.80 (8 and 78.34 (8°. The crystal structure is stabilized by aromatic π–π stacking interactions between the furan ring and the benzene rings of neighbouring benzofuran fragments from two symmetry-independent molecules; the centroid–centroid distances within the stacks are 3.689 (4, 3.702 (4, 3.825 (4 and 3.826 (4 Å. Additionally, the stacked molecules exhibit inter- and intramolecular C—H...O interactions.

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in Parkinson's disease.

Science.gov (United States)

Louis, Elan D; Michalec, Monika; Jiang, Wendy; Factor-Litvak, Pam; Zheng, Wei

2014-01-01

Parkinson's disease (PD) is a late-life neurodegenerative disease. Genetic and environmental factors play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin that shows structural resemblance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In 2002 and 2007, we demonstrated elevated blood harmane concentrations [HA] in essential tremor (ET) cases. We now assessed whether blood [HA] were elevated in Parkinson's disease (PD) as well. Blood [HA] were quantified by high performance liquid chromatography. Subjects comprised 113 PD cases and 101 controls. Mean log blood [HA] in PD cases was double that of controls (0.59±0.63 g(-10)/ml vs. 0.27±0.63 g(-10)/ml, p<0.001). A non-parametric test on non-transformed data (median blood [HA]=3.31 g(-10)/ml in cases and 1.44 g(-10)/ml in controls) also showed this difference (p<0.001). In unadjusted and then adjusted logistic regression analyses, log blood [HA] was associated with PD (odds ratio [OR]unadjusted 2.31, 95% confidence interval [CI] 1.46-3.67, p<0.001; OR(adjusted) 2.54, 95% CI 1.55-4.16, p<0.001). In PD, log blood [HA] co-varied with family history, being lowest in PD cases with no family history (0.54±0.60 g(-10)/ml) and highest in PD cases with a family history of both ET and PD (0.84±0.68 g(-10)/ml) (p=0.06). Blood harmane appears to be elevated in PD. The finding needs to be reproduced in additional cohorts to assess its generalizability. The higher concentration in familial PD suggests that the mechanism may involve genetic factors. Copyright © 2013 Elsevier Inc. All rights reserved.

DNA methylation of IGF2DMR and H19 is associated with fetal and infant growth: the generation R study.

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Marieke I Bouwland-Both

Full Text Available Changes in epigenetic programming of embryonic growth genes during pregnancy seem to affect fetal growth. Therefore, in a population-based prospective birth cohort in the Netherlands, we examined associations between fetal and infant growth and DNA methylation of IGF2DMR, H19 and MTHFR. For this study, we selected 69 case children born small-for-gestational age (SGA, birth weight <-2SDS and 471 control children. Fetal growth was assessed with serial ultrasound measurements. Information on birth outcomes was retrieved from medical records. Infant weight was assessed at three and six months. Methylation was assessed in DNA extracted from umbilical cord white blood cells. Analyses were performed using linear mixed models with DNA methylation as dependent variable. The DNA methylation levels of IGF2DMR and H19 in the control group were, median (90% range, 53.6% (44.5-61.6 and 30.0% (25.6-34.2 and in the SGA group 52.0% (43.9-60.9 and 30.5% (23.9-32.9, respectively. The MTHFR region was found to be hypomethylated with limited variability in the control and SGA group, 2.5% (1.4-4.0 and 2.4% (1.5-3.8, respectively. SGA was associated with lower IGF2DMR DNA methylation (β = -1.07, 95% CI -1.93; -0.21, P-value = 0.015, but not with H19 methylation. A weight gain in the first three months after birth was associated with lower IGF2DMR DNA methylation (β = -0.53, 95% CI -0.91; -0.16, P-value = 0.005. Genetic variants in the IGF2/H19 locus were associated with IGF2DMR DNA methylation (P-value<0.05, but not with H19 methylation. Furthermore, our results suggest a possibility of mediation of DNA methylation in the association between the genetic variants and SGA. To conclude, IGF2DMR and H19 DNA methylation is associated with fetal and infant growth.

5-(2,4-Dichlorophenoxy-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde

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S. Madan Kumar

2016-07-01

Full Text Available In the crystal structure of the title compound, C17H12Cl2N2O2, the pyrazole ring makes dihedral angles of 65.0 (2 and 43.9 (2° with the dichlorophenyl and phenyl rings, respectively. The dihedral angle between the chlorophenyl and phenyl rings is 59.1 (2°. In the crystal, the molecules are linked by C—H...O hydrogen bonds and weak C—Cl...π and C—H...π interactions, generating a three-dimensional network.

Mobility and molecular ions of dimethyl methyl phosphonate, methyl salicylate and acetone

Science.gov (United States)

Nowak, D. M.

1983-06-01

The mobilities of positive and negative reactant ions are reported for (H2O)nH(+); (H2O)2O2 and (H2O)2CO3(-) ion clusters. The formation of positive DMMP monomer and dimer is reported, and equilbria molecular reactions are reported. Acetone is reported as forming a dimer at 81 ppb with a reduced mobility (K sub o) of 1.82, Methyl salicylate is shown to form a protonated and hydrated positive monomer. Mixtures of DMMP and methyl salicylate with acetone showed a substantial change in DMMP ion clustering and little or no change in the methyl salicylate mobility spectra. Negative ions were not observed for DMMP, methyl salicylate, acetone and the mixtures under the conditions reported.

Crystal structure of 2-methylamino-4-(6-methyl-4-oxo-4H-chromen-3-yl-3-nitropyrano[3,2-c]chromen-5(4H-one with an unknown solvate

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Rajamani Raja

2015-09-01

Full Text Available In the title compound, C23H16N2O7, the mean planes of the two chromene units (r.m.s. deviations = 0.031 and 0.064 Å are almost normal to one another with a dihedral angle of 85.59 (6°. The central six-membered pyran ring has a distorted envelope conformation, with the methine C atom at the flap. There is an intramolecular N—H...O hydrogen bond, which generates an S(6 ring motif. In the crystal, molecules are linked by pairs of N—H...O hydrogen bonds, forming inversion dimers with an R22(12 ring motif. The dimers are linked by pairs of C—H...O hydrogen bonds, enclosing R22(6 ring motifs, forming zigzag chains along [001]. The chains are linked by a second pair of C—H...O hydrogen bonds, forming slabs parallel to (110. Within the slabs there are C—H...π interactions present. A region of disordered electron density was treated with the SQUEEZE procedure in PLATON [Spek (2015. Acta Cryst. C71, 9–18] following unsuccessful attempts to model it as plausible solvent molecule(s. The given chemical formula and other crystal data do not take into account the unknown solvent molecule(s.

Synthesis of (R,S)-[2,3-13C2]-1-(1'-methyl-2'-pyrrolidinyl)propan-2-one; {(R,S)-[2',3'-13C2]hygrinePound right bracePound

International Nuclear Information System (INIS)

Abraham, T.W.; Leete, Edward

1996-01-01

2-Ethoxy-1-methyl-5-pyrrolidinone (1) was reacted with ethyl [3,4- 13 C 2 ]-acetoacetate (2) in the presence of TiCl 4 to give ethyl [3,4- 13 C 2 ]-2-(1'-methyl-5'-oxo-2'-pyrrolidinyl)-3-oxobutanoate (3) in 85% yield. Decarboethoxylation of ethyl [3,4- 13 C 2 ]-2-(1'-methyl-5'-oxo-2'-pyrrolidinyl)-3-oxobutan-oate (3) was accomplished using NaCl and H 2 O in DMSO to give (R,S)-[2,3- 13 C 2 ]-1-(1'-methyl-5'-oxo-2'-pyrrolidinyl)propan-2-o ne (4) in 91% yield. Protection of the ketone as a ketal (ethylene glycol, H + ), followed by reduction of the amide to the amine using LiAlH 4 and subsequent deprotection of the ketal gave (R,S)-[2,3- 13 C 2 ]-1-(1'-methyl-2'-pyrrolidinyl)propan-2-one ((R,s)-[2', 3'- 13 C 2 ]Hygrine) (8) in 78% yield. (61% overall yield from ethyl [3,4- 13 C 2 ]acetoacetate). (Author)

Fragrance material review on 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)pent-3-en-2-one.

Science.gov (United States)

Scognamiglio, J; Letizia, C S; Api, A M

2013-12-01

A toxicologic and dermatologic review of 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)pent-3-en-2-one when used as a fragrance ingredient is presented. 3-Methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)pent-3-en-2-one is a member of the fragrance structural group Alkyl Cyclic Ketones. These fragrances can be described as being composed of an alkyl, R1, and various substituted and bicyclic saturated or unsaturated cyclic hydrocarbons, R2, in which one of the rings may include up to 12 carbons. Alternatively, R2 may be a carbon bridge of C2-C4 carbon chain length between the ketone and cyclic hydrocarbon. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)pent-3-en-2-one were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, sensitization, phototoxicity, photoallergy, and genotoxicity data. A safety assessment of the entire Alkyl Cyclic Ketones will be published simultaneously with this document; please refer to Belsito et al. (Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2013. A Toxicologic and Dermatologic Assessment of Alkyl Cyclic Ketones when used as fragrance ingredients. Submitted for publication) for an overall assessment of the safe use of this material and all Alkyl Cyclic Ketones in fragrances. Copyright © 2013 Elsevier Ltd. All rights reserved.

Synthesis and characterization of tris[butyl-(1-methyl-3-phenyl-propyl)-dithiocarbamato]-cobalt(III) seskvitoluene

OpenAIRE

TIBOR SABO; ISMET M. HODZIC; SRECKO R. TRIFUNOVIC; VESNA M. DJINOVIC; GORAN N. KALUDJEROVIC

2002-01-01

A new bidentate ligand butyl-(1-methyl-3-phenyl-propyl)-dithiocarbamate (bmFpdtc) was prepared, as the sodium salt. In the reaction of hexaaminecobalt(III) chloride with NabmFpdtc, the corresponding tris[butyl-(1-methyl-3-phenyl-propyl)-dithiocarbamato]cobalt(III), [Co(bmFpdtc)3] complex was prepared. The complex was characterized by elemental analysis, infrared, electronic absorption, 1H and 13C-NMR spectroscopy.

H19DMR methylation analysis in patients with Beckwith-Wiedemann syndrome and isolated hemihyperplasia

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Marcus Vinícius de Matos Gomes

2005-01-01

Full Text Available Beckwith-Wiedemann syndrome (BWS is a congenital overgrowth disorder of complex and heterogeneous etiology involving alterations in genomic imprinting. The cause of isolated hemihyperplasia (IHH is unknown but might be due to partial or incomplete expression of BWS because both these conditions share predisposition for the same types of neoplasias. We investigated the methylation pattern of the putative imprinting control region H19DMR using peripheral blood from 12 patients, six with clinical features of BWS and six with IHH. All the patients had normal karyotypes and paternal uniparental disomy (UPD was excluded in 10 informative cases. The normal H19DMR methylation pattern was found in eight informative patients, indicating that H19DMR methylation was not related to their condition. We suggest that the absence of neoplasias in the BWS and IHH patients studied might be related to the absence of UPD and to the presence of normal H19DMR methylation.

Synthesis of racemic [methyl-d3]-labeled cis- and trans-3'-hydroxycotinine

International Nuclear Information System (INIS)

Ravard, A.; Crooks, P.A.

1994-01-01

A method is described for the synthesis of the racemic [methyl-d 3 ] forms of the nicotine metabolites cis-3'-hydroxycotinine and trans-3'-hydroxycotinine. The key intermediate was [methyl-d 3 ]-N-methylhydroxylamine, obtained from a selective hydrogenation of d 3 -nitro-methane. This intermediate was converted to [methyl-d 3 ]-α-3-pyridyl-N-methylnitrone, which was condensed with methyl acrylate to give a mixture of isomeric isoxazolidines. The hydrogenolysis of this mixture afforded a 70:30 mixture of [methyl-d 3 ] cis- and trans-3'-hydroxycotinine, from which the pure cis-isomer could be isolated by recrystallization from acetone. [Methyl-d 3 ]-trans-3'-hydroxycotinine could be prepared in high yield from the cis-isomer via chiral inversion utilizing a Mitsunobu reaction, or by chromatographic separation from a mixture of the cis- and trans-3'-benzoyloxycotinine, followed by O-debenzoylation in methanolic NaOH. (author)

The multi-domain protein Np95 connects DNA methylation and histone modification.

Science.gov (United States)

Rottach, Andrea; Frauer, Carina; Pichler, Garwin; Bonapace, Ian Marc; Spada, Fabio; Leonhardt, Heinrich

2010-04-01

DNA methylation and histone modifications play a central role in the epigenetic regulation of gene expression and cell differentiation. Recently, Np95 (also known as UHRF1 or ICBP90) has been found to interact with Dnmt1 and to bind hemimethylated DNA, indicating together with genetic studies a central role in the maintenance of DNA methylation. Using in vitro binding assays we observed a weak preference of Np95 and its SRA (SET- and Ring-associated) domain for hemimethylated CpG sites. However, the binding kinetics of Np95 in living cells was not affected by the complete loss of genomic methylation. Investigating further links with heterochromatin, we could show that Np95 preferentially binds histone H3 N-terminal tails with trimethylated (H3K9me3) but not acetylated lysine 9 via a tandem Tudor domain. This domain contains three highly conserved aromatic amino acids that form an aromatic cage similar to the one binding H3K9me3 in the chromodomain of HP1ss. Mutations targeting the aromatic cage of the Np95 tandem Tudor domain (Y188A and Y191A) abolished specific H3 histone tail binding. These multiple interactions of the multi-domain protein Np95 with hemimethylated DNA and repressive histone marks as well as with DNA and histone methyltransferases integrate the two major epigenetic silencing pathways.

2-Methyl-1-(3-methylphenylsulfonylnaphtho[2,1-b]furan

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Hong Dae Choi

2014-04-01

Full Text Available In the title compound, C20H16O3S, the dihedral angle between the mean planes of the naphthofuran and 3-methylphenyl fragments is 88.56 (2°. In the crystal, molecules are linked via pairs of C—H...O hydrogen bonds, forming inversion dimers. These dimers are linked by π–π interactions between the furan rings of neighbouring molecules [centroid–centroid distance = 3.701 (2 Å] into supramolecular chains running along the a-axis direction.

Applications of 3H and 2H NMR spectroscopy in studies of β-lactam antibiotic biosynthesis

International Nuclear Information System (INIS)

Crout, D.H.G.

1986-01-01

Stereochemical studies have been invaluable in illuminating the mechanisms of enzymatic reactions. The formation of cephalosporin C from penicillin N is a biological process of fundamental importance in relation to cephalosporin C production. During this transformation, two methyl groups in penicillin N, (originally the two methyl groups of the precursor L-valine) are converted into methylene groups. One is involved in the ring expansion - sulphur migration step, the other in the formation of the acetoxymethyl side chain. By synthesizing 'chiral methyl' valine in which both methyl groups were stereospecifically labeled with deuterium and tritium, and by using 3 H and 2 H n.m.r. to analyse the valine, and the cephalosporin C produced from it biosynthetically, it has been possible in a single experiment to elucidate the stereochemical changes taking place during the transformations of both methyl groups. The results obtained support the hypothesis that both transformations involve radical intermediates. 8 refs.; 6 figs.; 4 schemes

Technetium(V)-nitrido complexes of dithiocarbazic acid derivatives. Reactivity of [Tc≡N]2+ core towards Schiff bases derived from S-methyl dithiocarbazate. Crystal structures of [S-methyl 3-(2-hydroxyphenyl-methylene) dithiocarbazato]intrido(triphenylphosphine)technetium(V) and bis(S-methyl 3-isopropylidenedithiocarbazato)nitridotechnetium(V)

International Nuclear Information System (INIS)

Marchi, A.; Duatti, A.; Rossi, R.; Magon, L.; Bertolasi, V.; Ferretti, V.; Gilli, G.; Pasqualini, R.

1988-01-01

As a potential alternative approach to lipophilic square-pyramidal technetium complexes, we investigate here the synthesis of new Tcsup(V) complexes, containing the [Tc''ident to''N] 2+ core, with bi- and tri-dentate Schiff bases derived from S-methyl dithiocarbazate, NH 2 NHC(=S)SCH 3 . Square-pyramidal complexes having an apical Tcsup(V) ≡ N group, with bis(quinoline-8-thiolato), [TcN(C 9 H 6 NS) 2 ], and bis(diethyldithiocarbamate), [TcN(S 2 CNEt 2 ) 2 ], have been reported. In this paper, we report the synthesis and characterization of a series of technetium(V)-nitrido complexes with the ligands illustrated, obtained by reduction of the technetium(VI) complex [TcNCl 4 ] - or by ligand substitution of the Tcsup(V) complex [TcNCl 2 (PPh 3 ) 2 ]. We discuss also the crystal structures of the complexes [TcNL 1 (PPh 3 )] [H 2 L 1 = S-methyl 3-(2-hydroxy-phenylmethylene)dithiocarbazate] and [TcN(L 12 ) 2 ] (HL 12 S-methyl 3-isopropylidenedithiocarbazate. (author)

cyclo-Tetrakis(μ-3-acetyl-4-methyl-1H-pyrazole-5-carboxylato-κ4N2,O3:N1,O5tetrakis[aquacopper(II] tetradecahydrate

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Sergey Malinkin

2011-09-01

Full Text Available The title compound, [Cu4(C7H6N2O34(H2O4]·14H2O, a tetranuclear [2 × 2] grid-type complex with S4 symmetry, contains four CuII atoms which are bridged by four pyrazolecarboxylate ligand anions and are additionally bonded to a water molecule. Each CuII atom is coordinated by two O atoms of the carboxylate and acetyl groups, two pyrazole N atoms of doubly deprotonated 3-acetyl-4-methyl-1H-pyrazole-5-carboxylic acid and one O atom of a water molecule. The geometry at each CuII atom is distorted square-pyramidal, with the two N and two O atoms in the equatorial plane and O atoms in the axial positions. O—H...O hydrogen-bonding interactions additionally stabilize the structure. One of the uncoordinated water molecules shows half-occupancy.

Synthesis and characterization of tris[butyl-(1-methyl-3-phenyl-propyl-dithiocarbamato]-cobalt(III seskvitoluene

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TIBOR SABO

2002-02-01

Full Text Available A new bidentate ligand butyl-(1-methyl-3-phenyl-propyl-dithiocarbamate (bmFpdtc was prepared, as the sodium salt. In the reaction of hexaaminecobalt(III chloride with NabmFpdtc, the corresponding tris[butyl-(1-methyl-3-phenyl-propyl-dithiocarbamato]cobalt(III, [Co(bmFpdtc3] complex was prepared. The complex was characterized by elemental analysis, infrared, electronic absorption, 1H and 13C-NMR spectroscopy.

Loss of TET1 facilitates DLD1 colon cancer cell migration via H3K27me3-mediated down-regulation of E-cadherin.

Science.gov (United States)

Zhou, Zhen; Zhang, Hong-Sheng; Liu, Yang; Zhang, Zhong-Guo; Du, Guang-Yuan; Li, Hu; Yu, Xiao-Ying; Huang, Ying-Hui

2018-02-01

Epigenetic modifications such as histone modifications and cytosine hydroxymethylation are linked to tumorigenesis. Loss of 5-hydroxymethylcytosine (5 hmC) by ten-eleven translocation 1 (TET1) down-regulation facilitates tumor initiation and development. However, the mechanisms by which loss of TET1 knockdown promotes malignancy development remains unclear. Here, we report that TET1 knockdown induced epithelial-mesenchymal transition (EMT) and increased cancer cell growth, migration, and invasion in DLD1 cells. Loss of TET1 increased EZH2 expression and reduced UTX-1 expression, thus increasing histone H3K27 tri-methylation causing repression of the target gene E-cadherin. Ectopic expression of the H3K27 demethylase UTX-1 or EZH2 depletion both impeded EZH2 binding caused a loss of H3K27 methylation at epithelial gene E-cadherin promoter, thereby suppressing EMT and tumor invasion in shTET1 cells. Conversely, UTX-1 depletion and ectopic expression of EZH2 enhanced EMT and tumor metastasis in DLD1 cells. These findings provide insight into the regulation of TET1 and E-cadherin and identify EZH2 as a critical mediator of E-cadherin repression and tumor progression. © 2017 Wiley Periodicals, Inc.

The Dnmt3L ADD Domain Controls Cytosine Methylation Establishment during Spermatogenesis

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Georgios Vlachogiannis

2015-02-01

Full Text Available A critical aspect of mammalian gametogenesis is the reprogramming of genomic DNA methylation. The catalytically inactive adaptor Dnmt3L is essential to ensuring this occurs correctly, but the mechanism by which it functions is unclear. Using gene targeting to engineer a single-amino-acid mutation, we show that the Dnmt3L histone H3 binding domain (ADD is necessary for spermatogenesis. Genome-wide single-base-resolution DNA methylome analysis of mutant germ cells revealed overall reductions in CG methylation at repetitive sequences and non-promoter CpG islands. Strikingly, we also observe an even more severe loss of non-CG methylation, suggesting an unexpected role for the ADD in this process. These epigenetic deficiencies were coupled with defects in spermatogonia, with mutant cells displaying marked changes in gene expression and reactivation of retrotransposons. Our results demonstrate that the Dnmt3L ADD is necessary for Dnmt3L function and full reproductive fitness.

13C and 1H nuclear magnetic resonance of methyl-substituted acetophenones and methyl benzoates: steric hindrance and inhibited conjugation.

Science.gov (United States)

Budesínský, Milos; Kulhánek, Jirí; Böhm, Stanislav; Cigler, Petr; Exner, Otto

2004-10-01

The 1H and 13C NMR spectra of 14 methyl-substituted acetophenones and 14 methyl-substituted methyl benzoates were assigned and interpreted with respect to the conformation of the C(ar)-C(O) bond. The substituent effects are proportional in the two series and can be divided into polar and steric: each has different effects on the 13C SCS of the individual atoms. In the case of C atoms C(O), C(1) and CH3(CO), the steric effects were quantitatively separated by comparing SCS in the ortho and para positions. The steric effects are proportional for the individual C atoms and also to steric effects estimated from other physical quantities. However, they do not depend simply on the angle of torsion phi of the functional group as anticipated hitherto. A better description distinguishes two classes of compounds: sterically not hindered or slightly hindered planar molecules and strongly sterically hindered, markedly non-planar. In order to confirm this reasoning without empirical correlations, the J(C,C) coupling constants were measured for three acetophenone derivatives labeled with 13C in the acetyl methyl group. The constants confirm unambiguously the conformation of 2-methylacetophenone; their zero values are in accord with the conformation of 2,6-dimethylacetophenone. The zero values in the unsubstituted acetophenone are at variance with previous erroneous report but all J(C,C) values are in accord with calculations at the B3LYP/6-311++G(2d,2p)//B3LYP/6-311+G(d,p) level. Copyright 2004 John Wiley & Sons, Ltd.

7-{[2-(4-Hydroxyphenylmethylidene]amino}-1,3-thiazol-4-yl-2-(methoxyiminoacetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-ylsulfanyl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic Acid

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Ghulam Fareed

2012-05-01

Full Text Available Novel 7-{[2-(4-hydroxyphenylmethylidene]amino}-1,3-thiazol-4-yl-2-(methoxyiminoacetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-ylsulfanyl]methyl}-8-oxo-5-thia-1azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid was prepared by condensation of ceftriaxone disodium (1 with 4-hydroxybenzaldehyde (2 in ethanol under reflux conditions for 3–4 h. The structure of synthesized compound was elucidated using LCMS, ¹H-NMR, and CHN techniques.

Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes

DEFF Research Database (Denmark)

Pasini, Diego; Malatesta, Martina; Jung, Hye Ryung

2010-01-01

Polycomb group (PcG) proteins are transcriptional repressors, which regulate proliferation and cell fate decisions during development, and their deregulated expression is a frequent event in human tumours. The Polycomb repressive complex 2 (PRC2) catalyzes trimethylation (me3) of histone H3 lysine...... are poorly understood. To gain insight into these mechanisms, we have determined the global changes in histone modifications in embryonic stem (ES) cells lacking the PcG protein Suz12 that is essential for PRC2 activity. We show that loss of PRC2 activity results in a global increase in H3K27 acetylation....... The methylation to acetylation switch correlates with the transcriptional activation of PcG target genes, both during ES cell differentiation and in MLL-AF9-transduced hematopoietic stem cells. Moreover, we provide evidence that the acetylation of H3K27 is catalyzed by the acetyltransferases p300 and CBP. Based...

Methyl 3′,4′,5′-trimethoxybiphenyl-4-carboxylate

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Sami Nummelin

2013-03-01

Full Text Available In the title compound, C17H18O5, the dihedral angle between the benzene rings is 31.23 (16°. In the crystal, the molecules are packed in an antiparallel fashion in layers along the a axis. In each layer, very weak C—H...O hydrogen bonds occur between the methoxy and methyl ester groups. Weak C—H...π interactions between the 4′- and 5′-methoxy groups and neighbouring benzene rings [methoxy-C–ring centroid distances = 4.075 and 3.486 Å, respectively] connect the layers.

Urine mercury levels correlate with DNA methylation of imprinting gene H19 in the sperm of reproductive-aged men.

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Zhaoxu Lu

Full Text Available Mercury (Hg is a well-recognized environmental pollutant known by its toxicity of development and neurotoxicity, which results in adverse health outcomes. However, the mechanisms underlying the teratogenic effects of Hg are not well understood. Imprinting genes are emerging regulators for fetal development subjecting to environmental pollutants impacts. In this study, we examined the association between preconceptional Hg exposure and the alteration of DNA methylation of imprinting genes H19, Meg3, and Peg3 in human sperm DNA.A total of 616 men, aged from 22 to 59, were recruited from Reproductive Medicine Clinic of Maternal and Child Care Service Center and the Urologic Surgery Clinic of Shanxi Academy of Medical Sciences during April 2015 and March 2016. Demographic information was collected through questionnaires. Urine was collected and urinary Hg concentrations were measured using a fully-automatic double-channel hydride generation atomic fluorescence spectrometer. Methylation of imprinting genes H19, Meg3 and Peg3 of sperm DNA from 242 participants were examined by bisulfite pyrosequencing. Spearman's rank and multivariate regression analysis were used for correlation analysis between sperm DNA methylation status of imprinting genes and urinary Hg levels.The median concentration of Hg for 616 participants was 9.14μg/l (IQR: 5.56-12.52 μg/l; ranging 0.16-71.35μg/l. A total of 42.7% of the participants are beyond normal level for non-occupational exposure according to the criterion of Hg poisoning (≥10 μg/L. Spearman's rank analysis indicated a negative correlation between urinary Hg concentrations and average DNA methylation levels of imprinted genes H19 (rs = -0.346, p <0.05, but there was no such a correlation for Peg3 and Meg3. Further, we analyzed the correlation between methylation level at individual CpG site of H19 and urinary Hg level. The results showed a negative correlation between urinary Hg concentrations and three out of

2-{[2-Methyl-3-(2-methylphenyl-4-oxo-3,4-dihydroquinazolin-8-yl]oxy}acetonitrile

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Adel S. El-Azab

2012-07-01

Full Text Available In the title compound, C18H15N3O2, the fused ring system is almost planar [the dihedral angle between the six-membered rings is 1.81 (6°]. The 2-tolyl ring is approximately orthogonal to this plane [dihedral angle = 83.03 (7°] as is the acetonitrile group [C—O—C—C torsion angle = 79.24 (14°] which is also syn to the methyl substituent of the tolyl group. In the crystal, supramolecular layers are formed in the bc plane mediated by C—H...O, C—H...N and C—H...π interactions. The tolyl group is disordered over two positions in a 0.852 (3:0.148 (3 ratio.

(Salicylato[tris(1-methyl-1H-benzimidazol-2-ylmethylamine]copper(II perchlorate dimethylformamide disolvate

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Huilu Wu

2008-01-01

Full Text Available In the title complex, [Cu(C7H5O3(C27H27N7]ClO4·2C3H7NO, the CuII ion is five-coordinated by four N atoms from the tris(1-methyl-1H-benzimidazol-2-ylmethylamine ligand and an O atom of the monodentate salicylate ligand. The N4O donor set defines a coordination geometry intermediate between square-pyramidal and trigonal–bipyramidal. The crystal structure is stabilized by O—H...O interactions. The atoms of the aromatic ring of the salicylate ligand are disordered over two sites of equal occupancy. In addition, one of the dimethylformamide solvent molecules is partially disordered over two positions, of approximately equal occupancy.

Chemical exchange-sensitive spin-lock MRI of glucose analog 3-O-methyl-d-glucose in normal and ischemic brain.

Science.gov (United States)

Jin, Tao; Mehrens, Hunter; Wang, Ping; Kim, Seong-Gi

2018-05-01

Glucose transport is important for understanding brain glucose metabolism. We studied glucose transport with a presumably non-toxic and non-metabolizable glucose analog, 3-O-methyl-d-glucose, using a chemical exchange-sensitive spin-lock MRI technique at 9.4 Tesla. 3-O-methyl-d-glucose showed comparable chemical exchange properties with d-glucose and 2-deoxy-d-glucose in phantoms, and higher and lower chemical exchange-sensitive spin-lock sensitivity than Glc and 2-deoxy-d-glucose in in vivo experiments, respectively. The changes of the spin-lattice relaxation rate in the rotating frame (Δ R 1 ρ) in normal rat brain peaked at ∼15 min after the intravenous injection of 1 g/kg 3-O-methyl-d-glucose and almost maintained a plateau for >1 h. Doses up to 4 g/kg 3-O-methyl-d-glucose were linearly correlated with Δ R 1 ρ. In rats with focal ischemic stroke, chemical exchange-sensitive spin-lock with 3-O-methyl-d-glucose injection at 1 h after stroke onset showed reduced Δ R 1 ρ in the ischemic core but higher Δ R 1 ρ in the peri-core region compared to normal tissue, which progressed into the ischemic core at 3 h after stroke onset. This suggests that the hyper-chemical exchange-sensitive spin-lock region observed at 1 h is the ischemic penumbra at-risk of infarct. In summary, 3-O-methyl-d-glucose-chemical exchange-sensitive spin-lock can be a sensitive MRI technique to probe the glucose transport in normal and ischemic brains.

Methionine kinetics in adult men: effects of dietary betaine on L-[2H3-methyl-1-13C]methionine

International Nuclear Information System (INIS)

Storch, K.J.; Wagner, D.A.; Young, V.R.

1991-01-01

The effects of a daily 3-g supplement of betaine on kinetic aspects of L-[2H3-methyl-1-13C]methionine (MET) metabolism in healthy young adult men were explored. Four groups of four subjects each were given a control diet, based on an L-amino acid mixture supplying 29.5 and 21.9 mg.kg-1.d-1 of L-methionine and L-cystine for 4 d before the tracer study, conducted on day 5 during the fed state. Two groups received the control diet and two groups received the betaine supplement. Tracer was given intravenously (iv) or orally. The transmethylation rate of MET (TM), homocysteine remethylation (RM), and oxidation of methionine were estimated from plasma methionine labeling and 13C enrichment of expired air. RM tended to increase (P = 0.14) but the TM and methionine oxidation were significantly (P less than 0.05) higher after betaine supplementation when estimated with the oral tracer. No differences were detected with the intravenous tracer. Methionine concentration in plasma obtained from blood taken from subjects in the fed state was higher (P less than 0.01) with betaine supplementation. These results suggest that excess methyl-group intake may increase the dietary requirement for methionine

Are clinicopathological features of colorectal cancers with methylation in half of CpG island methylator phenotype panel markers different from those of CpG island methylator phenotype-high colorectal cancers?

Science.gov (United States)

Bae, Jeong Mo; Rhee, Ye-Young; Kim, Kyung Ju; Wen, Xianyu; Song, Young Seok; Cho, Nam-Yun; Kim, Jung Ho; Kang, Gyeong Hoon

2016-01-01

CpG island methylator phenotype (CIMP)-high (CIMP-H) colorectal cancer (CRC) is defined when a tumor shows methylation at greater than or equal to 60% of CIMP panel markers. Although CRCs with methylation at 50% of panel markers are classified as CIMP-low/CIMP-0 tumors, little is known regarding the clinicopathological and molecular features of CRCs with methylation at 4/8 panel markers (4/8 methylated markers) and whether they are akin to CIMP-H or CIMP-low/CIMP-0 CRCs in terms of their clinicopathological or molecular features. A total of 1164 cases of surgically resected CRC were analyzed for their methylation status in 8 CIMP panel markers, and the frequencies of various clinicopathological and molecular features were compared between CRCs with 0/8, 1/8 to 3/8, 4/8, and 5/8 to 8/8 methylated markers. CRCs with 4/8 methylated markers were closer to CRCs with 5/8 to 8/8 methylated markers in terms of sex distribution, mucin production, serration, nodal metastasis, CK7 expression, CK20 loss, and CDX2 loss frequencies and overall survival rate. CRCs with methylation at 4/8 markers were closer to CRCs with 1/8 to 3/8 methylated markers in terms of less frequent right colon location and poor differentiation. CRCs with 4/8 methylated markers showed the shortest overall survival time compared with CRCs with 0/8, 1/8 to 3/8, 4/8, or 5/8 to 8/8 methylated markers. In terms of clinicopathological and molecular features, CRCs with 4/8 methylated markers appeared to be closer to CIMP-H than to CIMP-low/CIMP-0 and would thus be better classified as CIMP-H if the CRCs require classification into either CIMP-H or CIMP-low/CIMP-0. Copyright © 2015 Elsevier Inc. All rights reserved.

The COMPASS Family of Histone H3K4 Methylases: Mechanisms of Regulation in Development and Disease Pathogenesis

Science.gov (United States)

Shilatifard, Ali

2014-01-01

The Saccharomyces cerevisiae Set1/COMPASS was the first histone H3 lysine 4 (H3K4) methylase identified over ten years ago. Since then, it has been demonstrated that Set1/COMPASS and its enzymatic product, H3K4 methylation, is highly conserved across the evolutionary tree. Although there is only one COMPASS in yeast, human cells bear at least six COMPASS family members each capable of methylating H3K4 with non-redundant functions. In yeast, the monoubiquitination of histone H2B by Rad6/Bre1 is required for proper H3K4 and H3K79 trimethylations. This histone crosstalk and its machinery are also highly conserved from yeast to human. In this review, the process of histone H2B monoubiquitination-dependent and independent histone H3K4 methylation as a mark of active transcription, enhancer signatures, and developmentally poised genes will be discussed. The misregulation of histone H2B monoubiquitination and H3K4 methylation results in the pathogenesis of human diseases including cancer. Recent findings in this regard will also be examined. PMID:22663077

Generation of Five Human Lactoferrin Transgenic Cloned Goats Using Fibroblast Cells and Their Methylation Status of Putative Differential Methylation Regions of IGF2R and H19 Imprinted Genes

Science.gov (United States)

Sun, Yanyan; Zhang, Yanli; Wang, Ziyu; Song, Yang; Wang, Feng

2013-01-01

Background Somatic cell nuclear transfer (SCNT) is a promising technique to produce transgenic cloned mammalian, including transgenic goats which may produce Human Lactoferrin (hLF). However, success percentage of SCNT is low, because of gestational and neonatal failure of transgenic embryos. According to the studies on cattle and mice, DNA methylation of some imprinted genes, which plays a vital role in the reprogramming of embryo in NT maybe an underlying mechanism. Methodology/Principal Findings Fibroblast cells were derived from the ear of a two-month-old goat. The vector expressing hLF was constructed and transfected into fibroblasts. G418 selection, EGFP expression, PCR, and cell cycle distribution were applied sequentially to select transgenic cells clones. After NT and embryo transfer, five transgenic cloned goats were obtained from 240 cloned transgenic embryos. These transgenic goats were identified by 8 microsatellites genotyping and southern blot. Of the five transgenic goats, 3 were lived after birth, while 2 were dead during gestation. We compared differential methylation regions (DMR) pattern of two paternally imprinted genes (H19 and IGF2R) of the ear tissues from the lived transgenic goats, dead transgenic goats, and control goats from natural reproduction. Hyper-methylation pattern appeared in cloned aborted goats, while methylation status was relatively normal in cloned lived goats compared with normal goats. Conclusions/Significance In this study, we generated five hLF transgenic cloned goats by SCNT. This is the first time the DNA methylation of lived and dead transgenic cloned goats was compared. The results demonstrated that the methylation status of DMRs of H19 and IGF2R were different in lived and dead transgenic goats and therefore this may be potentially used to assess the reprogramming status of transgenic cloned goats. Understanding the pattern of gene imprinting may be useful to improve cloning techniques in future. PMID:24204972

Regional differential effects of the novel histamine H3 receptor antagonist 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on histamine release in the central nervous system of freely moving rats.

Science.gov (United States)

Giannoni, Patrizia; Medhurst, Andrew D; Passani, Maria Beatrice; Giovannini, Maria Grazia; Ballini, Chiara; Corte, Laura Della; Blandina, Patrizio

2010-01-01

After oral administration, the nonimidazole histamine H(3) receptor antagonist, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), increased histamine release from the tuberomammillary nucleus, where all histaminergic somata are localized, and from where their axons project to the entire brain. To further understand functional histaminergic circuitry in the brain, dual-probe microdialysis was used to pharmacologically block H(3) receptors in the tuberomammillary nucleus, and monitor histamine release in projection areas. Perfusion of the tuberomammillary nucleus with GSK189254 increased histamine release from the tuberomammillary nucleus, nucleus basalis magnocellularis, and cortex, but not from the striatum or nucleus accumbens. Cortical acetylcholine (ACh) release was also increased, but striatal dopamine release was not affected. When administered locally, GSK189254 increased histamine release from the nucleus basalis magnocellularis, but not from the striatum. Thus, defined by their sensitivity to GSK189254, histaminergic neurons establish distinct pathways according to their terminal projections, and can differentially modulate neurotransmitter release in a brain region-specific manner. Consistent with its effects on cortical ACh release, systemic administration of GSK189254 antagonized the amnesic effects of scopolamine in the rat object recognition test, a cognition paradigm with important cortical components.

Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer.

Directory of Open Access Journals (Sweden)

Miralem Mrkonjic

Full Text Available We previously identified an association between a mismatch repair gene, MLH1, promoter SNP (rs1800734 and microsatellite unstable (MSI-H colorectal cancers (CRCs in two samples. The current study expanded on this finding as we explored the genetic basis of DNA methylation in this region of chromosome 3. We hypothesized that specific polymorphisms in the MLH1 gene region predispose it to DNA methylation, resulting in the loss of MLH1 gene expression, mismatch-repair function, and consequently to genome-wide microsatellite instability.We first tested our hypothesis in one sample from Ontario (901 cases, 1,097 controls and replicated major findings in two additional samples from Newfoundland and Labrador (479 cases, 336 controls and from Seattle (591 cases, 629 controls. Logistic regression was used to test for association between SNPs in the region of MLH1 and CRC, MSI-H CRC, MLH1 gene expression in CRC, and DNA methylation in CRC. The association between rs1800734 and MSI-H CRCs, previously reported in Ontario and Newfoundland, was replicated in the Seattle sample. Two additional SNPs, in strong linkage disequilibrium with rs1800734, showed strong associations with MLH1 promoter methylation, loss of MLH1 protein, and MSI-H CRC in all three samples. The logistic regression model of MSI-H CRC that included MLH1-promoter-methylation status and MLH1 immunohistochemistry status fit most parsimoniously in all three samples combined. When rs1800734 was added to this model, its effect was not statistically significant (P-value  = 0.72 vs. 2.3×10(-4 when the SNP was examined alone.The observed association of rs1800734 with MSI-H CRC occurs through its effect on the MLH1 promoter methylation, MLH1 IHC deficiency, or both.

Thermal Decomposition of Potential Ester Biofuels. Part I: Methyl Acetate and Methyl Butanoate

Energy Technology Data Exchange (ETDEWEB)

Porterfield, Jessica P.; Bross, David H.; Ruscic, Branko; Thorpe, James H.; Nguyen, Thanh Lam; Baraban, Joshua H.; Stanton, John F.; Daily, John W.; Ellison, G. Barney

2017-06-09

Two methyl esters have been examined as models for the pyrolysis of biofuels. Dilute samples (0.06 - 0.13%) of methyl acetate (CH₃COOCH₃) and methyl butanoate (CH₃CH₂CH₂COOCH₃) were entrained in (He, Ar) carrier gas and decomposed in a set of flash-pyrolysis micro-reactors. The pyrolysis products resulting from the methyl esters were detected and identified by vacuum ultraviolet photoionization mass spectrometry. Complementary product identification was provided by matrix infrared absorption spectroscopy. Pyrolysis pressures in the pulsed micro-reactor were roughly 20 Torr and residence times through the reactors were approximately 25 - 150 µs. Reactor temperatures of 300 – 1600 K were explored. Decomposition of CH₃COOCH₃ commences at 1000 K and the initial products are (CH₂=C=O and CH₃OH). As the micro-reactor is heated to 1300 K, a mixture of (CH₂=C=O and CH₃OH, CH₃, CH₂=O, H, CO, CO₂) appears. The thermal cracking of CH₃CH₂CH₂COOCH₃ begins at 800 K with the formation of (CH₃CH₂CH=C=O, CH₃OH). By 1300 K, the pyrolysis of methyl butanoate yields a complex mixture of (CH₃CH₂CH=C=O, CH₃OH, CH₃, CH₂=O, CO, CO₂, CH₃CH=CH₂, CH₂CHCH₂, CH₂=C=CH₂, HCCCH₂, CH₂=C=C=O, CH₂=CH₂, HCΞCH, CH₂=C=O). Based on the results from the thermal cracking of methyl acetate and methyl butanoate, we predict several important decomposition channels for the pyrolysis of fatty acid methyl esters, R CH₂-COOCH₃. The lowest energy fragmentation will be a 4-center elimination of methanol to form the ketene, RCH=C=O. At higher temperatures, concerted

[PHI regulates histone methylation and acetylation in Burkitt lymphoma Daudi cell line].

Science.gov (United States)

Hong, Ling-Ling; Ma, Xu-Dong; Huang, Yi-Qun

2011-02-01

This study was purposed to investigate the effects of phenylhexyl isothiocyanate (PHI) on Burkitt lymphoma Daudi cell line and regulation of histone acetylation and methylation in Daudi cells, and to explore the potential mechanism. The apoptotic rate of Daudi cells treated with PHI was measured by flow cytometry, the changes of histone H3 and H4 acetylation, histone H3K9 and H3K4 methylation in Daudi cells treated with PHI were detected by Western blot. The results showed that PHI could induce apoptosis of Daudi cells, increased the acetylation level of H3 and H4, enhanced the methylation of H3K4, but reduced the methylation of H3K9. It is concluded that the PHI can up-regulate the acetylation level of histone H3 associated with transcription stimulation and the methylation of histone H3K4, down-regulate the methylation on histone H3K9 associated with transcription inhibition, promotes the apoptosis of Daudi cells. PHI may be a potential agent for target therapy of lymphoma.

Binding of [3H]MSX-2 (3-(3-hydroxypropyl)-7-methyl-8-(m-methoxystyryl)-1-propargylxanthine) to rat striatal membranes--a new, selective antagonist radioligand for A(2A) adenosine receptors.

Science.gov (United States)

Müller, C E; Maurinsh, J; Sauer, R

2000-01-01

The present study describes the preparation and binding properties of a new, potent, and selective A(2A) adenosine receptor (AR) antagonist radioligand, [3H]3-(3-hydroxypropyl)-7-methyl-8-(m-methoxystyryl)-1-propargy lxanth ine ([3H]MSX-2). [3H]MSX-2 binding to rat striatal membranes was saturable and reversible. Saturation experiments showed that [3H]MSX-2 labeled a single class of binding sites with high affinity (K(d)=8.0 nM) and limited capacity (B(max)=1.16 fmol.mg(-1) of protein). The presence of 100 microM GTP, or 10 mM magnesium chloride, respectively, had no effect on [3H]MSX-2 binding. AR agonists competed with the binding of 1 nM [3H]MSX-2 with the following order of potency: 5'-N-ethylcarboxamidoadenosine (NECA)>2-[4-(carboxyethyl)phenylethylamino]-5'-N-ethylcarboxami doaden osine (CGS-21680)>2-chloroadenosine (2-CADO)>N(6)-cyclopentyladenosine (CPA). AR antagonists showed the following order of potency: 8-(m-bromostyryl)-3, 7-dimethyl-1-propargylxanthine (BS-DMPX)>1, 3-dipropyl-8-cyclopentylxanthine (DPCPX)>(R)-5, 6-dimethyl-7-(1-phenylethyl)-2-(4-pyridyl)-7H-pyrrolo[2, 3-d]pyrimidine-4-amine (SH-128)>3,7-dimethyl-1-propargylxanthine (DMPX)>caffeine. The K(i) values for antagonists were in accordance with data from binding studies with the agonist radioligand [3H]CGS21680, while agonist affinities were 3-7-fold lower. [3H]MSX-2 is a highly selective A(2A) AR antagonist radioligand exhibiting a selectivity of at least two orders of magnitude versus all other AR subtypes. The new radioligand shows high specific radioactivity (85 Ci/mmol, 3150 GBq/mmol) and acceptable nonspecific binding at rat striatal membranes of 20-30%, at 1 nM.

Glucostatic regulation of (+)-[3H]amphetamine binding in the hypothalamus: correlation with Na+, K+-ATPase activity

International Nuclear Information System (INIS)

Angel, I.; Hauger, R.L.; Luu, M.D.; Giblin, B.; Skolnick, P.; Paul, S.M.

1985-01-01

Preincubation of rat hypothalamic slices in glucose-free Krebs-Ringer buffer (37 0 C) resulted in a time-dependent decrease in specific (+)-[ 3 H]amphetamine binding in the crude synaptosomal fraction prepared from these slices. The addition of D-glucose resulted in a dose- and time-dependent stimulation of (+)-[ 3 H]amphetamine binding, whereas incubations with L-glucose, 2-deoxy-D-glucose, or 3-O-methyl-D-glucose failed to increase the number of (+)-[ 3 H]amphetamine binding sites. Ouabain potently inhibited the glucose-induced stimulation of (+)-[ 3 H]amphetamine binding, suggesting the involvement of Na + , K + -ATPase. Preincubation of hypothalamic slices with glucose also resulted in an increase in Na + ,K + -ATPase activity and the number of specific high-affinity binding sites for [ 3 H]ouabain, and a good correlation was observed between the glucose-stimulated increase in (+)-[ 3 H]amphetamine and [ 3 H]ouabain binding. These data suggest that the (+)-[ 3 H]amphetamine binding site in hypothalamus, previously linked to the anorectic actions of various phenylethylamines, is regulated both in vitro and in vivo by physiological concentrations of glucose. Glucose and amphetamine appear to interact at common sites in the hypothalamus to stimulate Na + ,K + -ATPase activity, and the latter may be involved in the glucostatic regulation of appetite

Glutamine methylation in histone H2A is an RNA-polymerase-I-dedicated modification

Science.gov (United States)

Tessarz, Peter; Santos-Rosa, Helena; Robson, Sam C.; Sylvestersen, Kathrine B.; Nelson, Christopher J.; Nielsen, Michael L.; Kouzarides, Tony

2014-01-01

Nucleosomes are decorated with numerous post-translational modifications capable of influencing many DNA processes. Here we describe a new class of histone modification, methylation of glutamine, occurring on yeast histone H2A at position 105 (Q105) and human H2A at Q104. We identify Nop1 as the methyltransferase in yeast and demonstrate that fibrillarin is the orthologue enzyme in human cells. Glutamine methylation of H2A is restricted to the nucleolus. Global analysis in yeast, using an H2AQ105me-specific antibody, shows that this modification is exclusively enriched over the 35S ribosomal DNA transcriptional unit. We show that the Q105 residue is part of the binding site for the histone chaperone FACT (facilitator of chromatin transcription) complex. Methylation of Q105 or its substitution to alanine disrupts binding to FACT in vitro. A yeast strain mutated at Q105 shows reduced histone incorporation and increased transcription at the ribosomal DNA locus. These features are phenocopied by mutations in FACT complex components. Together these data identify glutamine methylation of H2A as the first histone epigenetic mark dedicated to a specific RNA polymerase and define its function as a regulator of FACT interaction with nucleosomes.

The multi-domain protein Np95 connects DNA methylation and histone modification

Science.gov (United States)

Rottach, Andrea; Frauer, Carina; Pichler, Garwin; Bonapace, Ian Marc; Spada, Fabio; Leonhardt, Heinrich

2010-01-01

DNA methylation and histone modifications play a central role in the epigenetic regulation of gene expression and cell differentiation. Recently, Np95 (also known as UHRF1 or ICBP90) has been found to interact with Dnmt1 and to bind hemimethylated DNA, indicating together with genetic studies a central role in the maintenance of DNA methylation. Using in vitro binding assays we observed a weak preference of Np95 and its SRA (SET- and Ring-associated) domain for hemimethylated CpG sites. However, the binding kinetics of Np95 in living cells was not affected by the complete loss of genomic methylation. Investigating further links with heterochromatin, we could show that Np95 preferentially binds histone H3 N-terminal tails with trimethylated (H3K9me3) but not acetylated lysine 9 via a tandem Tudor domain. This domain contains three highly conserved aromatic amino acids that form an aromatic cage similar to the one binding H3K9me3 in the chromodomain of HP1ß. Mutations targeting the aromatic cage of the Np95 tandem Tudor domain (Y188A and Y191A) abolished specific H3 histone tail binding. These multiple interactions of the multi-domain protein Np95 with hemimethylated DNA and repressive histone marks as well as with DNA and histone methyltransferases integrate the two major epigenetic silencing pathways. PMID:20026581

(Carbonyl-1κC)bis­[2,3(η5)-cyclo­penta­dien­yl][μ3-(S-methyl trithio­carbonato)methylidyne-1:2:3κ4 C,S′′:C:C](triphenyl­phosphine-1κP)(μ3-sulfido-1:2:3κ3 S)dicobalt(II)iron(II) trifluoro­methane­sulfonate

Science.gov (United States)

Manning, Anthony R.; McAdam, C. John; Palmer, Anthony J.; Simpson, Jim

2008-01-01

The asymmetric unit of the title compound, [FeCo2(C5H5)2(C3H3S3)S(C18H15P)(CO)]CF3SO3, consists of a triangular irondicobalt cluster cation and a trifluoro­methane­sulfonate anion. In the cation, the FeCo2 triangle is symmetrically capped on one face by an S atom and on the other by a C atom linked to a methyl trithio­carbonate residue that bridges the Fe—C bond. Each Co atom carries a cyclo­penta­dienyl ligand while the Fe atom coordinates to one carbonyl and one triphenyl­phosphine ligand. In the crystal structure, the cation is linked to the anion by a number of weak non-classical C—H⋯O and C—H⋯F hydrogen bonds and weak S⋯O (3.317 Å) and S⋯F (3.198 Å) inter­actions. The structure is further stabilized by additional inter­molecular C—H⋯O, C—H⋯F and O⋯O (2.942 Å) contacts, together with an unusual S⋯π(Cp) inter­action (S⋯centroid distance = 3.385 Å), generating an extended network. PMID:21202187

Genome-wide methylation profiling identifies an essential role of reactive oxygen species in pediatric glioblastoma multiforme and validates a methylome specific for H3 histone family 3A with absence of G-CIMP/isocitrate dehydrogenase 1 mutation.

Science.gov (United States)

Jha, Prerana; Pia Patric, Irene Rosita; Shukla, Sudhanshu; Pathak, Pankaj; Pal, Jagriti; Sharma, Vikas; Thinagararanjan, Sivaarumugam; Santosh, Vani; Suri, Vaishali; Sharma, Mehar Chand; Arivazhagan, Arimappamagan; Suri, Ashish; Gupta, Deepak; Somasundaram, Kumaravel; Sarkar, Chitra

2014-12-01

Pediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH)1 mutation with a DNA methylation signature. The present study aims to validate these findings in an independent cohort of pediatric GBM, compare it with adult GBM, and evaluate the involvement of important functionally altered pathways. Genome-wide methylation profiling of 21 pediatric GBM cases was done and compared with adult GBM data (GSE22867). We performed gene mutation analysis of IDH1 and H3 histone family 3A (H3F3A), status evaluation of glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and Gene Ontology analysis. Experimental evaluation of reactive oxygen species (ROS) association was also done. Distinct differences were noted between methylomes of pediatric and adult GBM. Pediatric GBM was characterized by 94 hypermethylated and 1206 hypomethylated cytosine-phosphate-guanine (CpG) islands, with 3 distinct clusters, having a trend to prognostic correlation. Interestingly, none of the pediatric GBM cases showed G-CIMP/IDH1 mutation. Gene Ontology analysis identified ROS association in pediatric GBM, which was experimentally validated. H3F3A mutants (36.4%; all K27M) harbored distinct methylomes and showed enrichment of processes related to neuronal development, differentiation, and cell-fate commitment. Our study confirms that pediatric GBM has a distinct methylome compared with that of adults. Presence of distinct clusters and an H3F3A mutation-specific methylome indicate existence of epigenetic subgroups within pediatric GBM. Absence of IDH1/G-CIMP status further indicates that findings in adult GBM cannot be simply extrapolated to pediatric GBM and that there is a strong need for identification of separate prognostic markers. A possible role of ROS in pediatric GBM pathogenesis is demonstrated for the first time and needs further evaluation. © The Author(s) 2014

Cross-species Analyses Unravel the Complexity of H3K27me3 and H4K20me3 in the Context of Neural Stem Progenitor Cells.

Science.gov (United States)

Rhodes, Christopher T; Sandstrom, Richard S; Huang, Shu-Wei Angela; Wang, Yufeng; Schotta, Gunnar; Berger, Mitchel S; Lin, Chin-Hsing Annie

2016-06-01

Neural stem progenitor cells (NSPCs) in the human subventricular zone (SVZ) potentially contribute to life-long neurogenesis, yet subtypes of glioblastoma multiforme (GBM) contain NSPC signatures that highlight the importance of cell fate regulation. Among numerous regulatory mechanisms, the post-translational methylations onto histone tails are crucial regulator of cell fate. The work presented here focuses on the role of two repressive chromatin marks tri-methylations on histone H3 lysine 27 (H3K27me3) and histone H4 lysine 20 (H4K20me3) in the adult NSPC within the SVZ. To best model healthy human NSPCs as they exist in vivo for epigenetic profiling of H3K27me3 and H4K20me3, we utilized NSPCs isolated from the adult SVZ of baboon brain ( Papio anubis ) with brain structure and genomic level similar to human. The putative role of H3K27me3 in normal NSPCs predominantly falls into the regulation of gene expression, cell cycle, and differentiation, whereas H4K20me3 is involved in DNA replication/repair, metabolism, and cell cycle. Using conditional knock-out mouse models to diminish Ezh2 and Suv4-20h responsible for H3K27me3 and H4K20me3, respectively, we found that both repressive marks have irrefutable function for cell cycle regulation in the NSPC population. While both EZH2/H3K27me3 and Suv4-20h/H4K20me3 have implication in cancers, our comparative genomics approach between healthy NSPCs and human GBM specimens revealed that substantial sets of genes enriched with H3K27me3 and H4K20me3 in the NSPCs are altered in the human GBM. In sum, our integrated analyses across species highlight important roles of H3K27me3 and H4K20me3 in normal and disease conditions in the context of NSPC.

Methylation changes of H19 gene in sperms of X-irradiated mouse and maintenance in offspring

International Nuclear Information System (INIS)

Zhu Bin; Huang Xinghua; Chen Jindong; Lu Yachao; Chen Ying; Zhao Jingyong

2006-01-01

The nature of imprinting is just differential methylation of imprinted genes. Unlike the non-imprinted genes, the methylation pattern of imprinted genes established during the period of gametogenesis remains unchangeable after fertilization and during embryo development. It implies that gametogenesis is the key stage for methylation pattern of imprinted genes. The imprinting interfered by exogenous factors during this stage could be inherited to offspring and cause genetic effect. Now many studies have proved that ionizing irradiation could disturb DNA methylation. Here we choose BALB/c mice as a research model and X-ray as interfering source to further clarify it. We discovered that the whole-body irradiation of X-ray to male BALB/c mice could influence the methylation pattern of H 19 gene in sperms, which resulted in some cytosines of partial CpG islands in the imprinting control region could not transform to methylated cytosines. Furthermore, by copulating the interfered male mice with normal female, we analyzed the promoter methylation pattern of H 19 in offspring fetal liver and compared the same to the pattern of male parent in sperms. We found that the majority of methylation changes in offspring liver were related to the ones in their parent sperms. Our data proved that the changes of the H 19 gene methylation pattern interfered by X-ray irradiation could be transmitted and maintained in First-generation offspring

Bromidotetra?kis?(1H-2-ethyl-5-methyl?imidazole-?N 3)copper(II) bromide

OpenAIRE

Godlewska, Sylwia; Baranowska, Katarzyna; Socha, Joanna; Do??ga, Anna

2011-01-01

The CuII ion in the title compound, [CuBr(C6H10N2)4]Br, is coordinated in a square-based-pyramidal geometry by the N atoms of four imidazole ligands and a bromide anion in the apical site. Both the CuII and Br− atoms lie on a crystallographic fourfold axis. In the crystal, the [CuBr(C6H10N2)4]+ complex cations are linked to the uncoordinated Br− anions (site symmetry overline{4}) by N—H...Br hydrogen bonds, generating a three-dimensional network. The ethyl group ...

Studies of H3K4me3 demethylation by KDM5B/Jarid1B/PLU1 reveals strong substrate recognition in vitro and identifies 2,4-pyridine-dicarboxylic acid as an in vitro and in cell inhibitor

DEFF Research Database (Denmark)

Kristensen, Line Hyltoft; Nielsen, Anders Laerke; Helgstrand, Charlotte

2012-01-01

Dynamic methylations and demethylations of histone lysine residues are important for gene regulation and are facilitated by histone methyltransferases and histone demethylases (HDMs). KDM5B/Jarid1B/PLU1 is an H3K4me3/me2 specific lysine demethylase belonging to the family of JmjC domain containing...... lysine specific HDMs (JHDMs). Several studies have linked KDM5B to breast, prostate and skin cancer, highlighting its potential as a drug target. However, most inhibitor studies have focused on other JHDMs, and inhibitors for KDM5B remain to be explored. Here, we report the expression, purification...... and characterization of the catalytic core of recombinant KDM5B (residues 1-769, ccKDM5B). We show that ccKDM5B, recombinantly expressed in insect cells, demethylates H3K4me3 and H3K4me2 in vitro. The kinetic characterization showed that ccKDM5B has a K(m) (app) value of 0.5 µM for its tri-methylated substrate H3...

(R,S-2′-Amino-6′-methyl-2,5′,5′-trioxo-6′H-spiro[indoline-3,4′-pyrano[3,2-c][2,1]benzothiazine]-3′-carbonitrile dimethylformamide monosolvate

Directory of Open Access Journals (Sweden)

Svitlana V. Shishkina

2014-07-01

Full Text Available The title solvate, C20H14N4O4S·C3H7NO, comprises a stereogenic centre but the centrosymmetric space group causes the presence of the racemate in the crystal. The spiro-joined fragments are almost orthogonal, with a dihedral angle of 86.8 (2° between the mean planes of the pyrane ring and the dihydroindolone ring system. The atoms of the indolinone bicycle are coplanar, with an r.m.s. deviation of 0.005 Å. In the crystal, pairs of N—H...O hydrogen bonds link the molecules into centrosymmetric dimers which are linked to the dimethylformamide solvent molecules by further N—H...O hydrogen bonds. N—H...N hydrogen bonds link neighbouring dimers into [010] chains.

Spectral Analysis of 3-(Adamantan-1-yl)-4-Ethyl-1-[(4-Phenylpiperazin-1-yl) Methyl]-1 H-1,2,4-Triazole-5(4 H)-Thione

Science.gov (United States)

Mindarava, Y. L.; Shundalau, M. B.; Al-Wahaibi, L. H.; El-Emam, A. A.; Matsukovich, A. S.; Gaponenko, S. V.

2018-05-01

Vibrational IR (3200-650 cm-1) and Raman spectra (3200-150 cm-1) of adamantane-containing 3-(adamantan-1-yl)-4-ethyl-1-[(4-phenylpiperazin-1-yl)methyl]-1H-1,2,4-triazole-5(4H)-thione, which is promising for drug design, were examined. The UV/Vis spectrum (450-200 nm) of the compound in EtOH was measured. Full geometry optimization using density functional theory (DFT) in the B3LYP/cc-pVDZ approximation allowed the equilibrium configuration of the molecule to be determined and IR and Raman spectra to be calculated. Based on these, the experimental vibrational IR and Raman spectra were interpreted and the biological activity indices were predicted. The UV/Vis spectrum of the title compound was simulated at the time-dependent DFT/CAM-B3LYP/cc-pVDZ level with and without solvent effects and at the ab initio multi-reference perturbation theory XMCQDPT2 level. The UV/Vis spectrum that was simulated using the multi-reference XMCQDPT2 approximation agreed very successfully with the experimental data, in contrast to the single-reference DFT method. This was probably a consequence of intramolecular charge transfer.

Spectral Analysis of 3-(Adamantan-1-yl)-4-Ethyl-1-[(4-Phenylpiperazin-1-yl) Methyl]-1H-1,2,4-Triazole-5(4H)-Thione

Science.gov (United States)

Mindarava, Y. L.; Shundalau, M. B.; Al-Wahaibi, L. H.; El-Emam, A. A.; Matsukovich, A. S.; Gaponenko, S. V.

2018-05-01

Vibrational IR (3200-650 cm-1) and Raman spectra (3200-150 cm-1) of adamantane-containing 3-(adamantan-1-yl)-4-ethyl-1-[(4-phenylpiperazin-1-yl)methyl]-1H-1,2,4-triazole-5(4H)-thione, which is promising for drug design, were examined. The UV/Vis spectrum (450-200 nm) of the compound in EtOH was measured. Full geometry optimization using density functional theory (DFT) in the B3LYP/cc-pVDZ approximation allowed the equilibrium configuration of the molecule to be determined and IR and Raman spectra to be calculated. Based on these, the experimental vibrational IR and Raman spectra were interpreted and the biological activity indices were predicted. The UV/Vis spectrum of the title compound was simulated at the time-dependent DFT/CAM-B3LYP/cc-pVDZ level with and without solvent effects and at the ab initio multi-reference perturbation theory XMCQDPT2 level. The UV/Vis spectrum that was simulated using the multi-reference XMCQDPT2 approximation agreed very successfully with the experimental data, in contrast to the single-reference DFT method. This was probably a consequence of intramolecular charge transfer.

Genome-wide methylation analysis identifies a core set of hypermethylated genes in CIMP-H colorectal cancer.

Science.gov (United States)

McInnes, Tyler; Zou, Donghui; Rao, Dasari S; Munro, Francesca M; Phillips, Vicky L; McCall, John L; Black, Michael A; Reeve, Anthony E; Guilford, Parry J

2017-03-28

Aberrant DNA methylation profiles are a characteristic of all known cancer types, epitomized by the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). Hypermethylation has been observed at CpG islands throughout the genome, but it is unclear which factors determine whether an individual island becomes methylated in cancer. DNA methylation in CRC was analysed using the Illumina HumanMethylation450K array. Differentially methylated loci were identified using Significance Analysis of Microarrays (SAM) and the Wilcoxon Signed Rank (WSR) test. Unsupervised hierarchical clustering was used to identify methylation subtypes in CRC. In this study we characterized the DNA methylation profiles of 94 CRC tissues and their matched normal counterparts. Consistent with previous studies, unsupervized hierarchical clustering of genome-wide methylation data identified three subtypes within the tumour samples, designated CIMP-H, CIMP-L and CIMP-N, that showed high, low and very low methylation levels, respectively. Differential methylation between normal and tumour samples was analysed at the individual CpG level, and at the gene level. The distribution of hypermethylation in CIMP-N tumours showed high inter-tumour variability and appeared to be highly stochastic in nature, whereas CIMP-H tumours exhibited consistent hypermethylation at a subset of genes, in addition to a highly variable background of hypermethylated genes. EYA4, TFPI2 and TLX1 were hypermethylated in more than 90% of all tumours examined. One-hundred thirty-two genes were hypermethylated in 100% of CIMP-H tumours studied and these were highly enriched for functions relating to skeletal system development (Bonferroni adjusted p value =2.88E-15), segment specification (adjusted p value =9.62E-11), embryonic development (adjusted p value =1.52E-04), mesoderm development (adjusted p value =1.14E-20), and ectoderm development (adjusted p value =7.94E-16). Our genome-wide characterization of DNA

21 CFR 172.872 - Methyl ethyl cellulose.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Methyl ethyl cellulose. 172.872 Section 172.872... CONSUMPTION Multipurpose Additives § 172.872 Methyl ethyl cellulose. The food additive methyl ethyl cellulose... a cellulose ether having the general formula [C6H(10 -x-y)O5(CH3)x(C2H5)y]n, where x is the number...

Antibacterial properties of 3 H-spiro[1-benzofuran-2,1'-cyclohexane] derivatives from Heliotropium filifolium.

Science.gov (United States)

Urzúa, Alejandro; Echeverría, Javier; Rezende, Marcos C; Wilkens, Marcela

2008-10-01

A re-examination of cuticular components of Heliotropium filifolium allowed the isolation of four new compounds: 3'-hydroxy-2',2',6'-trimethyl-3H-spiro[1-benzo-furan-2,1'-cyclohexane]-5-carboxylic acid(2), methyl 3'-acetyloxy-2',2',6'-trimethyl-3H-spiro[1-benzofuran-2,1'-cyclohexane]-5-carboxylate (3), methyl 3'-isopentanoyloxy-2',2',6'-trimethyl-3H-spiro[1-benzofuran-2,1'-cyclohexane]-5-carboxylate (4) and methyl 3'-benzoyloxy-2',2',6'-trimethyl-3H-spiro[1-benzofuran-2,1'-cyclohexane]-5-carboxylate (5).Compounds 2-5 were identified by their spectroscopic analogies with filifolinol (1), and their structures confirmed by chemical correlation with 1. The antimicrobial properties of the compounds were tested against Gram positive and Gram negative bacteria. Some of them proved to be active against Gram positive, but inactive against Gram negative bacteria. In searching for structure-activity relationships from the obtained MIC values, lipophilicity was shown to be an important variable.

Vitamin C induces specific demethylation of H3K9me2 in mouse embryonic stem cells via Kdm3a/b.

Science.gov (United States)

Ebata, Kevin T; Mesh, Kathryn; Liu, Shichong; Bilenky, Misha; Fekete, Alexander; Acker, Michael G; Hirst, Martin; Garcia, Benjamin A; Ramalho-Santos, Miguel

2017-01-01

Histone methylation patterns regulate gene expression and are highly dynamic during development. The erasure of histone methylation is carried out by histone demethylase enzymes. We had previously shown that vitamin C enhances the activity of Tet enzymes in embryonic stem (ES) cells, leading to DNA demethylation and activation of germline genes. We report here that vitamin C induces a remarkably specific demethylation of histone H3 lysine 9 dimethylation (H3K9me2) in naïve ES cells. Vitamin C treatment reduces global levels of H3K9me2, but not other histone methylation marks analyzed, as measured by western blot, immunofluorescence and mass spectrometry. Vitamin C leads to widespread loss of H3K9me2 at large chromosomal domains as well as gene promoters and repeat elements. Vitamin C-induced loss of H3K9me2 occurs rapidly within 24 h and is reversible. Importantly, we found that the histone demethylases Kdm3a and Kdm3b are required for vitamin C-induced demethylation of H3K9me2. Moreover, we show that vitamin C-induced Kdm3a/b-mediated H3K9me2 demethylation and Tet-mediated DNA demethylation are independent processes at specific loci. Lastly, we document Kdm3a/b are partially required for the upregulation of germline genes by vitamin C. These results reveal a specific role for vitamin C in histone demethylation in ES cells and document that DNA methylation and H3K9me2 cooperate to silence germline genes in pluripotent cells.

Synthesis of [[sup 123]I]tert-Butyl 8-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiaze pine 3-carboxylate, a potential SPECT imaging agent for diazepam-intensive (DI) benzodiazepine receptors

Energy Technology Data Exchange (ETDEWEB)

He, Xiaoshu; Matecka, Dorota; Gu, Ziqiang; Rice, K C; Costa, B.R. de [National Inst. of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (United States); Lee, K S [National Inst. of Mental Health, Washington, DC (United States); Wong, Garry; Skolnick, Phil [National Inst. of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (United States). Lab. of Neuroscience

1994-01-01

[[sup 123]I]tert-Butyl 8-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4]benzodiazepine 3-carboxylate ([[sup 123]I]3), a high affinity and selective radioligand for the diazepam insensitive (DI) benzodiazepine receptor was synthesized in 2 steps from tert-butyl 8-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiaz epine 3-carboxylate. (Author).

5-[(3-Fluorophenyl(2-hydroxy-6-oxocyclohex-1-en-1-ylmethyl]-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H-dione

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Assem Barakat

2016-09-01

Full Text Available 5-[(3-Fluorophenyl(2-hydroxy-6-oxocyclohex-1-en-1-yl-methyl]-6-hydroxy-1,3-di-methylpyrimidine-2,4(1H,3H-dione 3 was synthesized via a multicomponent reaction. The Aldol–Michael addition reactions of N,N-dimethylbarbituric acid, cyclohexane-1,3-dione, and 3-fluorobenzaldehyde in aqueous solution gave the product in high yield. The molecular structure of the compound was confirmed by spectroscopic methods and X-ray crystallography. The title compound (C19H19FN2O5·H2O crystallizes in the Monoclinic form, P21/c, a = 7.8630 (5 Å, b = 20.0308 (13 Å, c = 11.3987 (8 Å, β = 104.274 (3°, V = 1739.9 (2° Å3, Z = 4, Rint = 0.117, wR(F2 = 0.124, T = 100 K.

Presolvated Electron Reactions with Methyl Acetoacetate: Electron Localization, Proton-Deuteron Exchange, and H-Atom Abstraction

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Alex Petrovici

2014-09-01

Full Text Available Radiation-produced electrons initiate various reaction processes that are important to radiation damage to biomolecules. In this work, the site of attachment of the prehydrated electrons with methyl acetoacetate (MAA, CH3-CO-CH2-COOCH3 at 77 K and subsequent reactions of the anion radical (CH3-CO•−-CH2-COOCH3 in the 77 to ca. 170 K temperature range have been investigated in homogeneous H2O and D2O aqueous glasses by electron spin resonance (ESR spectroscopy. At 77 K, the prehydrated electron attaches to MAA forming the anion radical in which the electron is delocalized over the two carbonyl groups. This species readily protonates to produce the protonated electron adduct radical CH3-C(•OH-CH2-COOCH3. The ESR spectrum of CH3-C(•OH-CH2-COOCH3 in H2O shows line components due to proton hyperfine couplings of the methyl and methylene groups. Whereas, the ESR spectrum of CH3-C(•OH-CH2-COOCH3 in D2O glass shows only the line components due to proton hyperfine couplings of CH3 group. This is expected since the methylene protons in MAA are readily exchangeable in D2O. On stepwise annealing to higher temperatures (ca. 150 to 170 K, CH3-C(•OH-CH2-COOCH3 undergoes bimolecular H-atom abstraction from MAA to form the more stable radical, CH3-CO-CH•-COOCH3. Theoretical calculations using density functional theory (DFT support the radical assignments.

Presolvated electron reactions with methyl acetoacetate: electron localization, proton-deuteron exchange, and H-atom abstraction.

Science.gov (United States)

Petrovici, Alex; Adhikary, Amitava; Kumar, Anil; Sevilla, Michael D

2014-09-01

Radiation-produced electrons initiate various reaction processes that are important to radiation damage to biomolecules. In this work, the site of attachment of the prehydrated electrons with methyl acetoacetate (MAA, CH3-CO-CH2-COOCH3) at 77 K and subsequent reactions of the anion radical (CH3-CO•--CH2-COOCH3) in the 77 to ca. 170 K temperature range have been investigated in homogeneous H2O and D2O aqueous glasses by electron spin resonance (ESR) spectroscopy. At 77 K, the prehydrated electron attaches to MAA forming the anion radical in which the electron is delocalized over the two carbonyl groups. This species readily protonates to produce the protonated electron adduct radical CH3-C(•)OH-CH2-COOCH3. The ESR spectrum of CH3-C(•)OH-CH2-COOCH3 in H2O shows line components due to proton hyperfine couplings of the methyl and methylene groups. Whereas, the ESR spectrum of CH3-C(•)OH-CH2-COOCH3 in D2O glass shows only the line components due to proton hyperfine couplings of CH3 group. This is expected since the methylene protons in MAA are readily exchangeable in D2O. On stepwise annealing to higher temperatures (ca. 150 to 170 K), CH3-C(•)OH-CH2-COOCH3 undergoes bimolecular H-atom abstraction from MAA to form the more stable radical, CH3-CO-CH•-COOCH3. Theoretical calculations using density functional theory (DFT) support the radical assignments.

tert-Butyl 2-methyl-2-(4-nitrobenzoylpropanoate

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Chelsey M. Crosse

2010-02-01

Full Text Available The title compound, C15H19NO5, is bent with a dihedral angle of 61.8 (2° between the mean planes of the benzene ring and a group encompassing the ester functionality (O=C—O—C. The dihedral angle of 0.8 (2° between the mean planes of the nitro group and the benzene ring indicates near coplanarity. In the crystal, each molecule is linked to four adjacent molecules by weak C—H...O hydrogen-bonding interactions. Both benzene H atoms ortho to the ketone O atom form C—H...O hydrogen bonds with the keto O atoms of two neighboring molecules (of the keto and ester groups, respectively, and the two other interactions involve the H atoms from a methyl group of the dimethyl residue, displaying C—H...O interactions with the O atoms of the nitro groups. These four interactions for each molecule lead to the formation of two-dimensional sheets with a hydrophilic interior, held together by weak hydrogen-bonded interactions, and a hydrophobic exterior composed of protruding methyl groups which interstack with the methyl groups in adjacent sheets.

2-Bromo-2-methyl-N-p-tolylpropanamide

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Rodolfo Moreno-Fuquen

2011-06-01

Full Text Available In the title molecule, C11H14BrNO, there is twist between the mean plane of the amide group and the benzene ring [C(=O—N—C...;C torsion angle = −31.2 (5°]. In the crystal, intermolecular N—H...O and weak C—H...O hydrogen bonds link molecules into chains along [100]. The methyl group H atoms are disordered over two sets of sites with equal occupancy.

Enhancer-associated H3K4 monomethylation by trithorax-related, the drosophila homolog of mammalian MLL3/MLL4

NARCIS (Netherlands)

H.-M. Herz (Hans-Martin); M. Mohan (Man); A.S. Garruss (Alexander); K. Liang (Kaiwei); Y.-H. Takahashi (Yoh-hei); K. Mickey (Kristen); O. Voets (Olaf); C.P. Verrijzer (Peter); A. Shilatifard (Ali)

2012-01-01

textabstractMonomethylation of histone H3 on Lys 4 (H3K4me1) and acetylation of histone H3 on Lys 27 (H3K27ac) are histone modifications that are highly enriched over the body of actively transcribed genes and on enhancers. Although in yeast all H3K4 methylation patterns, including H3K4me1, are

Elimination of 3H-methylguanidine at limited renal function

International Nuclear Information System (INIS)

Berger, D.G.

1976-01-01

The serum levels, hepatic and renal excretions and the tissue concentrations of 3 H methyl guanidine 60 to 90 minutes after intravenous injection were measured in rats with healthy kidneys and rats with experimental renal insufficiences. The following results were obtained: Methyl guanidine is quickly eliminated through the kidney and the liver of organisms with healthy kidneys. In the case of experimental renal insufficiency, the renal excretion of methyl guanidine is reduced, whilst the hepatic excretion is increased. Methyl guanidine is subject to an enterohepatic circuit. Methyl guanidine can accumulate to much higher levels in various tissues examined than in serum. The highest organ accumulation level of methyl guanidine was found in the case of renal insufficiency. The most important finding of the study accordingly is the partial rehabilitation of methyl guanidine as a potential uremic poison. In the author's opinion, too much attention has so far been paid to the serum concentration, and too little attention to the tissue level of the substance. (orig.) [de

Biotransformation and neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its two-electron oxidation product, and 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) species

International Nuclear Information System (INIS)

Wu, E.Y.

1989-01-01

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) specifically destroys the nitrostriatal tract in humans and certain laboratory animals, and produces a Parkinsonian syndrome. The mechanism of cellular toxicity induced by the metabolites, however, has not been elucidated. The in vitro and in vivo metabolic behavior of MPTP and MPDP + and the possible role of factors other than MAO in determining the fate of these species was examined. Neuromelanin, which enhanced the rate of oxidation of MPDP + to MPP + , may also act as a reservoir in the substantia nigra to trap MPP + and prolong its exposure to susceptible brain neurons. Diethyldithiocarbamate (DDC), reported to increase the neurotoxic effect of MPTP in mice potentiated the formation of MPDP + from the MAO B catalyzed biotransformation of MPTP and significantly lowered brain dopamine levels in animals pretreated with DDC before MPTP administration. The ability of the dihydropyridinium species to gain access to susceptible neurons via the dopamine uptake system was assessed using the stable, 3,4-dihydro-2-methyl-9-H-indeno [2,1-c]pryidinium (DMIP + ) species. DMIP + , however, proved to be a poor inhibitor of both [ 3 H]dopamine and [ 3 H]MPP + uptake

Systems Level Analysis of Histone H3 Post-translational Modifications (PTMs) Reveals Features of PTM Crosstalk in Chromatin Regulation

DEFF Research Database (Denmark)

Schwämmle, Veit; Sidoli, Simone; Ruminowicz, Chrystian

2016-01-01

molecules contain multiple coexisting PTMs, some of which exhibit crosstalk, i.e. coordinated or mutually exclusive activities. Here, we present an integrated experimental and computational systems level molecular characterization of histone PTMs and PTM crosstalk. Using wild type and engineered mouse....... We characterized combinatorial PTM features across the four mESC lines and then applied statistical data analysis to predict crosstalk between histone H3 PTMs. We detected an overrepresentation of positive crosstalk (codependent marks) between adjacent mono-methylated and acetylated marks......, and negative crosstalk (mutually exclusive marks) among most of the seven characterized di- and tri-methylated lysine residues in the H3 tails. We report novel features of PTM interplay involving hitherto poorly characterized arginine methylation and lysine methylation sites, including H3R2me, H3R8me and H3K37...

Synergistic complexes of uranyl ion with 1-phenyl-3-methyl-4-acetyl-pyrazolone-5 and some oxo-donors

International Nuclear Information System (INIS)

Nagar, M.S.; Ruikar, P.B.; Subramanian, M.S.

1987-01-01

Complexes of uranyl ion with 1-phenyl-3-methyl-4-acetyl-pyrazolone-5(PMAP) and various oxo-donors such as aliphatic sulphoxides [R 2 SO, where R = i-C 5 H 11 (DISO), n-C 6 H 13 (DHSO), n-C 7 H 15 (DSSO), n-C 8 H 17 (DOSO), n-C 9 H 19 (DNSO), n-C 10 H 21 (DDSO), n-C 11 H 23 (DUDSO) and n-C 4 H 9 (DBUSO)] tributylphosphate (TBP) and tri-n-octyl phosphine oxide (TOPO) have been synthesised and characterized. Analytical data establish that they have the stoichiometry UO 2 (PMAP) 2 X where X is the oxo-donor. The IR spectra of the sulphoxide complexes in the S - O stretching region indicate that the ligands R 2 SO are O-bonded. The methyl protons of the pyrazole ring and acetyl group in the PMAP ligand are equivalent giving rise to a single sharp peak in the PMR spectra, whereas in the synergistic complexes with the oxo-donors, two deshielded peaks of equal intensity are observed which indicate the non-equivalence of the methyl groups. The peak which is more deshielded has been ascribed to the methyl of the acetyl group. The higher deshielding of these methyl protons arises due to the transfer of electron density to the metal atom on complexation. (author)

S-Alkylated/aralkylated 2-(1H-indol-3-yl-methyl)-1,3,4- oxadiazole-5 ...

African Journals Online (AJOL)

ylmethyl)-1,3,4- oxadiazole-5-thiol derivatives. Methods: 2-(1H-indol-3-yl)acetic acid (1) was reacted with absolute ethanol and catalytic amount of sulfuric acid to form ethyl 2-(1H-indol-3-yl)acetate (2) which was transformed to 2-(1H-indol-3- ...

2-{4-Methyl-N-[(2,3,4,9-tetrahydro-1H-carbazol-3-ylmethyl]benzenesulfonamido}ethyl 4-methylbenzenesulfonate

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Nagihan Çaylak Delibaş

2013-12-01

Full Text Available In the title compound, C29H32N2O5S2, the indole ring system is nearly planar, with a maximum deviation of 0.013 (2 Å, and the cyclohexenone ring has an envelope conformation with the methine C atom as the flap. The two methylbenzene rings are approximately perpendicular to each other, making a dihedral angle of 89.09 (8°. In the crystal, N—H...O hydrogen bonds link the molecules into a chain running along the a-axis direction, and weak C—H...O hydrogen bonds and C—H...π interactions are observed between the chains.

A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading

Energy Technology Data Exchange (ETDEWEB)

Shan, Chun-Min; Wang, Jiyong; Xu, Ke; Chen, Huijie; Yue, Jia-Xing; Andrews, Stuart; Moresco, James J.; Yates, John R.; Nagy, Peter L.; Tong, Liang; Jia, Songtao

2016-09-20

Histone lysine-to-methionine (K-to-M) mutations are associated with multiple cancers, and they function in a dominant fashion to block the methylation of corresponding lysines on wild type histones. However, their mechanisms of function are controversial. Here we show that in fission yeast, introducing the K9M mutation into one of the three histone H3 genes dominantly blocks H3K9 methylation on wild type H3 across the genome. In addition, H3K9M enhances the interaction of histone H3 tail with the H3K9 methyltransferase Clr4 in a SAM (S-adenosyl-methionine)-dependent manner, and Clr4 is trapped at nucleation sites to prevent its spreading and the formation of large heterochromatin domains. We further determined the crystal structure of an H3K9M peptide in complex with human H3K9 methyltransferase G9a and SAM, which reveales that the methionine side chain had enhanced van der Waals interactions with G9a. Therefore, our results provide a detailed mechanism by which H3K9M regulates H3K9 methylation.

Potential neuroleptic agents. 4. Chemistry, behavioral pharmacology, and inhibition of [3H]spiperone binding of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides.

Science.gov (United States)

de Paulis, T; Kumar, Y; Johansson, L; Rämsby, S; Hall, H; Sällemark, M; Angeby-Möller, K; Ogren, S O

1986-01-01

A series of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamides was synthesized, starting from the 2,6-dimethoxybenzoic acids, by boron tribromide demethylation of the corresponding 3,5-disubstituted 2,6-dimethoxybenzamides and separation of the two positional isomers. The correct structure assignments were based on selective decoupling studies on their 13C NMR spectra. The salicylamide derivatives were tested for antidopamine activity in vivo by their ability to inhibit the apomorphine syndrome in the rat and in vitro by their ability to displace [3H]spiperone from striatal preparations of the rat brain. The activity seems to reside exclusively in the S enantiomer. Several compounds were considerably more potent than haloperidol, particularly those having an ethyl group in the 3-position and a halogen atom in the 5-position of the aromatic ring. The corresponding 5-alkyl-3-halogen-substituted compounds were much less active. A low acute toxicity was found for the most potent compounds. Some of the salicylamides displayed a 10-20-fold separation between the dose which blocks apomorphine-induced hyperactivity and that which blocks apomorphine-induced stereotypy. One compound, S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamide (raclopride, FLA 870) (13) had a stereotypy--hyperactivity separation more than twice that of sulpiride while being 100 times more potent in blocking the apomorphine effects. On this basis, 13 was selected for clinical trials against schizophrenia.

Methyl 4′,5-dichloro-2-hydroxy-4,6-dimethylbiphenyl-3-carboxylate

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Muhammad Adeel

2012-04-01

Full Text Available In the title compound, C16H14Cl2O3, the dihedral angle between the mean planes of the two benzene rings is 55.30 (5°. The methyl ester group lies within the ring plane due to an intramolecular O—H...O hydrogen bond [maximum deviation from the C8O2 mean plane is 0.0383 (13 Å]. In the crystal, molecules are held together by rather weak C—H...O hydrogen bonds.

Synthesis, Spatial Structure and Analgesic Activity of Sodium 3-Benzylaminocarbonyl-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazin-4-olate Solvates

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Igor V. Ukrainets

2016-10-01

Full Text Available In order to obtain and then test pharmocologically any possible conformers of the new feasible analgesic N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, its 4-O-sodium salt was synthesized using two methods. X-ray diffraction study made possible to determine that, depending on the chosen synthesis conditions, the above-mentioned compound forms either monosolvate with methanol or monohydrate, where organic anion exists in the form of three different conformers. Pharmacological testing of the two known pseudo-enantiomeric forms of the original N-benzylamide and of the two solvates of its sodium salt was performed simultaneously under the same conditions and in equimolar doses. Comparison of the results obtained while studying the peculiarities of the synthesized compounds spatial structure and biological properties revealed an important structure-action relationship. In particular, it was shown that the intensity of analgesic effect of different conformational isomers of N-benzyl-4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide may change considerably: while low active conformers are comparable with piroxicam, highly active conformers are more than twice as effective as meloxicam.

Hexaaquabis[3,5-bis(hydroxyimino-1-methyl-2,4,6-trioxocyclohexanido-κ2N3,O4]barium tetrahydrate

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Nguyen Dinh Do

2013-11-01

Full Text Available In the title compound, [Ba(C7H5N2O52(H2O6]·4H2O, the Ba2+ cation lies on a twofold rotation axis and is ten-coordinated by two 3,5-bis(hydroxyimino-1-methyl-2,4,6-trioxocyclohexanide oxo O atoms [Ba—O = 2.8715 (17 Å], two hydroxyimino N atoms [Ba—N = 3.036 (2 Å], and six water molecules [Ba—O = 2.847 (2, 2.848 (2, and 2.880 (2 Å]. The 3,5-bis(hydroxyimino-1-methyl-2,4,6-trioxocyclohexanide monoanions act in a bidentate chelating manner, coordinating through an N atom of the non-deprotonated hydroxyimino group and an O atom of the neighboring oxo group. Two lattice water molecules are located in the cavities of the framework and are involved in hydrogen bonding to O atoms of one of the coordinating water molecules and the O atom of a keto group of the ligand. As a result, a three-dimensional network is formed.

H3K27me3 and H3K4me3 chromatin environment at super-induced dehydration stress memory genes of Arabidopsis thaliana.

Science.gov (United States)

Liu, Ning; Fromm, Michael; Avramova, Zoya

2014-03-01

Pre-exposure to a stress may alter the plant's cellular, biochemical, and/or transcriptional responses during future encounters as a 'memory' from the previous stress. Genes increasing transcription in response to a first dehydration stress, but producing much higher transcript levels in a subsequent stress, represent the super-induced 'transcription memory' genes in Arabidopsis thaliana. The chromatin environment (histone H3 tri-methylations of Lys 4 and Lys 27, H3K4me3, and H3K27me3) studied at five dehydration stress memory genes revealed existence of distinct memory-response subclasses that responded differently to CLF deficiency and displayed different transcriptional activities during the watered recovery periods. Among the most important findings is the novel aspect of the H3K27me3 function observed at specific dehydration stress memory genes. In contrast to its well-known role as a chromatin repressive mechanism at developmentally regulated genes, H3K27me3 did not prevent transcription from the dehydration stress-responding genes. The high H3K27me3 levels present during transcriptionally inactive states did not interfere with the transition to active transcription and with H3K4me3 accumulation. H3K4me3 and H3K27me3 marks function independently and are not mutually exclusive at the dehydration stress-responding memory genes.

5-Ethyl-3-(2-fluorophenylsulfonyl-2-methyl-1-benzofuran

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Hong Dae Choi

2012-10-01

Full Text Available In the title compound, C17H15FO3S, the 2-fluorophenyl ring makes a dihedral angle of 89.12 (8° with the mean plane of the benzofuran fragment. In the crystal, molecules are linked by weak C—H...O and C—H...π interactions.

2-Acetyl­amino-1,3,4,6-tetra-O-(tri­methyl­silyl)-2-de­oxy-α-d-gluco­pyran­ose

Science.gov (United States)

Cheng, Zhao-Dong; Cui, Yan-Li; Mao, Jian-Wei

2013-01-01

The title compound, C20H47NO6Si4, was synthesized by per-O-tri­methyl­silylation of N-acetyl-d-glucosa­mine using chloro­tri­methyl­silane in the presence of hexa­methyl­disiloxane. The tri­methyl­silyl group and acetamido group are located on the same side of the pyran ring, showing an α-configuration glycoside. One of the tri­methyl­silyl groups is disordered over two orientations, with site-occupancy factors of 0.625 (9) and 0.375 (9). In the crystal, N—H⋯O hydrogen bonds link the mol­ecules into supra­molecular chains along the a-axis direction. PMID:23795087

Crystal structure of 4-(4b,8a-dihydro-9H-pyrido[3,4-b]indol-1-yl-7-methyl-2H-chromen-2-one

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S. Samundeeswari

2017-01-01

Full Text Available The title compound, C21H14N2O2, was prepared by Pictet–Spengler cyclization of tryptamine and 4-formyl coumarin. In the molecule, the dihedral angle between the mean planes of the coumarin and β-carboline ring systems is 63.8 (2°. In the crystal, molecules are linked via N—H...N hydrogen bonds, forming chains along the b-axis direction. Within the chains, there are a number of offset π–π interactions present [shortest intercentroid distance = 3.457 (2 Å].

Crystal structure of (±-1-({[4-(allyloxyphenyl]sulfanyl}methyl-2-(diphenylthiophosphorylferrocene

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Audric Michelot

2015-08-01

Full Text Available The title compound, [Fe(C5H5(C27H24OPS2], is built up from a ferrocene moiety substituted in the 1- and 2-positions by {[4-(allyloxyphenyl]sulfanyl}methyl and diphenylthiophosphoryl groups, respectively. The two S atoms lie on opposite sides of the cyclopentadienyl ring plane to which they are attached. In the crystal, C—H...S hydrogen bonds link the molecules into a ribbon running parallel to the (-110 plane. C—H...π interactions link the ribbons to form a three-dimensional network.

Optically active antifungal azoles. XII. Synthesis and antifungal activity of the water-soluble prodrugs of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone.

Science.gov (United States)

Ichikawa, T; Kitazaki, T; Matsushita, Y; Yamada, M; Hayashi, R; Yamaguchi, M; Kiyota, Y; Okonogi, K; Itoh, K

2001-09-01

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.

Methylation of DNA Ligase 1 by G9a/GLP Recruits UHRF1 to Replicating DNA and Regulates DNA Methylation.

Science.gov (United States)

Ferry, Laure; Fournier, Alexandra; Tsusaka, Takeshi; Adelmant, Guillaume; Shimazu, Tadahiro; Matano, Shohei; Kirsh, Olivier; Amouroux, Rachel; Dohmae, Naoshi; Suzuki, Takehiro; Filion, Guillaume J; Deng, Wen; de Dieuleveult, Maud; Fritsch, Lauriane; Kudithipudi, Srikanth; Jeltsch, Albert; Leonhardt, Heinrich; Hajkova, Petra; Marto, Jarrod A; Arita, Kyohei; Shinkai, Yoichi; Defossez, Pierre-Antoine

2017-08-17

DNA methylation is an essential epigenetic mark in mammals that has to be re-established after each round of DNA replication. The protein UHRF1 is essential for this process; it has been proposed that the protein targets newly replicated DNA by cooperatively binding hemi-methylated DNA and H3K9me2/3, but this model leaves a number of questions unanswered. Here, we present evidence for a direct recruitment of UHRF1 by the replication machinery via DNA ligase 1 (LIG1). A histone H3K9-like mimic within LIG1 is methylated by G9a and GLP and, compared with H3K9me2/3, more avidly binds UHRF1. Interaction with methylated LIG1 promotes the recruitment of UHRF1 to DNA replication sites and is required for DNA methylation maintenance. These results further elucidate the function of UHRF1, identify a non-histone target of G9a and GLP, and provide an example of a histone mimic that coordinates DNA replication and DNA methylation maintenance. Copyright © 2017 Elsevier Inc. All rights reserved.

Methylation-sensitive linking libraries enhance gene-enriched sequencing of complex genomes and map DNA methylation domains

Directory of Open Access Journals (Sweden)

Bharti Arvind K

2008-12-01

Full Text Available Abstract Background Many plant genomes are resistant to whole-genome assembly due to an abundance of repetitive sequence, leading to the development of gene-rich sequencing techniques. Two such techniques are hypomethylated partial restriction (HMPR and methylation spanning linker libraries (MSLL. These libraries differ from other gene-rich datasets in having larger insert sizes, and the MSLL clones are designed to provide reads localized to "epigenetic boundaries" where methylation begins or ends. Results A large-scale study in maize generated 40,299 HMPR sequences and 80,723 MSLL sequences, including MSLL clones exceeding 100 kb. The paired end reads of MSLL and HMPR clones were shown to be effective in linking existing gene-rich sequences into scaffolds. In addition, it was shown that the MSLL clones can be used for anchoring these scaffolds to a BAC-based physical map. The MSLL end reads effectively identified epigenetic boundaries, as indicated by their preferential alignment to regions upstream and downstream from annotated genes. The ability to precisely map long stretches of fully methylated DNA sequence is a unique outcome of MSLL analysis, and was also shown to provide evidence for errors in gene identification. MSLL clones were observed to be significantly more repeat-rich in their interiors than in their end reads, confirming the correlation between methylation and retroelement content. Both MSLL and HMPR reads were found to be substantially gene-enriched, with the SalI MSLL libraries being the most highly enriched (31% align to an EST contig, while the HMPR clones exhibited exceptional depletion of repetitive DNA (to ~11%. These two techniques were compared with other gene-enrichment methods, and shown to be complementary. Conclusion MSLL technology provides an unparalleled approach for mapping the epigenetic status of repetitive blocks and for identifying sequences mis-identified as genes. Although the types and natures of

Synthesis of a Nanostructured Composite: Octakis(1-propyl-1H-1,2,3-triazole-4-yl(methyl 2-chlorobenzoate))octasilsesquioxane via Click Reaction.

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Ghodsi, Mohammadi Ziarani; Shakiba Nahad, Monireh; Lashgari, Negar; Alireza, Badiei

2015-01-01

Octakis(1-propyl-1H-1,2,3-triazole-4-yl(methyl 2-chlorobenzoate))octasilsesquioxanes as functionalized silsesquioxanes were synthesized via click reaction (copper-catalyzed Huisgen 1,3-dipolar cycloaddition reaction) between azidemoiety functionalized silsesquioxane and prop-2-ynyl 2-chlorobenzoate. The latter one was synthesized via the condensation reaction of propargyl alcohol and 2-chlorobenzoyl chloride in the presence of SBA-Pr-NH(2) (Santa Barbara Amorphous type material) as a nano basic catalyst. This approach provides a simple and convenient route to efficiently functionalize a wide range of new structures on the surface of silsesquioxanes.

Methyl CpG–binding proteins induce large-scale chromatin reorganization during terminal differentiation

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Brero, Alessandro; Easwaran, Hariharan P.; Nowak, Danny; Grunewald, Ingrid; Cremer, Thomas; Leonhardt, Heinrich; Cardoso, M. Cristina

2005-01-01

Pericentric heterochromatin plays an important role in epigenetic gene regulation. We show that pericentric heterochromatin aggregates during myogenic differentiation. This clustering leads to the formation of large chromocenters and correlates with increased levels of the methyl CpG–binding protein MeCP2 and pericentric DNA methylation. Ectopic expression of fluorescently tagged MeCP2 mimicked this effect, causing a dose-dependent clustering of chromocenters in the absence of differentiation. MeCP2-induced rearrangement of heterochromatin occurred throughout interphase, did not depend on the H3K9 histone methylation pathway, and required the methyl CpG–binding domain (MBD) only. Similar to MeCP2, another methyl CpG–binding protein, MBD2, also increased during myogenic differentiation and could induce clustering of pericentric regions, arguing for functional redundancy. This MeCP2- and MBD2-mediated chromatin reorganization may thus represent a molecular link between nuclear genome topology and the epigenetic maintenance of cellular differentiation. PMID:15939760

2′-Methyl-2′-nitro-1′-phenyl-2′,3′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-1′H-pyrrolizin]-2-one

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Yaghoub Sarrafi

2008-08-01

Full Text Available The title compound, C21H21N3O3, was synthesized by a multi-component 1,3-dipolar cycloaddition of azomethine ylide, derived from isatin and proline by a decarboxylative route, and (E-1-phenyl-2-nitropropene. In the molecule, the spiro junction links a planar oxindole ring and a pyrrolidine ring in an envelope conformation. The molecular packing is stabilized by an intermolecular N—H...N interaction of the oxindole and pyrrolizidine rings.

Synthesis of [3H]WIN 35,065-2; a new radioligand for cocaine receptors

International Nuclear Information System (INIS)

Naseree, T.M.; Abraham, P.; Kepler, J.A.; Carroll, F.I.; Lewin, A.H.; Kuhar, M.J.

1990-01-01

Treatment of methyl (-)-3β-phenylnortropane-2β-carboxylate with [ 3 H]CH 3 I afforded [ 3 H]WIN 35,065-2 with specific activity of 25 Ci/mmol, a new ligand for the cocaine recognition site. (author)

Female human pluripotent stem cells rapidly lose X chromosome inactivation marks and progress to a skewed methylation pattern during culture.

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Geens, M; Seriola, A; Barbé, L; Santalo, J; Veiga, A; Dée, K; Van Haute, L; Sermon, K; Spits, C

2016-04-01

Does a preferential X chromosome inactivation (XCI) pattern exist in female human pluripotent stem cells (hPSCs) and does the pattern change during long-term culture or upon differentiation? We identified two independent phenomena that lead to aberrant XCI patterns in female hPSC: a rapid loss of histone H3 lysine 27 trimethylation (H3K27me3) and long non-coding X-inactive specific transcript (XIST) expression during culture, often accompanied by erosion of XCI-specific methylation, and a frequent loss of random XCI in the cultures. Variable XCI patterns have been reported in female hPSC, not only between different hPSC lines, but also between sub-passages of the same cell line, however the reasons for this variability remain unknown. Moreover, while non-random XCI-linked DNA methylation patterns have been previously reported, their origin and extent have not been investigated. We investigated the XCI patterns in 23 human pluripotent stem cell (hPSC) lines, during long-term culture and after differentiation, by gene expression analysis, histone modification assessment and study of DNA methylation. The presence and location of H3K27me3 was studied by immunofluorescence, XIST expression by real-time PCR, and mono- or bi-allelic expression of X-linked genes was studied by sequencing of cDNA. XCI-specific DNA methylation was analysed using methylation-sensitive restriction and PCR, and more in depth by massive parallel bisulphite sequencing. All hPSC lines showed XCI, but we found a rapid loss of XCI marks during the early stages of in vitro culture. While this loss of XCI marks was accompanied in several cases by an extensive erosion of XCI-specific methylation, it did not result in X chromosome reactivation. Moreover, lines without strong erosion of methylation frequently displayed non-random DNA methylation, which occurred independently from the loss of XCI marks. This bias in X chromosome DNA methylation did not appear as a passenger event driven by clonal culture

N-(3-{[(Z-(3-Hydroxy-4-methylphenylimino]methyl}pyridin-2-ylpivalamide

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Şehriman Atalay

2016-03-01

Full Text Available The molecular structure of the title compound, C18H21N3O2, contains pivalamide, pyridin and hydroxy-methylphenyl moieties. The whole molecule is not planar, the dihedral angle between the benzene rings being 34.84 (7°. The molecular conformation is stabilized by an intramolecular N—H...N hydrogen bond. In the crystal, molecules are linked by O—H...O, O—H...N and C—H...O hydrogen bonds. The C and H atoms of the tert-butyl group disordered over two sets of sites with an occupancy ratio of 0.692 (5:0.308 (5.

Vibrational spectroscopic (FT-IR, FT-Raman) and quantum mechanical study of 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4] diazepine

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Kuruvilla, Tintu K.; Prasana, Johanan Christian; Muthu, S.; George, Jacob

2018-04-01

The spectroscopic properties of 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine were investigated in the present study using FT-IR and FT-Raman techniques. The results obtained were compared with quantum mechanical methods, as it serves as an important tool in interpreting and predicting vibrational spectra. The optimized molecular geometry, the vibrational wavenumbers, the infrared intensities and Raman scattering were calculated using density functional theory B3LYP method with 6-311++g (d,p) basis set. All the experimental results were in line with the theoretical data. The molecular electrostatic potential (MEP) and HOMO LUMO energies of the title compound were accounted. The results indicated that the title compound has a lower softness value (0.27) and high electrophilicity index (4.98) hence describing its biological activity. Further, natural bond orbital was also analyzed as part of the work. Fukui functions were calculated in order to explain the chemical selectivity or the reactivity site in 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine. The thermodynamic properties of the title compound were closely examined at different temperatures. It revealed the correlations between heat capacity (C), entropy (S) and enthalpy changes (H) with temperatures. The paper further explains that the title compound can act as good antidepressant through molecular docking studies.

catena-Poly[[[trans-diaquabis(pyridine-κNcobalt(II]-μ-(4-{N′-[1-(3-acetyl-4-methyl-1H-pyrazol-5-ylethylidene]hydrazino}benzoato-κ3O:N,N′-[bis(pyridine-κNcobalt(III]-μ-(4-{N′-[1-(3-acetyl-4-methyl-1H-pyrazol-5-ylethylidene]hydrazino}benzoato-κ3N,N′:O]perchlorate 3.66-hydrate

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Igor O. Fritsky

2008-02-01

Full Text Available The title compound, {[Co2(C15H14N4O32(C5H5N4(H2O2]ClO4·3.66H2O}n, is a one-dimensional coordination polymer, with both CoII and CoIII centres in its structure. The ligand environment surrounding CoIII is formed by two N,N-chelating pyrazole-containing ligands and two pyridine molecules in axial positions. The high-spin CoII ions, situated at crystallographic centres of inversion, exhibit a distorted octahedral coordination mode. The ClO4− anion is linked to the polymer chain via hydrogen bonds. The chains are connected by hydrogen bonds to produce a three-dimensional structure.

Methylation of ribonucleic acid by the carcinogens dimethyl sulphate, N-methyl-N-nitrosourea and N-methyl-N′-nitro-N-nitrosoguanidine. Comparisons of chemical analyses at the nucleoside and base levels

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Lawley, P. D.; Shah, S. A.

1972-01-01

1. The following methods for hydrolysis of methyl-14C-labelled RNA, and for chromatographic isolation and determination of the products, were investigated: enzymic digestion to nucleosides at pH6 or 8; alkaline hydrolysis and conversion into nucleosides; hydrolysis by acid to pyrimidine nucleotides and purine bases, or completely to bases; chromatography on Dowex 50 (NH4+ form) at pH6 or 8.9, or on Dowex 50 (H+ form), or on Sephadex G-10. 2. The suitability of the various methods for determination of methylation products was assessed. The principal product, 7-methylguanosine, was unstable under the conditions used for determinations of nucleosides. 3- and 7-Methyladenine and 3- and 7-methylguanine are best determined as bases; 1-methyladenine and 3-methylcytosine can be isolated as either nucleosides or bases; O6-methylguanine is unstable under the acid hydrolysis conditions used and can be determined as the nucleoside; 3-methyluracil was detected, but may be derived from methylation of the ionized form of uracil. 3. Differences between the patterns of methylation of RNA and homopolyribonucleotides by the N-methyl-N-nitroso compounds and dimethyl sulphate were found: the nitroso compounds were able to methylate O-6 of guanine, were relatively more reactive at N-7 of adenine and probably at N-3 of guanine, but less reactive at N-1 of adenine, N-3 of cytosine and probably at N-3 of uridine. They probably reacted more with the ribose–phosphate chain, but no products from this were identified. 4. The possible influences of these differences on biological action of the methylating agents is discussed. Nitroso compounds may differ principally in their ability to induce miscoding in the Watson–Crick sense by reaction at O-6 of guanine. Both types of agent may induce miscoding to a lesser extent through methylation at N-3 of guanine; both can methylate N atoms, presumably preventing Watson–Crick hydrogen-bonding. N-Methyl-N-nitrosourea can degrade RNA, possibly

3-Ethylsulfinyl-2-(4-iodophenyl-5-methyl-1-benzofuran

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Hong Dae Choi

2010-08-01

Full Text Available In the title compound, C17H15IO2S, the 4-iodophenyl ring makes a dihedral angle of 35.39 (8° with the plane of the benzofuran fragment. In the crystal, molecules are linked by intermolecular C—H...O and C—H...π interactions, and an I...O contact [3.378 (2 Å]. The crystal structure also exhibits aromatic π–π interactions between the benzene rings of neighbouring molecules [centroid–centroid distance = 3.495 (3 Å].

IGFBP3 Promoter Methylation in Colorectal Cancer: Relationship with Microsatellite Instability, CpG Island Methylator Phenotype, p53

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Takako Kawasaki

2007-12-01

Full Text Available Insulin-like growth factor binding protein 3 (IGFBP3, which is induced by wild-type p53, regulates IGF and interacts with the TGF-β pathway. IGFBP3 promoter methylation may occur in colorectal cancer with or without the CpG island methylator phenotype (CIMP, which is associated with microsatellite instability (MSI and TGFBR2 mutation. We examined the relationship between IGFBP3 methylation, p53 expression, CIMP and MSI in 902 population-based colorectal cancers. Utilizing real-time PCR (MethyLight, we quantified promoter methylation in IGFBP3 and eight other CIMP-high-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1. IGFBP3 methylation was far more frequent in non-MSI-high CIMP-high tumors (85% = 35/41 than in MSI-high CIMPhigh (49% = 44/90, P < .0001, MSI-high non-CIMP-high (17% = 6/36, P < .0001, non-MSI-high non-CIMP-high tumors (22% = 152/680, P < .0001. Among CIMPhigh tumors, the inverse relationship between MSI and IGFBP3 methylation persisted in p53-negative tumors (P < .0001, but not in p53-positive tumors. IGFBP3 methylation was associated inversely with TGFBR2 mutation in MSI-high non-CIMP-high tumors (P = .02. In conclusion, IGFBP3 methylation is inversely associated with MSI in CIMP-high colorectal cancers, this relationship is limited to p53-negative tumors. Our data suggest complex relationship between global genomic/epigenomic phenomena (such as MSI/ CIMP, single molecular events (e.g., IGFBP3 methylation, TP53 mutation, TGFBR2 mutation, the related pathways.

5-Bromo-3-(4-chlorophenylsulfinyl-2-methyl-1-benzofuran

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Hong Dae Choi

2010-11-01

Full Text Available In the title compound, C15H10BrClO2S, the 4-chlorophenyl ring is oriented approximately perpendicular to the mean plane of the benzofuran ring [dihedral angle = 89.55 (9°]. In the crystal, molecules are linked through weak intermolecular C—H...O hydrogen bonds and and a Br...Br contact [3.783 (3 Å].

(Dimethylformamide-κO(2-hydroxybenzoato-κ2O1,O1′[tris(1-methyl-1H-benzimidazol-2-ylmethyl-κN3amine-κN]manganese(II perchlorate dimethylformamide monosolvate

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Baoliang Qi