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Sample records for 5-methyl uracil

  1. [Uracil-DNA glycosylases].

    Science.gov (United States)

    Pytel, Dariusz; Słupianek, Artur; Ksiazek, Dominika; Skórski, Tomasz; Błasiak, Janusz

    2008-01-01

    Uracil is one of four nitrogen bases, most frequently found in normal RNA. Uracyl can be found also in DNA as a result of enzymatic or non-enzymatic deamination of cytosine as well as misincorporation of dUMP instead of dTMP during DNA replication. Uracil from DNA can be removed by DNA repair enzymes with apirymidine site as an intermediate. However, if uracil is not removed from DNA a pair C:G in parental DNA can be changed into a T:A pair in the daughter DNA molecule. Therefore, uracil in DNA may lead to a mutation. Uracil in DNA, similarly to thymine, forms energetically most favorable hydrogen bonds with adenine, therefore uracil does not change the coding properties of DNA. Uracil in DNA is recognized by uracil DNA glycosylase (UDGs), which initiates DNA base excision repair, leading to removing of uracil from DNA and replacing it by thymine or cytosine, when arose as a result of cytosine deamination. Eukaryotes have at least four nuclear UDGs: UNG2, SMUG1, TDG i MBD4, while UNG1 operates in the mitochondrium. UNG2 is involved in DNA repair associated with DNA replication and interacts with PCNA and RPA proteins. Uracil can also be an intermediate product in the process of antigen-dependent antibody diversification in B lymphocytes. Enzymatic deamination of viral DNA by host cells can be a defense mechanism against viral infection, including HIV-1. UNG2, MBD4 and TDG glycosylases may cooperate with mismatch repair proteins and TDG can be involved in nucleotide excision repair system.

  2. Genomic uracil and human disease

    DEFF Research Database (Denmark)

    Hagen, Lars; Pena Diaz, Javier; Kavli, Bodil;

    2006-01-01

    , mutations resulting from uracil in DNA are prevented by error-free base excision repair. However, in B-cells uracil in DNA is also a physiological intermediate in acquired immunity. Here, activation-induced cytosine deaminase (AID) introduces template uracils that give GC to AT transition mutations...

  3. Multiphoton ionization of Uracil

    Science.gov (United States)

    Prieto, Eladio; Martinez, Denhi; Guerrero, Alfonso; Alvarez, Ignacio; Cisneros, Carmen

    2016-05-01

    Multiphoton ionization and dissociation of Uracil using a Reflectron time of flight spectrometer was performed along with radiation from the second harmonic of a Nd:YAG laser. Uracil is one of the four nitrogen bases that belong to RNA. The last years special interest has been concentrated on the study of the effects under UV radiation in nucleic acids1 and also in the role that this molecule could have played in the origin and development of life on our planet.2 The MPI mass spectra show that the presence and intensity of the resulting ions strongly depend on the density power. The identification of the ions in the mass spectra is presented. The results are compared with those obtained in other laboratories under different experimental conditions and some of them show partial agreement.3 The present work was supported by CONACYT-Mexico Grant 165410 and DGAPA UNAM Grant IN101215 and IN102613.

  4. Vibrational properties of uracil

    Institute of Scientific and Technical Information of China (English)

    WANG Zhiping; ZHANG Fengshou; ZENG Xianghua; ZHOU Hongyu; GU Bin; CHENG Wei

    2006-01-01

    A semiempirical molecular dynamics model is developed to study the vibrational frequencies of uracil at very low kinetic temperature by using the Fourier transform of velocity autocorrelation function of trajectories of molecular dynamics simulations. The finite difference harmonic method is used to assign the vibrational frequency of each mode. The calculated frequencies are found to be in good agreement with experimental measurements. Moreover, we make up for the lost vibrational modes in experiments self-consistently. A total of 30 vibrational modes and their corresponding frequencies are reported.

  5. Infrared multiple photon dissociation action spectroscopy of protonated uracil and thiouracils: Effects of thioketo-substitution on gas-phase conformation

    NARCIS (Netherlands)

    Nei, Y. W.; Akinyemi, T. E.; Steill, J. D.; Oomens, J.; Rodgers, M. T.

    2010-01-01

    The gas-phase structures of protonated complexes of uracil and five thiouracils including 2-thiouracil (2SU), 5-methyl-2-thiouracil (5Me2SU), 6-methyl-2-thiouracil (6Me2SU), 4-thiouracil (4SU), and 2,4-dithiouracil (24dSU) are examined via infrared multiple photon dissociation (IRMPD) action

  6. Infrared multiple photon dissociation action spectroscopy of sodiated uracil and thiouracils: effects of thioketo-substitution on gas-phase conformation

    NARCIS (Netherlands)

    Nei, Y.W.; Akinyemi, T.E.; Kaczan, C.M.; Steill, J.D.; Berden, G.; Oomens, J.; Rodgers, M.T.

    2011-01-01

    The gas phase structures of sodium cationized complexes of uracil and five thiouracils including 2-thiouracil (2SU), 5-methyl-2-thiouracil (5Me2SU), 6-methyl-2-thiouracil (6Me2SU), 4-thiouracil (4SU), and 2,4-dithiouracil (24dSU) are examined via infrared multiple photon dissociation (IRMPD) action

  7. Infrared multiple photon dissociation action spectroscopy of sodiated uracil and thiouracils: Effects of thioketo-substitution on gas-phase conformation

    NARCIS (Netherlands)

    Nei, Y. W.; Akinyemi, T. E.; Kaczan, C. M.; Steill, J. D.; G. Berden,; Oomens, J.; Rodgers, M. T.

    2011-01-01

    The gas phase structures of sodium cationized complexes of uracil and five thiouracils including 2-thiouracil (2SU), 5-methyl-2-thiouracil (5Me2SU), 6-methyl-2-thiouracil (6Me2SU), 4-thiouracil (4SU), and 2,4-dithiouracil (24dSU) are examined via infrared multiple photon dissociation (IRMPD) action

  8. Two Genes Encoding Uracil Phosphoribosyltransferase Are Present in Bacillus subtilis

    DEFF Research Database (Denmark)

    Martinussen, Jan; Glaser, Philippe; Andersen, Paal S.

    1995-01-01

    Uracil phosphoribosyltransferase (UPRTase) catalyzes the key reaction in the salvage of uracil in many microorganisms. Surprisingly, two genes encoding UPRTase activity were cloned from Bacillus subtilis by complementation of an Escherichia coli mutant. The genes were sequenced, and the putative...

  9. Uracil Excision for Assembly of Complex Pathways

    DEFF Research Database (Denmark)

    Cavaleiro, Mafalda; Nielsen, Morten Thrane; Kim, Se Hyeuk

    2015-01-01

    Despite decreasing prices on synthetic DNA constructs, higher-order assembly of PCR-generated DNA continues to be an important exercise in molecular and synthetic biology. Simplicity and robustness are attractive features met by the uracil excision DNA assembly method, which is one of the most in...

  10. Uracil Excision for Assembly of Complex Pathways

    DEFF Research Database (Denmark)

    Cavaleiro, Mafalda; Nielsen, Morten Thrane; Kim, Se Hyeuk

    2015-01-01

    inexpensive technologies available. Here, we describe four different protocols for uracil excision-based DNA editing: one for simple manipulations such as site-directed mutagenesis, one for plasmid-based multigene assembly in Escherichia coli, one for one-step assembly and integration of single or multiple...... genes into the genome, and a standardized assembly pipeline using benchmarked oligonucleotides for pathway assembly and multigene expression optimization....

  11. Electron affinities of uracil: microsolvation effects and polarizable continuum model.

    Science.gov (United States)

    Melicherčík, Miroslav; Pašteka, Lukáš F; Neogrády, Pavel; Urban, Miroslav

    2012-03-08

    We present adiabatic electron affinities (AEAs) and the vertical detachment energies (VDEs) of the uracil molecule interacting with one to five water molecules. Credibility of MP2 and DFT/B3LYP calculations is supported by comparison with available benchmark CCSD(T) data. AEAs and VDEs obtained by MP2 and DFT/B3LYP methods copy trends of benchmark CCSD(T) results for the free uracil and uracil-water complexes in the gas phase being by 0.20 - 0.28 eV higher than CCSD(T) values depending on the particular structure of the complex. AEAs and VDEs from MP2 are underestimated by 0.09-0.15 eV. For the free uracil and uracil-(H(2)O)(n) (n = 1,2,3,5) complexes, we also consider the polarizable continuum model (PCM) and discuss the importance of the microsolvation when combined with PCM. AEAs and VDEs of uracil and uracil-water complexes enhance rapidly with increasing relative dielectric constant (ε) of the solvent. Highest AEAs and VDEs of the U(H(2)O)(5) complexes from B3LYP with ε = 78.4 are 2.03 and 2.81 eV, respectively, utilizing the correction from CCSD(T). Specific structural features of the microsolvated uracil-(H(2)O)(n) complexes and their anions are preserved also upon considering PCM in calculations of AEAs and VDEs.

  12. Study of proton radiolysis of solid uracil film

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    In order to understand the molecules mechanism of ion irradiation,which has been widelyused in many fields such as cancer therapy, uracil, one of the bases ofnucleic acid,waschosen in the low energy ion radiolysis research. The solid uracil films with mass thickness of0.314 mg/cm2 were irradiated by 200 keV H+ ions.The experimental results show that 200 keVH+ ions are effective in decomposition of uracil molecules. One of the decomposition products,5,6-dihydro-uracil, was separated by high performance liquid chromatograph (HPLC) anddetected using an UV-light detector. Its yield increases first but then decreases as the ion doseincreasing. In addition, the mechanism of uracil decomposition and 5,6-dihydro-uracilformation was also discussed.

  13. Identification of a poxvirus gene encoding a uracil DNA glycosylase.

    OpenAIRE

    Upton, C; Stuart, D T; McFadden, G

    1993-01-01

    An open reading frame, BamHI D6R, from the central highly conserved region of the Shope fibroma virus (SFV) genome was sequenced and found to have significant homology to that of uracil DNA glycosylases from a number of organisms. Uracil DNA glycosylase catalyzes the initial step in the repair pathway that removes potentially mutagenic uracil from duplex DNA. The D6R polypeptide was expressed in reticulocyte lysates programmed with RNA transcribed from an expression vector containing the T7 R...

  14. UFT (tegafur-uracil) in rectal cancer

    DEFF Research Database (Denmark)

    Casado, E; Pfeiffer, P; Feliu, J

    2008-01-01

    BACKGROUND: Major achievements in the treatment of localised rectal cancer include the development of total mesorectal excision and the perioperative administration of radiotherapy in combination with continuous infusion (CI) 5-fluorouracil (5-FU). This multimodal approach has resulted in extended...... survival and lower local relapse rates, with the potential for sphincter-preserving procedures. However, CI 5-FU is inconvenient for patients and is costly. Oral fluoropyrimidines like UFT (tegafur-uracil) offer a number of advantages over 5-FU. METHODS: We undertook a review of published articles...... and abstracts relating to clinical studies of UFT in the treatment of locally advanced rectal cancer (LARC). Pre- and postoperative studies carried out in patients with newly diagnosed or recurrent disease were included. RESULTS: The combination of UFT and radiotherapy was effective and well tolerated...

  15. Trypanosoma cruzi contains a single detectable uracil-DNA glycosylase and repairs uracil exclusively via short patch base excision repair

    DEFF Research Database (Denmark)

    Pena Diaz, Javier; Akbari, Mansour; Sundheim, Ottar;

    2004-01-01

    Enzymes involved in genomic maintenance of human parasites are attractive targets for parasite-specific drugs. The parasitic protozoan Trypanosoma cruzi contains at least two enzymes involved in the protection against potentially mutagenic uracil, a deoxyuridine triphosphate nucleotidohydrolase (...

  16. Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair

    Science.gov (United States)

    Bulgar, A D; Weeks, L D; Miao, Y; Yang, S; Xu, Y; Guo, C; Markowitz, S; Oleinick, N; Gerson, S L; Liu, L

    2012-01-01

    Uracil DNA glycosylase (UDG) specifically removes uracil bases from DNA, and its repair activity determines the sensitivity of the cell to anticancer agents that are capable of introducing uracil into DNA. In the present study, the participation of UDG in the response to pemetrexed-induced incorporation of uracil into DNA was studied using isogenic human tumor cell lines with or without UDG (UDG+/+/UDG−/−). UDG−/− cells were very sensitive to pemetrexed. Cell killing by pemetrexed was associated with genomic uracil accumulation, stalled DNA replication, and catastrophic DNA strand breaks. By contrast, UDG+/+ cells were >10 times more resistant to pemetrexed due to the rapid removal of uracil from DNA by UDG and subsequent repair of the resultant AP sites (abasic sites) via the base excision repair (BER). The resistance to pemetrexed in UDG+/+ cells could be reversed by the addition of methoxyamine (MX), which binds to AP sites and interrupts BER pathway. Furthermore, MX-bound AP sites induced cell death was related to their cytotoxic effect of dual inactivation of UDG and topoisomerase IIα, two genes that are highly expressed in lung cancer cells in comparison with normal cells. Thus, targeting BER-based therapy exhibits more selective cytotoxicity on cancer cells through a synthetic lethal mechanism. PMID:22237209

  17. Poxvirus uracil-DNA glycosylase-An unusual member of the family I uracil-DNA glycosylases: Poxvirus Uracil-DNA Glycosylase

    Energy Technology Data Exchange (ETDEWEB)

    Schormann, Norbert [Department of Medicine, University of Alabama at Birmingham, Birmingham Alabama 35294; Zhukovskaya, Natalia [Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia Pennsylvania 19104; Bedwell, Gregory [Department of Microbiology, University of Alabama at Birmingham, Birmingham Alabama 35294; Nuth, Manunya [Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia Pennsylvania 19104; Gillilan, Richard [MacCHESS (Macromolecular Diffraction Facility at CHESS) Cornell University, Ithaca New York 14853; Prevelige, Peter E. [Department of Microbiology, University of Alabama at Birmingham, Birmingham Alabama 35294; Ricciardi, Robert P. [Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia Pennsylvania 19104; Abramson Cancer Center, School of Medicine, University of Pennsylvania, Philadelphia Pennsylvania 19104; Banerjee, Surajit [Department of Chemistry and Chemical Biology, Cornell University, and NE-CAT Argonne Illinois 60439; Chattopadhyay, Debasish [Department of Medicine, University of Alabama at Birmingham, Birmingham Alabama 35294

    2016-11-02

    We report that uracil-DNA glycosylases are ubiquitous enzymes, which play a key role repairing damages in DNA and in maintaining genomic integrity by catalyzing the first step in the base excision repair pathway. Within the superfamily of uracil-DNA glycosylases family I enzymes or UNGs are specific for recognizing and removing uracil from DNA. These enzymes feature conserved structural folds, active site residues and use common motifs for DNA binding, uracil recognition and catalysis. Within this family the enzymes of poxviruses are unique and most remarkable in terms of amino acid sequences, characteristic motifs and more importantly for their novel non-enzymatic function in DNA replication. UNG of vaccinia virus, also known as D4, is the most extensively characterized UNG of the poxvirus family. D4 forms an unusual heterodimeric processivity factor by attaching to a poxvirus-specific protein A20, which also binds to the DNA polymerase E9 and recruits other proteins necessary for replication. D4 is thus integrated in the DNA polymerase complex, and its DNA-binding and DNA scanning abilities couple DNA processivity and DNA base excision repair at the replication fork. In conclusion, the adaptations necessary for taking on the new function are reflected in the amino acid sequence and the three-dimensional structure of D4. We provide an overview of the current state of the knowledge on the structure-function relationship of D4.

  18. Allosteric regulation and communication between subunits in uracil phosphoribosyltransferase from Sulfolobus solfataricus

    DEFF Research Database (Denmark)

    Arent, Susan; Harris, Pernille; Jensen, Kaj Frank

    2005-01-01

    Uracil phosphoribosyltransferase (UPRTase) catalyzes the conversion of 5-phosphate-alpha-1-diphosphate (PRPP) and uracil to uridine 5'-monophosphate (UMP) and diphosphate. The UPRTase from Sulfolobus solfataricus has a unique regulation by nucleoside triphosphates compared to UPRTases from other...

  19. Effects of microsolvation on uracil and its radical anion: Uracil.(H2O)n (n=1-5)

    Science.gov (United States)

    Kim, Sunghwan; Schaefer, Henry F.

    2006-10-01

    Microsolvation effects on the stabilities of uracil and its anion have been investigated by explicitly considering the structures of complexes of uracil with up to five water molecules at the B3LYP /DZP++ level of theory. For all five systems, the global minimum of the neutral cluster has a different equilibrium geometry from that of the radical anion. Both the vertical detachment energy (VDE) and adiabatic electron affinity (AEA) of uracil are predicted to increase gradually with the number of hydrating molecules, qualitatively consistent with experimental results from a photodetachment-photoelectron spectroscopy study [J. Schiedt et al., Chem. Phys. 239, 511 (1998)]. The trend in the AEAs implies that while the conventional valence radical anion of uracil is only marginally bound in the gas phase, it will form a stable anion in aqueous solution. The gas-phase AEA of uracil (0.24eV) was higher than that of thymine by 0.04eV and this gap was not significantly affected by microsolvation. The largest AEA is that predicted for uracil•(H2O)5, namely, 0.96eV. The VDEs range from 0.76to1.78eV.

  20. Electronic structure of uracil-like nucleobases adsorbed on Si(001): uracil, thymine and 5-fluorouracil

    Science.gov (United States)

    Molteni, Elena; Onida, Giovanni; Cappellini, Giancarlo

    2016-04-01

    We study the electronic properties of the Si(001):Uracil, Si(001):Thymine, and Si(001):5-Fluorouracil systems, focusing on the Si dimer-bridging configuration with adsorption governed by carbonyl groups. While the overall structural and electronic properties are similar, with small differences due to chemical substitutions, much larger effects on the surface band dispersion and bandgap show up as a function of the molecular orientation with respect to the surface. An off-normal orientation of the molecular planes is favored, showing larger bandgap and lower total energy than the upright position. We also analyze the localization of gap-edge occupied and unoccupied surface states. Supplementary material in the form of one pdf file available from the Journal web page at http://dx.doi.org/10.1140/epjb/e2016-70011-1

  1. DFT studies of CNT-functionalized uracil-acetate hybrids

    Science.gov (United States)

    Mirzaei, Mahmoud; Gulseren, Oguz

    2015-09-01

    Calculations based on density functional theory (DFT) have been performed to investigate the stabilities and properties of hybrid structures consisting of a molecular carbon nanotube (CNT) and uracil acetate (UA) counterparts. The investigated models have been relaxed to minimum energy structures and then various physical properties and nuclear magnetic resonance (NMR) properties have been evaluated. The results indicated the effects of functionalized CNT on the properties of hybrids through comparing the results of hybrids and individual structures. The oxygen atoms of uracil counterparts have been seen as the detection points of properties for the CNT-UA hybrids.

  2. The regioselective iodination of quinolines, quinolones, pyridones, pyridines and uracil.

    Science.gov (United States)

    Dutta, Uttam; Deb, Arghya; Lupton, David W; Maiti, Debabrata

    2015-12-28

    A radical based direct C-H iodination protocol for quinolines, quinolones, pyridones, pyridines, and uracil has been developed. The iodination occurs in a C3 selective manner for quinolines and quinolones. Pyridones and pyridines undergo C3 and C5 iodination, while dimethyl uracil undergoes C5 iodination. Scope of the method was demonstrated through the rapid synthesis of both electron rich as well as electron poor heteroaromatic iodides. The protocol was found to be scalable and general, while a mechanism has been proposed.

  3. Biochemical Characterization of Uracil Phosphoribosyltransferase from Mycobacterium tuberculosis

    Science.gov (United States)

    Villela, Anne Drumond; Ducati, Rodrigo Gay; Rosado, Leonardo Astolfi; Bloch, Carlos Junior; Prates, Maura Vianna; Gonçalves, Danieli Cristina; Ramos, Carlos Henrique Inacio; Basso, Luiz Augusto; Santos, Diogenes Santiago

    2013-01-01

    Uracil phosphoribosyltransferase (UPRT) catalyzes the conversion of uracil and 5-phosphoribosyl-α-1-pyrophosphate (PRPP) to uridine 5′-monophosphate (UMP) and pyrophosphate (PPi). UPRT plays an important role in the pyrimidine salvage pathway since UMP is a common precursor of all pyrimidine nucleotides. Here we describe cloning, expression and purification to homogeneity of upp-encoded UPRT from Mycobacterium tuberculosis (MtUPRT). Mass spectrometry and N-terminal amino acid sequencing unambiguously identified the homogeneous protein as MtUPRT. Analytical ultracentrifugation showed that native MtUPRT follows a monomer-tetramer association model. MtUPRT is specific for uracil. GTP is not a modulator of MtUPRT ativity. MtUPRT was not significantly activated or inhibited by ATP, UTP, and CTP. Initial velocity and isothermal titration calorimetry studies suggest that catalysis follows a sequential ordered mechanism, in which PRPP binding is followed by uracil, and PPi product is released first followed by UMP. The pH-rate profiles indicated that groups with pK values of 5.7 and 8.1 are important for catalysis, and a group with a pK value of 9.5 is involved in PRPP binding. The results here described provide a solid foundation on which to base upp gene knockout aiming at the development of strategies to prevent tuberculosis. PMID:23424660

  4. Uracil misincorporation into DNA and folic acid supplementation

    Science.gov (United States)

    BACKGROUND: Folate deficiency decreases thymidylate synthesis from deoxyuridylate, which results in an imbalance of deoxyribonucleotide that may lead to excessive uracil misincorporation (UrMis) into DNA during replication and repair. OBJECTIVE: We evaluated the relation between UrMis in different ...

  5. Biochemical characterization of uracil phosphoribosyltransferase from Mycobacterium tuberculosis.

    Directory of Open Access Journals (Sweden)

    Anne Drumond Villela

    Full Text Available Uracil phosphoribosyltransferase (UPRT catalyzes the conversion of uracil and 5-phosphoribosyl-α-1-pyrophosphate (PRPP to uridine 5'-monophosphate (UMP and pyrophosphate (PP(i. UPRT plays an important role in the pyrimidine salvage pathway since UMP is a common precursor of all pyrimidine nucleotides. Here we describe cloning, expression and purification to homogeneity of upp-encoded UPRT from Mycobacterium tuberculosis (MtUPRT. Mass spectrometry and N-terminal amino acid sequencing unambiguously identified the homogeneous protein as MtUPRT. Analytical ultracentrifugation showed that native MtUPRT follows a monomer-tetramer association model. MtUPRT is specific for uracil. GTP is not a modulator of MtUPRT ativity. MtUPRT was not significantly activated or inhibited by ATP, UTP, and CTP. Initial velocity and isothermal titration calorimetry studies suggest that catalysis follows a sequential ordered mechanism, in which PRPP binding is followed by uracil, and PP(i product is released first followed by UMP. The pH-rate profiles indicated that groups with pK values of 5.7 and 8.1 are important for catalysis, and a group with a pK value of 9.5 is involved in PRPP binding. The results here described provide a solid foundation on which to base upp gene knockout aiming at the development of strategies to prevent tuberculosis.

  6. Oscillatory shear and high-pressure dielectric study of 5-methyl-3-heptanol

    DEFF Research Database (Denmark)

    Hecksher, Tina; Jakobsen, Bo; Dyre, J. C.

    2014-01-01

    The monohydroxy alcohol 5-methyl-3-heptanol is studied using rheology at ambient pressure and using dielectric spectroscopy at elevated pressures up to 1.03 GPa. Both experimental techniques reveal that the relaxational behavior of this liquid is intermediate between those that show a large Debye...

  7. Lgr5 Methylation in Cancer Stem Cell Differentiation and Prognosis-Prediction in Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Shasha Su

    Full Text Available Leucine-rich-repeat-containing G-protein-coupled receptor 5 (lgr5 is a candidate marker for colorectal cancer stem cells (CSC. In the current study, we investigated the methylation status within thelgr5 promoter and evaluated its relationship with CSC differentiation, prognosis for colorectal cancer, and its clinicopathological features.The methylation status within Lgr5 promoter was detected with a methylation-specific PCR in six colorectal cancer cell lines as well as 169 primary colorectal tumor tissues. Differentiation of CSC was examined with immunofluorescence and immunocytochemistry. Down-regulation of lgr5 was achieved with gene-specific siRNA. The associations between lgr5 methylation and the clinicopathological features as well as survival of patients were analyzed with statistical methods.The lgr5 promoter was methylated to different degrees for the six colorectal cell lines examined, with complete methylation observed in HCT116 cells in which the lgr5 expression was partially recovered following DAC treatment. The stem-cell sphere formation from HCT116 cells was accompanied by increasing methylation within the lgr5 promoter and decreasing expression of lgr5. Knocking down lgr5 by siRNA also led to stem-cell spheres formation. Among primary colorectal tumors, 40% (67/169 were positive for lgr5 methylation, while none of the normal colon tissues were positive for lgr5 methylation. Furthermore, lgr5 methylation significantly associated with higher tumor grade, and negative distant metastasis (p < 0.05, as well as better prognosis (p = 0.001 in patients with colorectal cancer.Our data suggests that lgr5 methylation, through the regulation of lgr5 expression and colorectal CSC differentiation, may constitute a novel prognostic marker for colorectal cancer patients.

  8. A Novel Photoproduct of Uracil in Phosphate-Buffered Saline

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The photolysis of uracil in phosphate-buffered saline (PBS, pH 8.0) under the irradiation of medium pressure mercury lamp (MPML) leads to the production of a novel compound C4H5N2O6P. The composition and structure of the compound has been identified by elemental analysis, EI-MS, UV, IR, 1H, 13C, 31P-NMR.

  9. Uracil-containing DNA in Drosophila: stability, stage-specific accumulation, and developmental involvement.

    Directory of Open Access Journals (Sweden)

    Villő Muha

    Full Text Available Base-excision repair and control of nucleotide pools safe-guard against permanent uracil accumulation in DNA relying on two key enzymes: uracil-DNA glycosylase and dUTPase. Lack of the major uracil-DNA glycosylase UNG gene from the fruit fly genome and dUTPase from fruit fly larvae prompted the hypotheses that i uracil may accumulate in Drosophila genomic DNA where it may be well tolerated, and ii this accumulation may affect development. Here we show that i Drosophila melanogaster tolerates high levels of uracil in DNA; ii such DNA is correctly interpreted in cell culture and embryo; and iii under physiological spatio-temporal control, DNA from fruit fly larvae, pupae, and imago contain greatly elevated levels of uracil (200-2,000 uracil/million bases, quantified using a novel real-time PCR-based assay. Uracil is accumulated in genomic DNA of larval tissues during larval development, whereas DNA from imaginal tissues contains much less uracil. Upon pupation and metamorphosis, uracil content in DNA is significantly decreased. We propose that the observed developmental pattern of uracil-DNA is due to the lack of the key repair enzyme UNG from the Drosophila genome together with down-regulation of dUTPase in larval tissues. In agreement, we show that dUTPase silencing increases the uracil content in DNA of imaginal tissues and induces strong lethality at the early pupal stages, indicating that tolerance of highly uracil-substituted DNA is also stage-specific. Silencing of dUTPase perturbs the physiological pattern of uracil-DNA accumulation in Drosophila and leads to a strongly lethal phenotype in early pupal stages. These findings suggest a novel role of uracil-containing DNA in Drosophila development and metamorphosis and present a novel example for developmental effects of dUTPase silencing in multicellular eukaryotes. Importantly, we also show lack of the UNG gene in all available genomes of other Holometabola insects, indicating a potentially

  10. Synthesis of 1-isopropyl-3-acyl-5-methyl-benzimidazolone Derivatives and Their Antimicrobial Activity

    Directory of Open Access Journals (Sweden)

    Shaopeng Wei

    2013-03-01

    Full Text Available A series of N-acylated analogues of 1-isopropyl-3-acyl-5-methyl-benzimidazolone were synthesized. Bioassay results indicated that analogues 5-07 and 5-19 exhibited the most potency against Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Analogues 5-02, 5-07, 5-12, 5-15, 5-19, 5-20 and 5-25 could effectively inhibit the spore germination of Botrytis cinerea. The relationship between structure and their antimicrobial activity (SAR has also been discussed according to aliphatic acids and aromatic acids derivatives, respectively. This implied that the N-acylated derivatives of 5-methyl-benzimidazolone might be potential antimicrobial agents.

  11. Crystal Structure of N,N-bis-(3-Carbomethoxy-5-methyl-pyrazol-1-ylmethylaniline

    Directory of Open Access Journals (Sweden)

    Taibi Ben-Hadda

    2002-09-01

    Full Text Available The tripodal ligand N,N-bis-(3-carbomethoxy-5-methylpyrazol-1-ylmethyl aniline (2 has been prepared by the condensation of aniline with two equivalents of N-hydroxymethyl[3-carbomethoxy-5-methyl]pyrazole. The molecule consists of two structurally analogous 3-carbomethoxy-5-methylpyrazol-1-ylmethyl moieties, which adopt a transoidal conformation via a central aniline ring, suggesting that this tripodal ligand is highly flexible and could accommodate many metals by coordination.

  12. Stable isotope dilution analysis of orotic acid and uracil in amniotic fluid

    NARCIS (Netherlands)

    Jakobs, C.; Sweetman, L.; Nyhan, W.L.; Gruenke, L.; Craig, J.C.; Wadman, S.K.

    1984-01-01

    Rapid, sensitive and accurate stable isotope dilution assays were developed for the measurement of orotic acid and uracil in amniotic fluid. The method utilizes [15N2]orotic acid and [15N2]uracil as internal standards, isolation by liquid partition chromatography and quantitation by chemical ionizat

  13. Synthesis of Novel Uracil Non-Nucleoside Derivatives as Potential Reverse Transcriptase Inhibitors of HIV-1

    DEFF Research Database (Denmark)

    El-Brollosy, Nasser R.; Al-Deeb, Omar. A.; El-Emam, Ali A.

    2009-01-01

    Novel emivirine and TNK-651 analogues 5a-d were synthesized by reaction of chloromethyl ethyl ether and / or benzyl chloromethyl ether, respectively, with uracils having 5-ethyl and 6-(4-methylbenzyl) or 6-(3,4-dimethoxybenzyl) substituents. A series of new uracil non-nucleosides substituted at N-1...... with cyclopropylmethyloxymethyl 9a-d, 2-phenylethyloxymethyl 9e-h, and 3-phenylprop-1-yloxymethyl 9i-l were prepared on treatment of the corresponding uracils with the appropriate acetals 8a-c. Some of the tested compounds showed good activity against HIV-1 wild type. Among them, 1-cyclopropylmethyloxymethyl-5-ethyl-6......-(3,5-dimethylbenzyl)uracil 9c and 5-ethyl-6-(3,5-dimethylbenzyl)-1-(2-phenylethyloxymethyl)uracil 9g showed inhibitory potency equally to emivirine against HIV-1 wild type. Furthermore, compounds 9c and 9g showed marginal better activity against NNRTI resistant mutants than emivirine....

  14. Fingerprinting DNA oxidation processes: IR characterization of the 5-methyl-2'-deoxycytidine radical cation.

    Science.gov (United States)

    Bucher, Dominik B; Pilles, Bert M; Pfaffeneder, Toni; Carell, Thomas; Zinth, Wolfgang

    2014-02-24

    Methylated cytidine plays an important role as an epigenetic signal in gene regulation. Its oxidation products are assumed to be involved in active demethylation processes but also in damaging DNA. Here, we report the photochemical production of the 5-methyl-2'-deoxycytidine radical cation via a two-photon ionization process. The radical cation is detected by time-resolved IR spectroscopy and identified by band assignment using density functional theory calculations. Two final oxidation products are characterized with liquid chromatography coupled to mass spectrometry.

  15. A New Technique of Synthesizing 10-Hydroxy-5-methyl- 5,10- dihydrophenophosphazine 10-Oxide

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    10-Hydroxy-5-methyl-5, 10- dihydrophenophosphazine 10-oxide (1) was prepared by a new technique of treating 10-methoxy-5,10-dihydrophenophosphazine 10-oxide (2) with an equivalent of NaH in anhydrous DMF, and then at 120℃ for 3~4 h, which not only avoided poisonous and expensive methyl iodide used in literature, but made the consumption of NaH greatly decrease as well. The possible reaction mechanism was also described. The chemical structure of 1 was confirmed by IR, NMR, and mass spectroscopy.

  16. Antimicrobial N-brominated hydantoin and uracil grafted polystyrene beads.

    Science.gov (United States)

    Farah, Shady; Aviv, Oren; Laout, Natalia; Ratner, Stanislav; Domb, Abraham J

    2015-10-28

    Hydantoin-N-halamine derivatives conjugated on polystyrene beads are promising disinfectants with broad antimicrobial activity affected by the gradual release of oxidizing halogen in water. The objective of this work was to identify and test of hydantoin-like molecules possessing urea moiety, which may provide N-haloamines releasing oxidizing halogens when exposed to water at different rates and release profiles for tailored antimicrobial agents. In this work, several hydantoin (five member ring) and for the first time reported, uracil (six member ring) derivatives have been conjugated to polystyrene beads and tested for their lasting antimicrobial activity. Four molecules of each series were conjugated onto polystyrene beads from the reaction of the N-potassium hydantoin or uracil derivatives onto chloromethylated polystyrene beads. A distinct difference in bromine loading capacity and release profiles was found for the different conjugated derivatives. All tested materials exhibit strong antimicrobial activity against Escherichia coli and bacteriophages MS2 of 7 and ~4 log reduction, respectively. These results highlight the antimicrobial potential of halogenated cyclic molecules containing urea groups as water disinfection agents.

  17. H{sup .} atom and OH{sup .} radical reactions with 5-methyl-cytosine

    Energy Technology Data Exchange (ETDEWEB)

    Grand, A.; Morell, C.; Labet, V.; Cadet, J. [CEA Grenoble, Lab Les Acides Nucl, DRFMC/SCIB, UMR-E 3, CEA-UJF, F-38054 Grenoble, (France); Eriksson, L.A. [Univ Orebro, Dept Nat Sci and Orebro Life Sci Ctr, S-70182 Orebro, (Sweden)

    2007-07-01

    The reactions between either a hydrogen atom or a hydroxyl radical and 5-methyl-cytosine (5-MeCyt) are studied by using the hybrid kinetic energy meta-GGA functional MPW1B95. H{sup .} atom and OH{sup .} radical addition to positions C5 and C6 of 5-MeCyt, or OH{sup .} radical induced H-abstraction from the C5 methyl group, are explored. All systems are optimized in bulk solvent. The data presented show that the barriers to reaction are very low: ca. 7 kCal/mol for the H{sup .} atom additions and 1 kCal/mol for the reactions involving the OH{sup .} radical. Thermodynamically, the two C6 radical adducts and the H{sup .}- abstraction product are the most stable ones. The proton hyperfine coupling constants (HFCC), computed at the IEFPCM/MPW1B95/6-311++G(2d,2p) level, agree well with B3LYP results and available experimental and theoretical data on related thymine and cytosine radicals. (authors)

  18. Lewis Acid Triggered Regioselective Magnesiation and Zincation of Uracils, Uridines, and Cytidines.

    Science.gov (United States)

    Klier, Lydia; Aranzamendi, Eider; Ziegler, Dorothée; Nickel, Johannes; Karaghiosoff, Konstantin; Carell, Thomas; Knochel, Paul

    2016-03-04

    The Lewis acid MgCl2 allows control of the metalation regioselectivity of uracils and uridines. In the absence of the Lewis acid, metalation of uracil and uridine derivatives with TMPMgCl·LiCl occurs at the position C(5). In the presence of MgCl2, zincation using TMP2Zn·2LiCl·2MgCl2 occurs at the position C(6). This metalation method provides easy access to functionalized uracils and uridines. Using TMP2Zn·2LiCl·2MgCl2 also allows to functionalize cytidine derivatives at the position C(6).

  19. Keeping Uracil Out of DNA: Physiological Role, Structure and Catalytic Mechanism of dUTPases

    OpenAIRE

    2009-01-01

    The thymine-uracil exchange constitutes one of the major chemical differences between DNA and RNA. Although these two bases form the same Watson-Crick base pairs with adenine and are equivalent for both information storage and transmission, uracil incorporation in DNA is usually a mistake that needs to be excised. There are two ways for uracil to appear in DNA: thymine replacement and cytosine deamination. Most DNA polymerases readily incorporate dUMP as well as dTMP depending solely on the a...

  20. Cloning and Characterization of upp, a Gene Encoding Uracil Phosphoribosyltransferase from Lactococcus lactis

    DEFF Research Database (Denmark)

    Martinussen, Jan; Hammer, Karin

    1994-01-01

    Uracil phosphoribosyltransferase catalyzes the key reaction in the salvage of uracil in many microorganisms. The gene encoding uracil phosphoribosyltransferase (upp) was cloned from Lactococcus lactis subsp. cremoris MG1363 by complementation of an Escherichia coli mutant. The gene was sequenced...... construction of an internal deletion, a upp mutant was constructed by a double-crossover event. This implicated the utilization of a plasmid with a thermosensitive origin of replication and a new and easy way to screen for double crossover events in both gram-positive and gram-negative bacterial strains...

  1. 3-Hydroxy-N′-[(Z-(5-methyl-2-furylmethylidene]naphthalene-2-carbohydrazide

    Directory of Open Access Journals (Sweden)

    Zahid Shafiq

    2009-11-01

    Full Text Available The asymmetric unit of title compound, C17H14N2O3, contains three independent molecules. In one of these molecules, the 5-methyl-2-furyl group is disordered over two sets of sites with an occupancy ratio of 0.747 (3:0.253 (3. In the two ordered molecules, the furan and naphthalene rings are oriented at dihedral angles of 11.05 (12 and 32.2 (5°. In the disordered molecule, the furan rings with major and minor occupancies are oriented at dihedral angles of 41.4 (2 and 26.6 (13°, respectively, with the corresponding naphthalene ring. An intramolecular O—H...O hydrogen bond occurs within each molecule. In the crystal, molecules are linked by N—H...O, N—H...(N,O and C—H...O interactions.

  2. 5-Methyl-1-[(4-methylphenylsulfonyl]-1H-pyrazol-3-yl 4-methylbenzenesulfonate

    Directory of Open Access Journals (Sweden)

    Shahzad Murtaza

    2012-07-01

    Full Text Available In the title compound, C18H18N2O5S2, the tolyl rings are oriented at a dihedral angle of 16.15 (11° with respect to one another. The 5-methyl-1H-pyrazol-3-ol ring is roughly planar (r.m.s. deviation = 0.0231 Å and subtends angles of 73.82 (8 and 89.85 (8° with the tolyl rings. In the crystal, very weak π–π interactions between tolyl groups, with centroid–centroid distances of 4.1364 (19 and 4.0630 (16 Å, together with a C—H...π contact generate a three-dimensional network.

  3. Diaqua(5-methyl-1H-pyrazole-3-carboxylato(4-nitrobenzoatocopper(II

    Directory of Open Access Journals (Sweden)

    Shan-shan Zhang

    2009-02-01

    Full Text Available In the title complex, [Cu(C7H4NO4(C5H5N2O2(H2O2], the CuII ion is coordinated in a slightly distorted square-pyramidal enviroment. The basal plane is formed by an N atom and an O atom from a 5-methyl-1H-pyrazole-3-carboxylate ligand and by two O atoms from two water ligands. The apical position is occupied by a carboxylate O atom from a 4-nitrobenzoate ligand. In the crystal structure, intermolecular O—H...O and N—H...O hydrogen bonds link complex moleclues, forming extended chains parallel to the a axis.

  4. Regiospecific Addition of Uracil to Acrylates Catalyzed by Alkaline Protease from Bacillus subtilis

    Institute of Scientific and Technical Information of China (English)

    Ying CAI; Jian Yi WU; Na WANG; Xiao Feng SUN; Xian Fu LIN

    2004-01-01

    Michael addition reactions of uracil to acrylates were catalyzed by an alkaline protease from Bacillus subtilis in dimethyl sulfoxide at 55 ℃ for 72 h. The adducts were determined by TLC, IR and 1H NMR.

  5. Carbon nanotube-nucleobase hybrids: nanorings from uracil-modified single-walled carbon nanotubes.

    Science.gov (United States)

    Singh, Prabhpreet; Toma, Francesca Maria; Kumar, Jitendra; Venkatesh, V; Raya, Jesus; Prato, Maurizio; Verma, Sandeep; Bianco, Alberto

    2011-06-06

    Single-walled carbon nanotubes (SWCNTs) have been covalently functionalized with uracil nucleobase. The hybrids have been characterized by using complementary spectroscopic and microscopic techniques including solid-state NMR spectroscopy. The uracil-functionalized SWCNTs are able to self-assemble into regular nanorings with a diameter of 50-70 nm, as observed by AFM and TEM. AFM shows that the rings do not have a consistent height and thickness, which indicates that they may be formed by separate bundles of CNTs. The simplest model for the nanoring formation likely involves two bundles of CNTs interacting with each other via uracil-uracil base-pairing at both CNT ends. These nanorings can be envisaged for the development of advanced electronic circuits.

  6. Production of uracil from methane by a newly isolated Methylomonas sp. SW1.

    Science.gov (United States)

    Kim, Sangwoo; Lee, Wangjun; Song, Insu; Kwon, Yuhyun; Yun, Seokhun; Park, Soohyun; Cho, Sukhyeong; Oh, Byung-Keun; Oh, Han Bin; Lee, Jinwon

    2016-12-20

    Methane is an abundant, inexpensive one-carbon feedstock and one of the most powerful greenhouse gases. Because it does not compete with food demand, it is considered a promising carbon feedstock for the production of valuable products using methanotrophic bacteria. Here, we isolated a novel methanotrophic bacterium, Methylomonas sp. SW1, from a sewage sample obtained from Wonju City Water Supply Drainage Center, Republic of Korea. The conditions for uracil production by Methylomonas sp. SW1, such as Cu(2+) concentration and temperature were investigated and optimized. As a result, Methylomonas sp. SW1 produced uracil from methane as a sole carbon source with a titer of 2.1mg/L in 84h without genetic engineering under the optimized condition. The results in this study demonstrate the feasibility of using Methylomonas sp. SW1 for the production of uracil from methane. This is the first report of uracil production from gas feedstock by methanotrophic bacteria.

  7. Uracil and beta-alanine degradation in Saccharomyces Kluyveri - discovery of a novel catabolic pathway

    DEFF Research Database (Denmark)

    Andersen, Gorm

    2006-01-01

    ’en i gær og de genetiske forudsætninger for uracil og beta-alanine (BAL) katabolisme i S. kluyveri undersøgt. Evnen til at bruge uracil, dihydrouracil (DHU), beta-ureidopropionate (BUP) og BAL som nitrogenkilde blev studeret i 38 gær arter. Disse var udvalgt, så de dækkede “Saccharomyces komplekset...

  8. N-1 regioselective Michael-type addition of 5-substituted uracils to (2-hydroxyethyl acrylate

    Directory of Open Access Journals (Sweden)

    Walczak Krzysztof Z

    2007-11-01

    Full Text Available Abstract N-1 regioselective Michael-type addition of 5-substituted uracils to (2-hydroxyethyl acrylate is presented. The reactions were performed in polar aprotic solvents and with avoidance of polymerization of acrylic substrate. The obtained adducts may serve as versatile substrates for further functionalization, e.g. into (3-uracil-1-ylpropanoic acids or transformations, with participation of hydroxyl group, into ester-conjugated acyclic nucleosides.

  9. Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells

    Science.gov (United States)

    Hansen, Erik C; Ransom, Monica; Hesselberth, Jay R; Hosmane, Nina N; Capoferri, Adam A; Bruner, Katherine M; Pollack, Ross A; Zhang, Hao; Drummond, Michael Bradley; Siliciano, Janet M; Siliciano, Robert; Stivers, James T

    2016-01-01

    We report that a major subpopulation of monocyte-derived macrophages (MDMs) contains high levels of dUTP, which is incorporated into HIV-1 DNA during reverse transcription (U/A pairs), resulting in pre-integration restriction and post-integration mutagenesis. After entering the nucleus, uracilated viral DNA products are degraded by the uracil base excision repair (UBER) machinery with less than 1% of the uracilated DNA successfully integrating. Although uracilated proviral DNA showed few mutations, the viral genomic RNA was highly mutated, suggesting that errors occur during transcription. Viral DNA isolated from blood monocytes and alveolar macrophages (but not T cells) of drug-suppressed HIV-infected individuals also contained abundant uracils. The presence of viral uracils in short-lived monocytes suggests their recent infection through contact with virus producing cells in a tissue reservoir. These findings reveal new elements of a viral defense mechanism involving host UBER that may be relevant to the establishment and persistence of HIV-1 infection. DOI: http://dx.doi.org/10.7554/eLife.18447.001 PMID:27644592

  10. Optical Isomers of 5-Methyl-1- (1-naphthyl) -1,2,3-triazole in the Crystal Structure

    Institute of Scientific and Technical Information of China (English)

    DONG Heng-Shan; ZHUANG Shan-Xue; LIU Shi-Qian; QUAN Bin; ZHANG Tong-Qiang

    2003-01-01

    @@ ( ± )-5-Methyl-1-( 1-naphthyl )-1,2, 3-triazole by which 5-methyl-1-( 1-naphthyl )-1,2, 3-triazol-4-carboxylic acid was prepared from aromatic amine was reported. The product was investigated with X-ray crystallography. Compound, C13H 11N3, Mr = 209.25, crystallized in the orthorhombic space group Pbca with unit cell parameters a = 1.0373(2) nm, b=1.1691(2) nm, c=1.7579(4) nm, α=90.00°, β=90.00°, γ=90.00°, V=2.1318(7)nm3, Z = 8, Dm = 1. 304 Mg/m3. The optical isomers of 5-methyl-1-(1-naphthyl)-1, 2,3-triazole was investigated in the crystal structure.

  11. Infrared spectra of protonated uracil, thymine and cytosine.

    Science.gov (United States)

    Salpin, Jean-Yves; Guillaumont, Sébastien; Tortajada, Jeanine; MacAleese, Luke; Lemaire, Joël; Maitre, Philippe

    2007-10-22

    The gas-phase structures of protonated uracil, thymine, and cytosine are probed by using mid-infrared multiple-photon dissociation (IRMPD) spectroscopy performed at the Free Electron Laser facility of the Centre Laser Infrarouge d'Orsay (CLIO), France. Experimental infrared (IR) spectra are recorded for ions that were generated by electrospray ionization, isolated, and then irradiated in a quadrupole ion trap; the results are compared to the calculated infrared absorption spectra of the different low-lying isomers (computed at the B3LYP/6-31++G(d,p) level). For each protonated base, the global energy minimum corresponds to an enolic tautomer, whose infrared absorption spectrum matched very well with the experimental IRMPD spectrum, with the exception of a very weak IRMPD signal observed at about 1800 cm(-1) in the case of the three protonated bases. This signal is likely to be the signature of the second-energy-lying oxo tautomer. We thus conclude that within our experimental conditions, two tautomeric ions are formed which coexist in the quadrupole ion trap.

  12. Chemical transformations drive complex self-assembly of uracil on close-packed coinage metal surfaces.

    Science.gov (United States)

    Papageorgiou, Anthoula C; Fischer, Sybille; Reichert, Joachim; Diller, Katharina; Blobner, Florian; Klappenberger, Florian; Allegretti, Francesco; Seitsonen, Ari P; Barth, Johannes V

    2012-03-27

    We address the interplay of adsorption, chemical nature, and self-assembly of uracil on the Ag(111) and Cu(111) surfaces as a function of molecular coverage (0.3 to 1 monolayer) and temperature. We find that both metal surfaces act as templates and the Cu(111) surface acts additionally as a catalyst for the resulting self-assembled structures. With a combination of STM, synchrotron XPS, and NEXAFS studies, we unravel a distinct polymorphism on Cu(111), in stark contrast to what is observed for the case of uracil on the more inert Ag(111) surface. On Ag(111) uracil adsorbs flat and intact and forms close-packed two-dimensional islands. The self-assembly is driven by stable hydrogen-bonded dimers with poor two-dimensional order. On Cu(111) complex structures are observed exhibiting, in addition, a strong annealing temperature dependence. We determine the corresponding structural transformations to be driven by gradual deprotonation of the uracil molecules. Our XPS study reveals unambiguously the tautomeric signature of uracil in the contact layer and on Cu(111) the molecule's deprotonation sites. The metal-mediated deprotonation of uracil and the subsequent electron localization in the molecule determine important biological reactions. Our data show a dependence between molecular coverage and molecule-metal interaction on Cu(111), as the molecules tilt at higher coverages in order to accommodate a higher packing density. After deprotonation of both uracil N atoms, we observe an adsorption geometry that can be understood as coordinative anchoring with a significant charge redistribution in the molecule. DFT calculations are employed to analyze the surface bonding and accurately describe the pertaining electronic structure.

  13. Effect of C5-Methylation of Cytosine on the UV-Induced Reactivity of Duplex DNA: Conformational and Electronic Factors.

    Science.gov (United States)

    Banyasz, Akos; Esposito, Luciana; Douki, Thierry; Perron, Marion; Lepori, Clément; Improta, Roberto; Markovitsi, Dimitra

    2016-05-12

    C5-methylation of cytosines is strongly correlated with UV-induced mutations detected in skin cancers. Mutational hot-spots appearing at TCG sites are due to the formation of pyrimidine cyclobutane dimers (CPDs). The present study, performed for the model DNA duplex (TCGTA)3·(TACGA)3 and the constitutive single strands, examines the factors underlying the effect of C5-methylation on pyrimidine dimerization at TCG sites. This effect is quantified for the first time by quantum yields ϕ. They were determined following irradiation at 255, 267, and 282 nm and subsequent photoproduct analysis using HPLC coupled to mass spectrometry. C5-methylation leads to an increase of the CPD quantum yield up to 80% with concomitant decrease of that of pyrimidine(6-4) pyrimidone adducts (64PPs) by at least a factor of 3. The obtained ϕ values cannot be explained only by the change of the cytosine absorption spectrum upon C5-methylation. The conformational and electronic factors that may affect the dimerization reaction are discussed in light of results obtained by fluorescence spectroscopy, molecular dynamics simulations, and quantum mechanical calculations. Thus, it appears that the presence of an extra methyl on cytosine affects the sugar puckering, thereby enhancing conformations of the TC step that are prone to CPD formation but less favorable to 64PPs. In addition, C5-methylation diminishes the amplitude of conformational motions in duplexes; in the resulting stiffer structure, ππ* excitations may be transferred from initially populated exciton states to reactive pyrimidines giving rise to CPDs.

  14. Correlated Mutation in the Evolution of Catalysis in Uracil DNA Glycosylase Superfamily

    Science.gov (United States)

    Xia, Bo; Liu, Yinling; Guevara, Jose; Li, Jing; Jilich, Celeste; Yang, Ye; Wang, Liangjiang; Dominy, Brian N.; Cao, Weiguo

    2017-01-01

    Enzymes in Uracil DNA glycosylase (UDG) superfamily are essential for the removal of uracil. Family 4 UDGa is a robust uracil DNA glycosylase that only acts on double-stranded and single-stranded uracil-containing DNA. Based on mutational, kinetic and modeling analyses, a catalytic mechanism involving leaving group stabilization by H155 in motif 2 and water coordination by N89 in motif 3 is proposed. Mutual Information analysis identifies a complexed correlated mutation network including a strong correlation in the EG doublet in motif 1 of family 4 UDGa and in the QD doublet in motif 1 of family 1 UNG. Conversion of EG doublet in family 4 Thermus thermophilus UDGa to QD doublet increases the catalytic efficiency by over one hundred-fold and seventeen-fold over the E41Q and G42D single mutation, respectively, rectifying the strong correlation in the doublet. Molecular dynamics simulations suggest that the correlated mutations in the doublet in motif 1 position the catalytic H155 in motif 2 to stabilize the leaving uracilate anion. The integrated approach has important implications in studying enzyme evolution and protein structure and function. PMID:28397787

  15. Single nucleotide polymorphisms in uracil-processing genes, intake of one-carbon nutrients and breast cancer risk

    Science.gov (United States)

    Background/Objectives: The misincorporation of uracil into DNA leads to genomic instability. In a previous study, some of us identified four common single nucleotide polymorphisms (SNPs) in uracil-processing genes (rs2029166 and rs7296239 in SMUG1, rs34259 in UNG and rs4775748 in DUT) that were asso...

  16. QSAR Studies of 6-Amino Uracil Base Analogues: A Thymidine Phosphorylase Inhibitor in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Surya Prakash B. N. Gupta

    2008-01-01

    Full Text Available A novel series of 6-amino uracil base analogue were synthesized. QSAR study was used to relate the selective nonsubstrate inhibitory activity of 6-amino uracil base analogue with various physicochemical descriptors. Stepwise multiple regression analysis was performed to find out the correlation between various physicochemical descriptors and biological activity of the compounds by using Openstat 2 version 6.5.1 and valstat statistical software. Out of the several equations developed, the best equation having the highest significance was selected for further study. The equation is able to explain 60% of total variance and are more than 95% significant as revealed by the F value.

  17. Highly charged ion impact on uracil: Cross sections measurements and scaling

    Science.gov (United States)

    Agnihotri, A. N.; Kasthurirangan, S.; Champion, C.; Rivarola, R. D.; Tribedi, L. C.

    2014-04-01

    Absolute total ionization cross sections (TCS) of uracil in collisions with highly charge C, O and F ions are measured. The scaling properties of cross sections are obtained as a function of projectile charge state and energy. The measurements are compared with the CDW-EIS, CB1 and CTMC calculations. The absolute double differential cross sections (DDCS) of secondary electron emission from uracil in collisions with bare MeV energy C and O ions are also measured. Large enhancement in forward emission is observed.

  18. Accurate DNA assembly and genome engineering with optimized uracil excision cloning

    DEFF Research Database (Denmark)

    Cavaleiro, Mafalda; Kim, Se Hyeuk; Seppala, Susanna

    2015-01-01

    Simple and reliable DNA editing by uracil excision (a.k.a. USER cloning) has been described by several research groups, but the optimal design of cohesive DNA ends for multigene assembly remains elusive. Here, we use two model constructs based on expression of gfp and a four-gene pathway that pro......Simple and reliable DNA editing by uracil excision (a.k.a. USER cloning) has been described by several research groups, but the optimal design of cohesive DNA ends for multigene assembly remains elusive. Here, we use two model constructs based on expression of gfp and a four-gene pathway...

  19. Different organization of base excision repair of uracil in DNA in nuclei and mitochondria and selective upregulation of mitochondrial uracil-DNA glycosylase after oxidative stress

    DEFF Research Database (Denmark)

    Akbari, M; Otterlei, M; Pena Diaz, Javier

    2007-01-01

    , indicating regulatory effects of oxidative stress on mitochondrial BER. To examine the overall organization of uracil-BER in nuclei and mitochondria, we constructed cell lines expressing EYFP (enhanced yellow fluorescent protein) fused to UNG1 or UNG2. These were used to investigate the possible presence...... of multi-protein BER complexes in nuclei and mitochondria. Extracts from nuclei and mitochondria were both proficient in complete uracil-BER in vitro. BER assays with immunoprecipitates demonstrated that UNG2-EYFP, but not UNG1-EYFP, formed complexes that carried out complete BER. Although apurinic....../apyrimidinic site endonuclease 1 (APE1) is highly enriched in nuclei relative to mitochondria, it was apparently the major AP-endonuclease required for BER in both organelles. APE2 is enriched in mitochondria, but its possible role in BER remains uncertain. These results demonstrate that nuclear and mitochondrial...

  20. Observed and predicted hydrogen bond motifs in crystal structures of hydantoins, dihydrouracils and uracils

    NARCIS (Netherlands)

    Cruz-Cabeza, A.J.; Schwalbe, C.H.

    2012-01-01

    A survey of crystal structures containing hydantoin, dihydrouracil and uracil derivatives in the Cambridge Structural Database revealed four main types of hydrogen bond motifs when derivatives with extra substituents able to interfere with the main motif are excluded. All these molecules contain two

  1. Cq+-induced excitation and fragmentation of uracil : effects of the projectile electronic structure

    NARCIS (Netherlands)

    de Vries, J.; Hoekstra, R.A.; Morgenstern, R.W.H.; Schlathölter, T.A.

    2002-01-01

    Ionization and fragmentation of the RNA base uracil (C4H4N2O2) by means of Cq+ ions (q = 1-6) has been studied for ion kinetic energies ranging from ;2 to 120 keV. Whereas for Cq+ (q = 1, 3, 4, 5, 6) very similar fragmentation yields are observed which increase with the projectile velocity v, C2+

  2. Compartmentalized self-replication (CSR) selection of Thermococcus litoralis Sh1B DNA polymerase for diminished uracil binding.

    Science.gov (United States)

    Tubeleviciute, Agne; Skirgaila, Remigijus

    2010-08-01

    The thermostable archaeal DNA polymerase Sh1B from Thermococcus litoralis has a typical uracil-binding pocket, which in nature plays an essential role in preventing the accumulation of mutations caused by cytosine deamination to uracil and subsequent G-C base pair transition to A-T during the genomic DNA replication. The uracil-binding pocket recognizes and binds uracil base in a template strand trapping the polymerase. Since DNA replication stops, the repair systems have a chance to correct the promutagenic event. Archaeal family B DNA polymerases are employed in various PCR applications. Contrary to nature, in PCR the uracil-binding property of archaeal polymerases is disadvantageous and results in decreased DNA amplification yields and lowered sensitivity. Furthermore, in diagnostics qPCR, RT-qPCR and end-point PCR are performed using dNTP mixtures, where dTTP is partially or fully replaced by dUTP. Uracil-DNA glycosylase treatment and subsequent heating of the samples is used to degrade the DNA containing uracil and prevent carryover contamination, which is the main concern in diagnostic laboratories. A thermostable archaeal DNA polymerase with the abolished uracil binding would be a highly desirable and commercially interesting product. An attempt to disable uracil binding in DNA polymerase Sh1B from T. litoralis by generating site-specific mutants did not yield satisfactory results. However, a combination of random mutagenesis of the whole polymerase gene and compartmentalized self-replication was successfully used to select variants of thermostable Sh1B polymerase capable of performing PCR with dUTP instead of dTTP.

  3. Effects of protonation and C5 methylation on the electrophilic addition reaction of cytosine: a computational study.

    Science.gov (United States)

    Jin, Lingxia; Wang, Wenliang; Hu, Daodao; Min, Suotian

    2013-01-10

    The mechanism for the effects of protonation and C5 methylation on the electrophilic addition reaction of Cyt has been explored by means of CBS-QB3 and CBS-QB3/PCM methods. In the gas phase, three paths, two protonated paths (N3 and O2 protonated paths B and C) as well as one neutral path (path A), were mainly discussed, and the calculated results indicate that the reaction of the HSO(3)(-) group with neutral Cyt is unlikely because of its high activation free energy, whereas O2-protonated path (path C) is the most likely to occur. In the aqueous phase, path B is the most feasible mechanism to account for the fact that the activation free energy of path B decreases compared with the corresponding path in the gas phase, whereas those of paths A and C increase. The main striking results are that the HSO(3)(-) group directly interacts with the C5═C6 bond rather than the N3═C4 bond and that the C5 methylation, compared with Cyt, by decreasing values of global electrophilicity index manifests that C5 methylation forms are less electrophilic power as well as by decreasing values of NPA charges on C5 site of the intermediates make the trend of addition reaction weaken, which is in agreement with the experimental observation that the rate of 5-MeCyt reaction is approximately 2 orders of magnitude slower than that of Cyt in the presence of bisulfite. Apart from cis and trans isomers, the rare third isomer where both the CH(3) and SO(3) occupy axial positions has been first found in the reactions of neutral and protonated 5-MeCyt with the HSO(3)(-) group. Furthermore, the transformation of the third isomer from the cis isomer can occur easily.

  4. GRAFT POLYMERIZATION OF ACRYLAMIDE ONTO HOMOPOLYMER OF 5-METHYL-5-HEXEN-2, 4-DIONE INITIATED BY CERIC ION

    Institute of Scientific and Technical Information of China (English)

    ZHAO Jingbo; ZHAO Tong; QIU Kunyuan

    1997-01-01

    The homopolymerization of 5-methyl-5-hexen-2,4-dione (methacryloylacetone, MAA),a vinyl monomer having β-diketone group, was carried out in the presence of benzophenone (BP)/N, N-dimenthyl-4-toluidine (DMT) system. Graft polymerization of acrylamide initiated by ceric ion onto the homopolymer film was investigated and the mechanism of the grafting reaction was proposed on the basis of ESR study. The grafted copolymer was characterized by means of grafting percentage, water absorption, XPS spectra and scanning electron photomicrographs.

  5. Uracil phosphoribosyltransferase from the extreme thermoacidophilic archaebacterium Sulfolobus shibatae is an allosteric enzyme, activated by GTP and inhibited by CTP

    DEFF Research Database (Denmark)

    Linde, Lise; Jensen, Kaj Frank

    1996-01-01

    -fold without much effect on Km for the substrates. The concentration of GTP required for half-maximal activation was about 80 µM. CTP was a strong inhibitor and acted by raising the concentration of GTP needed for half-maximal activation of the enzyme. We conclude that uracil phosphoribosyltransferase......Uracil phosphoribosyltransferase, which catalyses the formation of UMP and pyrophosphate from uracil and 5-phosphoribosyl a-1-pyrophosphate (PRPP), was partly purified from the extreme thermophilic archaebacterium Sulfolobus shibatae. The enzyme required divalent metal ions for activity...... and it showed the highest activity at pH 6.4. The specific activity of the enzyme was 50-times higher at 95°C than at 37°C, but the functional half-life was short at 95°C. The activity of uracil phosphoribosyltransferase was strongly activated by GTP, which increased Vmax of the reaction by approximately 20...

  6. A computational study of adenine, uracil, and cytosine adsorption upon AlN and BN nano-cages

    Energy Technology Data Exchange (ETDEWEB)

    Baei, Mohammad T. [Department of Chemistry, Islamic Azad University, Azadshahr Branch, Azadshahr, Golestan (Iran, Islamic Republic of); Taghartapeh, Mohammad Ramezani [Young Researchers and Elite Club, Islamic Azad University, Gorgan Branch, Gorgan (Iran, Islamic Republic of); Lemeski, E. Tazikeh [Department of Chemistry, Islamic Azad University, Gorgan Branch, Gorgan (Iran, Islamic Republic of); Soltani, Alireza, E-mail: alireza.soltani46@yahoo.com [Young Researchers and Elite Club, Islamic Azad University, Gorgan Branch, Gorgan (Iran, Islamic Republic of)

    2014-07-01

    Density-functional theory calculations are used to investigate the interaction of Al{sub 12}N{sub 12} and B{sub 12}N{sub 12} clusters with the adenine (A), uracil (U), and cytosine (C) molecules. The current calculations demonstrate that these hybrid adsorbent materials are able to adsorb the adenine, uracil, and cytosine molecules through exothermic processes. Our theoretical results reveal improvement in the adsorption of adenine, uracil, and cytosine on Al{sub 12}N{sub 12} and B{sub 12}N{sub 12}. It is observed that B{sub 12}N{sub 12} is highly sensitive to adenine, uracil, and cytosine compared with Al{sub 12}N{sub 12} to serve as a biochemical sensor.

  7. Aldol Reactions of Axially Chiral 5-Methyl-2-(o-arylimino-3-(o-aryl-thiazolidine-4-ones

    Directory of Open Access Journals (Sweden)

    Sule Erol Gunal

    2016-06-01

    Full Text Available Axially chiral 5-methyl-2-(o-arylimino-3-(o-aryl-thiazolidine-4-ones have been subjected to aldol reactions with benzaldehyde to produce secondary carbinols which have been found to be separable by HPLC on a chiral stationary phase. Based on the reaction done on a single enantiomer resolved via a chromatographic separation from a racemic mixture of 5-methyl-2-(α-naphthylimino-3-(α-naphthyl-thiazolidine-4-one by HPLC on a chiral stationary phase, the aldol reaction was shown to proceed via an enolate intermediate. The axially chiral enolate of the thiazolidine-4-one was found to shield one face of the heterocyclic ring rendering face selectivity with respect to the enolate. The selectivities observed at C-5 of the ring varied from none to 11.5:1 depending on the size of the ortho substituent. Although the aldol reaction proceeded with a lack of face selectivity with respect to benzaldehyde, recrystallization returned highly diastereomerically enriched products.

  8. Synthesis and antiprotozoal activity of mono- and bis-uracil isatin conjugates against the human pathogen Trichomonas vaginalis.

    Science.gov (United States)

    Kumar, Kewal; Liu, Nicole; Yang, Donald; Na, Daniel; Thompson, John; Wrischnik, Lisa A; Land, Kirkwood M; Kumar, Vipan

    2015-08-15

    A library of mono- and bis-uracil isatin conjugates were synthesized and subjected for the assessment of their in vitro activity against the protozoal pathogen Trichomonas vaginalis. The structure activity studies (SAR) revealed that the bis-uracil-isatin based conjugates were more effective than their corresponding mono conjugates in inhibiting the growth of T. vaginalis at approximately 10 μM with no visual effect on mammalian cells at the same concentration.

  9. Platinum(IV) complexes with some derivatives of 5-methyl-5-(4-pyridyl) hydantoin. Synthesis, study and comparative pharmacological investigation.

    Science.gov (United States)

    Bakalova, A; Buyukliev, R; Ivanova, Z; Momekov, G; Ivanov, D

    2013-08-01

    3 Pt(IV) complexes with 3-ethyl-5-methyl-5-(4-pyridyl)hydantoin (4), 3-propyl-5-methyl-5-(4-pyridyl)hydantoin (5) and 3-benzyl-5-methyl-5-(4-pyridyl)hydantoin (6) with general formulae cis-[Pt(L)2Cl4] were synthesized. The novel compounds were characterized by elemental analysis, IR, 1H, 13C, NMR spectra in solid state and in solution. The studies showed that the ligands coordinate to the platinum ions in a monodentate manner through the nitrogen atom from the pyridine ring. The cytotoxic activity in vitro of newly synthesized complexes as well as their previously prepared analogous of Pt(IV) with other derivatives like 3-amino-5-methyl-5-(4-pyridyl)hydantoin (1), 5-methyl-5-(4-pyridyl)hydantoin (2), 3,5-dimethyl-5-(4-pyridyl)hydantoin (3) was screened against a panel of human tumor cell lines. The tested compounds displayed cytotoxic activity which was invariably superior with the Pt(IV) complex with 3-benzyl-5-methyl-5-(4-pyridyl)hydantoin (6) causing 50% inhibition of cellular viability at micromolar concentration, though the activity of the other studied Pt(IV) complexes proved to greatly decrease in the order 5-4-3-2-1. © Georg Thieme Verlag KG Stuttgart · New York.

  10. The Photochemistry of Pyrimidine in Pure H2O Ice Subjected to Different Radiation Environments and the Formation of Uracil

    Science.gov (United States)

    Nuevo, M.; Chen, Y.-J.; Materese. C. K..; Hu, W.-J.; Qiu, J.-M.; Wu, S.-R.; Fung, H.-S.; Sandford, S. A.; Chu, C.-C.; Yih, T.-S.; Wu, R.; Ip, W.-H.

    2013-01-01

    Nucleobases are N-heterocycles which are the informational subunits of DNA and RNA. They include pyrimidine bases (uracil, cytosine, and thymine) and purine bases (adenine and guanine). Nucleobases have been detected in several meteorites, although no Nheterocycles have been observed in space to data. Laboratory experiments showed that the ultraviolet (UV) irradiation of pyrimidine in pure H2O ice at low temperature (<=20 K) leads to the formation of pyrimidine derivatives including the nucleobase uracil and its precursor 4(3H)-pyrimidone. These results were confirmed by quantum chemical calculations. When pyrimidine is mixed with combinations of H2O, NH3, CH3OH, and CH4 ices under similar conditions, uracil and cytosine are formed. In the present work we study the formation of 4(3H)-pyrimidone and uracil from the irradiation of pyrimidine in H2O ice with high-energy UV photons (Lyman , He I, and He II lines) provided by a synchrotron source. The photo-destruction of pyrimidine in these H2O ices as well as the formation yields for 4(3H)-pyrimidone and uracil are compared with our previous results in order to study the photo-stability of pyrimidine and the production efficiency of uracil as a function of the photon energy.

  11. Study of the Molecular Recognition of Nucleotides and Bases by a Novel Calixarene Derivative Containing Uracil

    Institute of Scientific and Technical Information of China (English)

    SHI,Hui-Jie; SHI,Xian-Fa; YAO,Tian-Ming; JI,Liang-Nian

    2008-01-01

    A calix[4]arene derivative containing uracil, 5-(uracil-N1-acetamido)-25,26,27,28-tetrahy droxycalix[4]-arene (UC), was designed and synthesized. The interaction with nucleotides and bases has also been studied by ESI-MS and π-A isotherms. The results of ESI-MS showed that UC could recognize adenine and adenosine from other nucleotides and bases. In addition, π-A isotherms at the air-water interface indicated that there was interaction between UC and the species in the subphase, and the respective complexes were formed in the monolayer. The mean molecular area at zero surface pressure increased with the sizes of the nucleotides and bases in the subphase in the order: water<adenine<adenosine<ATP·Na2.

  12. Uracil Grafted Carbon Electrode: Electrocatalytic Behavior of Tryptophan, Tyrosine, Catecholamine and Related Compounds

    Institute of Scientific and Technical Information of China (English)

    LIN Xiang-Qin; KANG Guang-Feng; ZHU Xiao-Hong

    2008-01-01

    A uracil grafted glassy carbon electrode (Ura/GCE) was fabricated and characterized by X-ray photoelectron spectroscopy (XPS), cyclic voltammertry (CV) and differential pulse voltammetry (DPV) techniques. The electrochemical behavior of tryptophan (Trp), tyrosine (Tyr), catecholamine such as dopamine (DA), epinephrine (EP) and norepinephrine (NE), and related compounds involving uric acid (UA) and ascorbic acid (AA) at the Ura/GCE was investigated. All these bioactive species could be electrocatalytically oxidized to generate very different current sensitivities. This electrode can be used as a versatile electrochemical sensor for DA, EP, NE, UA, Trp and Tyr determination. The DPV peak potential, current sensitivity, linear range and detection limit of these species were obtained and used for analysis of molecular interactions between uracil and those electroactive species. A mechanism for the surface accumulation was discussed.

  13. Electron-induced hydrogen loss in uracil in a water cluster environment

    Energy Technology Data Exchange (ETDEWEB)

    Smyth, M.; Kohanoff, J. [Atomistic Simulation Centre, Queen' s University Belfast, Belfast BT7 1NN, Northern Ireland (United Kingdom); Fabrikant, I. I., E-mail: ifabrikant1@unl.edu [Department of Physics and Astronomy, University of Nebraska, Lincoln, Nebraska 68588, USA and Department of Physical Sciences, The Open University, Walton Hall, Milton Keynes MK7 6AA (United Kingdom)

    2014-05-14

    Low-energy electron-impact hydrogen loss due to dissociative electron attachment (DEA) to the uracil and thymine molecules in a water cluster environment is investigated theoretically. Only the A{sup ′}-resonance contribution, describing the near-threshold behavior of DEA, is incorporated. Calculations are based on the nonlocal complex potential theory and the multiple scattering theory, and are performed for a model target with basic properties of uracil and thymine, surrounded by five water molecules. The DEA cross section is strongly enhanced when the attaching molecule is embedded in a water cluster. This growth is due to two effects: the increase of the resonance lifetime and the negative shift in the resonance position due to interaction of the intermediate negative ion with the surrounding water molecules. A similar effect was earlier found in DEA to chlorofluorocarbons.

  14. Theoretical DFT and experimental NMR studies on uracil and 5-fluorouracil

    Science.gov (United States)

    Blicharska, Barbara; Kupka, Teobald

    2002-08-01

    The results of extended MO calculations using density functional theory (DFT) approximation and multinuclear HR NMR studies on uracil (U) and 5-fluorouracil (5FU) are reported. The performance of the B3PW91 hybrid density functional was compared with the ab initio restricted Hartree-Fock (RHF) method. With the basis set 6-31G ∗, or better quality, the DFT calculated bond lengths, dipole moments and harmonic stretching vibrations were predicted in good agreement with available experimental data. Structure and harmonic vibrations of U and 5FU were also calculated in the presence of water within a simple Onsager model. A linear correlation between proton and carbon GIAO NMR shieldings of uracil and 5FU and experimental data was shown.

  15. Action of uracil analogs on human immunodeficiency virus type 1 and its reverse transcriptase.

    OpenAIRE

    Piras, G; Dutschman, G E; Im, G J; B.C. Pan; Chu, S H; Cheng, Y C

    1995-01-01

    Three structural analogs of 5-ethyl-1-benzyloxymethyl-6-(phenylthio)uracil (E-BPU) inhibited human immunodeficiency virus type 1 (HIV-1) replication without cytotoxicity in vitro and were more potent than azidothymidine and were as potent as E-BPU. The target of these compounds is HIV-1 reverse transcriptase. Reverse transcriptases resistant to nevirapine (tyrosine at position 181 to cysteine) and TIBO R82150 (leucine at position 100 to isoleucine) are cross resistant to E-BPU analogs. Nevira...

  16. UV-Photodimerization in Uracil-substituted dendrimers for high density data storage

    DEFF Research Database (Denmark)

    Lohse, Brian; Vestberg, Robert; Ivanov, Mario Tonev

    2007-01-01

    Two series of uracil-functionalized dendritic macromolecules based on poly (amidoamine) PAMAM and 2,2-bis(hydroxymethylpropionic acid) bis-MPA backbones were prepared and their photoinduced (2 pi+2 pi) cycloaddition reactions upon exposure to UV light at 257 nm examined. Dendrimers up to 4th...... nm with an intensity of 70 mW/cm(2) could be obtained suggesting future use as recording media for optical data storage. (c) 2007 Wiley Periodicals, Inc....

  17. Cq+-induced excitation and fragmentation of uracil : effects of the projectile electronic structure

    NARCIS (Netherlands)

    Hoekstra, R; Morgenstern, R; Schlatholter, T

    2002-01-01

    Ionization and fragmentation of the RNA base uracil (C4H4N2O2) by means of Cq+ ions (q = 1-6) has been studied for ion kinetic energies ranging from ;2 to 120 keV. Whereas for Cq+ (q = 1, 3, 4, 5, 6) very similar fragmentation yields are observed which increase with the projectile velocity v, C2+ io

  18. Proton-induced ionization of isolated uracil molecules: A theory/experiment confrontation

    Energy Technology Data Exchange (ETDEWEB)

    Champion, C., E-mail: champion@cenbg.in2p3.fr [Université Bordeaux 1, CNRS/IN2P3, Centre d’Etudes Nucléaires de Bordeaux-Gradignan, CENBG (France); Galassi, M.E. [Instituto de Física Rosario, CONICET and Universidad Nacional de Rosario (Argentina); Weck, P.F. [Department of Chemistry and Harry Reid Center for Environmental Studies, University of Nevada Las Vegas (United States); Incerti, S. [Université Bordeaux 1, CNRS/IN2P3, Centre d’Etudes Nucléaires de Bordeaux-Gradignan, CENBG (France); Rivarola, R.D.; Fojón, O. [Instituto de Física Rosario, CONICET and Universidad Nacional de Rosario (Argentina); Hanssen, J. [Laboratoire de Physique Moléculaire et des Collisions, UMR CNRS 7565, Université de Lorraine (France); Iriki, Y.; Itoh, A. [Department of Nuclear Engineering, Kyoto University, Kyoto 606-8501 (Japan)

    2013-11-01

    Proton-induced ionization of RNA-uracil target is here theoretically described by two quantum-mechanical models, namely, a first perturbative one developed within the 1st Born approximation and a second one based on the continuum distorted wave approximation. Comparisons between theory and experiments are reported in terms of differential as well as total cross sections exhibiting a very good agreement for the kinematics here investigated.

  19. Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase.

    Science.gov (United States)

    Kronenberg, Golo; Harms, Christoph; Sobol, Robert W; Cardozo-Pelaez, Fernando; Linhart, Heinz; Winter, Benjamin; Balkaya, Mustafa; Gertz, Karen; Gay, Shanna B; Cox, David; Eckart, Sarah; Ahmadi, Michael; Juckel, Georg; Kempermann, Gerd; Hellweg, Rainer; Sohr, Reinhard; Hörtnagl, Heide; Wilson, Samuel H; Jaenisch, Rudolf; Endres, Matthias

    2008-07-09

    Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung-/- embryonic fibroblasts, and conferred death of cultured Ung-/- hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung-/- but not Ung+/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung-/- mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency.

  20. Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties.

    Science.gov (United States)

    Segal, Meirav; Fischer, Bilha

    2012-02-28

    Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

  1. Diaqua-(5-methyl-1H-pyrazole-3-carboxyl-ato)(4-nitro-benzoato)copper(II).

    Science.gov (United States)

    Hu, Fei-Long; Yin, Xian-Hong; Feng, Yu; Mi, Yan; Zhang, Shan-Shan

    2009-01-23

    In the title complex, [Cu(C(7)H(4)NO(4))(C(5)H(5)N(2)O(2))(H(2)O)(2)], the Cu(II) ion is coordinated in a slightly distorted square-pyramidal enviroment. The basal plane is formed by an N atom and an O atom from a 5-methyl-1H-pyrazole-3-carboxyl-ate ligand and by two O atoms from two water ligands. The apical position is occupied by a carboxylate O atom from a 4-nitro-benzoate ligand. In the crystal structure, inter-molecular O-H⋯O and N-H⋯O hydrogen bonds link complex moleclues, forming extended chains parallel to the a axis.

  2. Synthesis and Herbicidal Activities of Novel 4-(4-(5-methyl-3-arylisoxazol-4-ylthiazol-2-ylpiperidyl Carboxamides and Thiocarboxamides

    Directory of Open Access Journals (Sweden)

    Ai-Dong Zhang

    2009-03-01

    Full Text Available A series of novel 4-(4-(5-methyl-3-arylisoxazol-4-ylthiazol-2-ylpiperidyl carboxamides and thiocarboxamides were synthesized as potential lead compounds of inhibitors targeting D1 protease in plants. These compounds were designed on the basis of a D1 protease inhibitor hit structure identified by homology modeling and virtual screening. The syntheses of these compounds were accomplished via a four-step procedure including the isoxazole ring formation, a-bromination of acetyl group, thiazole ring formation, and carboxamide/thiocarboxamide attachment. The in vivo herbicidal activity tests show that most compounds possess moderate to good herbicidal activities. The enzyme activity of one compound against the native spinach D1 protease exhibits a competitive inhibition. The results suggest that these compounds are indeed potential inhibitors for targeting D1 protease in plants.

  3. Enamine Configuration of 5-Methyl-2-phenyl-4-[(Z)-3-tolylamino-phenylmethylene]pyrazol-3(2H)-one

    Institute of Scientific and Technical Information of China (English)

    QIAO Yu-Qin; Lü Xing-Qiang; BAO Feng; KANG Bei-Sheng

    2005-01-01

    Compound 5-methyl-2-phenyl-4-[(Z)-3-tolylamino-phenylmethylene]pyrazol-3(2H)-c = 12.035(4)(。A), α = 97.896(6), β = 103.865(6), γ = 107.950(6)°, Mr= 367.44, Z = 2, V= 993.2(6)(。A)3,Dc = 1.229 g/cm3,μ(MoKα) = 0.077 mm 1 and F(000) = 388.The structure was refined to R =0.0444 and wR = 0.1199 for 2903 observed reflections (I > 2σ(I)).The results of 1H NMR and single-crystal X-ray diffraction studies showed the enamine character of the compound.The strong intramolecular hydrogen bonds in the large conjugate system, together with weak intermolecular supramolecular network.

  4. The thermodynamic contribution of the 5-methyl group of thymine in the two- and three-stranded complexes formed by poly(dU) and poly(dT) with poly(dA).

    Science.gov (United States)

    Ross, Philip D; Howard, Frank B

    2003-02-01

    To assess the thermodynamic contribution of the 5-methyl group of thymine, we have studied the two-stranded helical complexes poly(dA).poly(dU) and poly(dA).poly(dT) and the three-stranded complexes--poly(dA).2poly(dU), poly(dA).poly(dT).poly(dU) and poly(dA).2poly(dT)--by differential scanning calorimetry, and uv optical melting experiments. The thermodynamic quantities associated with the 3 --> 2, 2 --> 1, and 3 --> 1 melting transitions are found to vary with salt concentration and temperature in a more complex manner than commonly believed. The transition temperatures, T(m), are generally not linear in the logarithm of concentration or activity of NaCl. The change in enthalpy and in entropy upon melting varies with salt concentration and temperature, and a change in heat capacity accompanies each transition. The poly(dA).2poly(dU) triple helix is markedly different from poly(dA).2poly(dT) in both its CD spectrum and thermodynamic behavior, while the poly(dA).poly(dT).poly(dU) triple helix resembles poly(dA).2poly(dT) in these properties. In comparing poly(dA).2poly(dT) with either the poly(dA).poly(dT).poly(dU) or the poly(dA).2poly(dU) triplexes, the substitution of thymine for uracil in the third strand results in an enhancement of stability against the 3 --> 2 dissociation of deltadeltaG degrees = -135 +/- 85 cal (mol A)(-1) at 37 degrees C. This represents a doubling of the absolute stability toward dissociation compared to the triplexes with poly(dU) as the third strand. The poly (dA).poly (dT) duplex is more stable than poly(dA).poly(dU) by deltadeltaG degrees = -350 +/- 60 cal (mol base pair)(-1) at 37 degrees C. Poly(dA).poly(dT) has 50% greater stability than poly(dA).poly(dU) as a result of the dT for dU substitution in the duplex.

  5. Action of uracil analogs on human immunodeficiency virus type 1 and its reverse transcriptase.

    Science.gov (United States)

    Piras, G; Dutschman, G E; Im, G J; Pan, B C; Chu, S H; Cheng, Y C

    1995-02-01

    Three structural analogs of 5-ethyl-1-benzyloxymethyl-6-(phenylthio)uracil (E-BPU) inhibited human immunodeficiency virus type 1 (HIV-1) replication without cytotoxicity in vitro and were more potent than azidothymidine and were as potent as E-BPU. The target of these compounds is HIV-1 reverse transcriptase. Reverse transcriptases resistant to nevirapine (tyrosine at position 181 to cysteine) and TIBO R82150 (leucine at position 100 to isoleucine) are cross resistant to E-BPU analogs. Nevirapine- or TIBO R82150-resistant HIV-1 were cross resistant to E-BPU analogs but were inhibited at concentrations 11- to 135-fold lower than the cytotoxic doses.

  6. Synthesis, characterization and application of new azo dyes derived from uracil for polyester fibre dyeing

    Science.gov (United States)

    Yazdanbakhsh, Mohamad-reza; Abbasnia, Masoumeh; Sheykhan, Mehdi; Ma'mani, Leila

    2010-08-01

    Some novel uracil derived azo compounds were synthesized by diazotization of substituted aromatic amines, amidine- and guanidine-like amines such as 2-aminopyridine and 2-aminopyrimidine, ortho-hydroxy aniline and ortho-hydroxy naphthyl amines and coupling reaction with 6-amino-1,3-dimethyluracil. Structures of the dyes were fully characterized by spectroscopic techniques (UV, 1H NMR, 13C NMR, CHN and IR). The dyes were applied to polyester, affording orange-yellow shades and the wash fastness of the dyeings was excellent.

  7. Biological evaluation of some uracil derivatives as potent glutathione reductase inhibitors

    Science.gov (United States)

    Güney, Murat; Ekinci, Deniz; Ćavdar, Huseyin; Şentürk, Murat; Zilbeyaz, Kani

    2016-04-01

    Discovery of glutathione reductase (GR) inhibitors has become very popular recently due to antimalarial and anticancer activities. In this study, GR inhibitory capacities of some uracil derivatives (UDCs) (1-4) were reported. Some commercially available molecules (5-6) were also tested for comparison reasons. The novel UDCs were obtained in high yields using simple chemical procedures and exhibited much potent inhibitory activities against GR at low nanomolar concentrations with IC50 values ranging from 2.68 to 166.6 nM as compared with well-known agents.

  8. Kinetic Mechanism of Uracil Phosphoribosyltransferase from Escherichia coli and Catalytic Importance of the Conserved Proline in the PRPP Binding Site

    DEFF Research Database (Denmark)

    Lundegaard, Claus; Jensen, Kaj Frank

    1999-01-01

    catalytic properties with the properties of the wild-type protein. We found that UPRTase of E. coli obeyed the kinetics of a sequential mechanism with the binding of PRPP preceding the binding of uracil. The basic kinetic constants were derived from initial velocity measurements, product inhibition......, and ligand binding assays. The change of Pro 131 to Asp caused a 50-60-fold reduction of the catalytic rate (kcat) in both directions of the reaction and approximately a 100-fold increase in the KM for uracil. The KM for PRPP was strongly diminished by the mutation, but kcat/KM,PRPP and the dissociation...... constant (KD,PRPP) were nearly unaffected. We conclude that the proline in the PRPP binding site of UPRTase is of only little importance for binding of PRPP to the free enzyme, but is critical for binding of uracil to the enzyme-PRPP complex and for the catalytic rate....

  9. FT-IR, Laser-Raman spectra and computational analysis of 5-Methyl-3-phenylisoxazole-4-carboxylic acid

    Science.gov (United States)

    Sert, Yusuf; Mahendra, M.; Keskinoğlu, S.; Chandra; Srikantamurthy, N.; Umesha, K. B.; Çırak, Ç.

    2015-03-01

    In this study the experimental and theoretical vibrational frequencies of a newly synthesized anti-tumor, antiviral, hypoglycemic, antifungal and anti-HIV agent namely, 5-Methyl-3-phenylisoxazole-4-carboxylic acid has been investigated. The experimental FT-IR (4000-400 cm-1) and Laser-Raman spectra (4000-100 cm-1) of the molecule in solid phase have been recorded. The theoretical vibrational frequencies and optimized geometric parameters (bond lengths, bond angles and torsion angles) have been calculated by using density functional theory (DFT/B3LYP: Becke, 3-parameter, Lee-Yang-Parr and DFT/M06-2X: highly parametrized, empirical exchange correlation function) with 6-311++G(d,p) basis set by Gaussian 09W software, for the first time. The assignments of the vibrational frequencies have been done by potential energy distribution (PED) analysis by using VEDA 4 software. The theoretical optimized geometric parameters and vibrational frequencies have been found to be in good agreement with the corresponding experimental data and results in the literature. In addition, the highest occupied molecular orbital (HOMO) energy, the lowest unoccupied molecular orbital (LUMO) energy and the other related molecular energy values of the compound have been investigated by using the same theoretical calculations.

  10. Dimer of Bis[trans-5-methyl-2-[2-(4-methoxylphenyl) ethenyl]-benzoxazole]di-μ-nitratosilver(I)

    Institute of Scientific and Technical Information of China (English)

    LIU Hui-Min; ZHANG Wei; XIN Ying; ZHANG Wen-Qin

    2004-01-01

    The title complex [AgNO3(C17H15NO2)2]2 was synthesized and characterized by X-ray diffraction analysis. The compound crystallizes in triclinic, space group Pī with a = 11.226(7), b = 11.906(7), c = 12.144(7) (A。), α = 99.796(10), β = 91.631(10), γ = 101.225(10)°, V = 1565.6(16)(A。)3, Z = 1, Mr = 1400.96, Dc = 1.486 g/cm3, F(000) = 716 and μ(Mo-Kα) = 0.697 mm-1. The final R and wR are 0.0401 and 0.0995, respectively for 5492 independent observable reflections with I > 2σ(I). The results show that the central Ag atom is four-coordinated with two O atoms from two distinct NO3- anions and two N atoms from two trans-5-methyl-2-[2-(4-methoxylphenyl)ethenyl]- benzoxazole ligands, and the two Ag atoms bridged with two O atoms give an interesting Ag-O-Ag-O parallelogram structure. The coordination sphere of Ag atom exhibits a heavily distorted tetrahedral geometry and the coordination angles lie in the range of 66.73(12)~129.59(10)°. The intra- molecular dihedral angles between the benzoxazolyl and phenyl planes are 4.1(3) and 2.9(3)°, respectively.

  11. Self-assembly of extended structures through non-coordination intermolecular forces: Synthesis, crystal structures, and properties of metal complexes with 5-methyl-2-pyrazinecarboxylate

    NARCIS (Netherlands)

    Tanase, S.; Son, M. van; Albada, G.A. van; Gelder, R. de; Bouwman, E.; Reedijk, J.

    2006-01-01

    Three new complexes of 5-methyl-2-pyrazinecarboxylate (Hmpca) with cobalt(II), [Co(mpca)(2)(H2O)(2)], nickel(II), [Ni(mpca)(2)(H2O)(2)] and iron(III) [Fe(mpca)(2)(OH)](2) center dot 2H(2)O, have been synthesized and characterized by spectroscopic techniques, X-ray crystallography and low-temperature

  12. Polymerase recognition of 2-thio-iso-guanine·5-methyl-4-pyrimidinone (iGs·P)--A new DD/AA base pair.

    Science.gov (United States)

    Lee, Dong-Kye; Switzer, Christopher

    2016-02-15

    Polymerase specificity is reported for a previously unknown base pair with a non-standard DD/AA hydrogen bonding pattern: 2-thio-iso-guanine·5-methyl-4-pyrimidinone. Our findings suggest that atomic substitution may provide a solution for low fidelity previously associated with enzymatic copying of iso-guanine.

  13. Classical treatment of the electron emission from collisions of uracil molecules with fast protons

    Science.gov (United States)

    Sarkadi, L.

    2015-12-01

    The electron emission from the uracil molecule induced by fast proton impact has been investigated using the classical-trajectory Monte Carlo (CTMC) method. Applying the independent-particle model, the full three-body dynamics of the projectile, an active electron, and the molecule core is considered. The interactions with the molecule core are described by a multicenter potential built from screened atomic potentials. Double and single differential, as well as total ionization cross sections are calculated and compared with the predictions of the first Born approximation with correct boundary conditions (CB1), the continuum-distorted-wave-eikonal-initial-state (CDW-EIS) approach, as well as the combined classical-trajectory Monte Carlo-classical over-the-barrier (CTMC-COB) model. The effect of the molecular treatment of the ionization by the multicenter potential is analyzed by simplified CTMC calculations in which the ionization cross section of the uracil is determined as a linear combination of the contributions of the constituent atoms of the molecule.

  14. Optical properties of organically functionalized silicon surfaces: Uracil-like nucleobases on Si(001)

    Science.gov (United States)

    Molteni, Elena; Cappellini, Giancarlo; Onida, Giovanni; Fratesi, Guido

    2017-02-01

    We predict UV reflectance anisotropy spectra (RAS) of the organically functionalized silicon (001) surface covered by pyrimidinic uracil-like nucleobases. First-principles results based on density functional theory show characteristic spectral features appearing in the UV range between 3 and 7 eV, besides the expected quench in the well-known two-minima RAS signal of clean Si(001). Nucleobase adsorption in the energetically favored "dimer bridge" configuration gives rise to a characteristic RAS line shape, common to thymine, uracil, and 5-fluorouracil. We trace back the origin of such spectral features by singling out RAS structures induced by relaxation and passivation effects on the Si surface, and those directly associated with molecular excitations. The former turn out to be the same for the three nucleobases, and are totally unaffected by molecular tilting. The sign and position of the latter RAS peaks at higher energy exhibit a moderate nucleobase dependence, and can be fully rationalized in terms of the molecular orbitals involved. The present theoretical results call for a RAS experimental study in the UV region extending up to ≃6 -7 eV.

  15. Generation of a recombinant single-chain variable fragment (scFv) targeting 5-methyl-2'-deoxycytidine.

    Science.gov (United States)

    Ohshima, Motohiro; Tadakuma, Tomomi; Hayashi, Hideki; Inoue, Kazuyuki; Itoh, Kunihiko

    2010-01-01

    We generated a single-chain variable fragment (scFv) against 5-methyl-2'-deoxycytidine (m(5)dCyd) using phage display technology. The heavy and light chain variable region genes were amplified by the polymerase chain reaction (PCR) from hybridoma cell line FMC9 and assembled as an scFv fragment with a flexible linker (Gly(4)-Ser)(3). The scFv DNA fragment was then cloned into pCANTAB-5E, and a phage displaying the scFv was produced. Antigen-positive phage clones were successfully selected by enzyme-linked immunosorbent assay (ELISA). The scFv was modified with FLAG and His tags for detection and purification. The scFv reacted strongly with m(5)dCyd and weakly with 5-methylcytidine (m(5)Cyd) but not with cytidine (Cyd) and 1-methyladenosine in a manner similar to the monoclonal antibody (MoAb). Although the specificities of scFv and MoAb were almost identical, the sensitivity of the scFv (IC(50) 0.054 microg/ml) was approximately 80 times higher than that of the parent MoAb (IC(50) 4.27 microg/ml), determined by inhibition ELISA. As a biochemical application of this scFv, we quantified the m(5)dCyd content of genomic DNA by enzymatic hydrolysis using inhibition ELISA. The cancer cell lines HeLa, HeLa S3 and MDA-MB-453 contained approximately 1% of the methylated DNA in total genomic DNA, as did peripheral blood cell genomic DNA from healthy volunteers, but HT29 and T-47D showed hypomethylation compared with the HeLa, HeLa S3 and MDA-MB-453 cell lines. The scFv generated here may be applicable to the assessment of cellular DNA methylation levels and is more sensitive than the MoAb.

  16. Synthesis of Novel Nucleoside Analog (3R)-2,3-Dideoxy-3- (N-hydroxy-N-methylamino)-L-arabinofuranosyl Uracil

    Institute of Scientific and Technical Information of China (English)

    Ji Cheng CHU; Hong Sheng GUO; Jun Biao CHANG; Kang ZHAO

    2004-01-01

    The synthesis of novel nucleoside analog (3R)-2,3-dideoxy-3-(N-hydroxy-N- methylamino)-L-arabinofuranosyl uracil was studied. A twelve-step synthetic route, started from L-ascorbic acid, was designed, and the final product was obtained in 20.8% yield.

  17. Eimeria tenella: parasite-specific incorporation of /sup 3/H-uracil as a quantitative measure of intracellular development

    Energy Technology Data Exchange (ETDEWEB)

    Schmatz, D.M.; Crane, M.S.; Murray, P.K.

    1986-02-01

    An assay has been developed using parasite-specific incorporation of /sup 3/H-uracil to assess the intracellular growth of Eimeria tenella in vitro. As shown by both scintillation counts and autoradiography, /sup 3/H-uracil was incorporated specifically into intracellular parasites from the onset of infection and continued throughout development of the first generation schizonts. Mature schizonts and first generation merozoites did not continue to incorporate additional /sup 3/H-uracil, indicating that RNA synthesis had halted in these stages. Based on these findings, a semi-automated microscale uracil incorporation assay was developed to determine parasite viability. This method should be useful for biochemical studies with intracellular parasites and for screening compounds for anticoccidial activity. The ease, rapidity, and quantitative nature of this assay contrasts favorably with standard morphometric approaches of determining parasite development. In addition, parallel studies using host cell incorporation of /sup 3/H-uridine have been introduced as a method of determining whether antiparasitic activity is direct or indirect in relation to effects on the host cell.

  18. Positive selection for uracil auxotrophs of the sulfur-dependent thermophilic archaebacterium Sulfolobus acidocaldarius by use of 5-fluoroorotic acid.

    OpenAIRE

    Kondo, S; Yamagishi, A; Oshima, T

    1991-01-01

    Uracil auxotrophs of Sulfolobus acidocaldarius were positively selected by using 5-fluoroorotic acid. The wild-type strain was unable to grow in medium containing 5-fluoroorotic acid, whereas the mutants grew normally. Positive selection could be done for the auxotrophs. Mutants deficient in orotidine-5'-monophosphate pyrophosphorylase activity were isolated.

  19. Time-resolved photoelectron imaging of the iodide-thymine and iodide-uracil binary cluster systems.

    Science.gov (United States)

    King, Sarah B; Yandell, Margaret A; Neumark, Daniel M

    2013-01-01

    The energetics and dynamics of thymine and uracil transient negative ions were examined using femtosecond time-resolved photoelectron imaging. The vertical detachment energies (VDEs) of these systems were found to be 4.05 eV and 4.11 eV for iodide-thymine (I(-) x T) and iodide-uracil (I(-) x U) clusters, respectively. An ultraviolet pump pulse was used to promote intracluster charge transfer from iodide to the nucleobase. Subsequent electron detachment using an infrared probe pulse monitored the dynamics of the resulting transient negative ion. Photoelectron spectra reveal two primary features: a near-zero electron kinetic energy signal attributed to autodetachment and a transient feature representing photodetachment from the excited anion state. The transient state exhibits biexponential decay in both thymine and uracil complexes with short and long decay time constants ranging from 150-600 fs and 1-50 ps, respectively, depending on the excitation energy. However, both time constants are systematically shorter for I(-) x T. Vibrational autodetachment and iodine loss are identified as the primary decay mechanisms of the transient negative ions of thymine and uracil.

  20. Is uracil aromatic? The enthalpies of hydrogenation in the gaseous and crystalline phases, and in aqueous solution, as tools to obtain an answer.

    Science.gov (United States)

    Galvão, Tiago L P; Rocha, Inês M; da Silva, Maria D M C Ribeiro; da Silva, Manuel A V Ribeiro

    2013-07-18

    The enthalpy of hydrogenation of uracil was derived from the experimental enthalpies of formation, in the gaseous phase, of uracil and 5,6-dihydrouracil, in order to analyze its aromaticity. The enthalpy of formation of 5,6-dihydrouracil was obtained from combustion calorimetry, Knudsen effusion technique and Calvet microcalorimetry results. High-level computational methods were tested for the enthalpy of hydrogenation of uracil, but only with G3 was possible to obtain results in agreement with the experimental ones. It was found that uracil possesses 30.0% of aromatic character in the gaseous phase. Using both implicit, explicit, and hybrid solvation methods, it was possible to obtain a reference value for the enthalpy of hydrogenation of uracil in the aqueous solution and the effect of polarity and hydrogen bonds on the aromaticity of uracil was analyzed. The value of the hydrogenation enthalpy of uracil in aqueous solution was compared with the experimental value in the crystal phase, also dominated by polarity and hydrogen bonds, derived from combustion calorimetry results. The supramolecular effects on the crystal lattice were explored by the computational simulation of π-π staking dimers and hydrogen bonded dimers.

  1. The Role of Sarcosine, Uracil, and Kynurenic Acid Metabolism in Urine for Diagnosis and Progression Monitoring of Prostate Cancer

    Science.gov (United States)

    Gkotsos, Georgios; Virgiliou, Christina; Lagoudaki, Ioanna; Sardeli, Chrysanthi; Raikos, Nikolaos; Theodoridis, Georgios; Dimitriadis, Georgios

    2017-01-01

    The aim of this pilot study is to evaluate sarcosine, uracil, and kynurenic acid in urine as potential biomarkers in prostate cancer detection and progression monitoring. Sarcosine, uracil, and kynurenic acid were measured in urine samples of 32 prostate cancer patients prior to radical prostatectomy, 101 patients with increased prostate-specific antigen prior to ultrasonographically-guided prostatic biopsy collected before and after prostatic massage, and 15 healthy volunteers (controls). The results were related to histopathologic data, Gleason score, and PSA (Prostate Specific Antigen). Metabolites were measured after analysis of urine samples with Ultra-High Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) instrumentation. Multivariate, nonparametric statistical tests including receiver operating characteristics analyses, one-way analysis of variance (Kruskal–Wallis test), parametric statistical analysis, and Pearson correlation, were performed to evaluate diagnostic performance. Decreased median sarcosine and kynurenic acid and increased uracil concentrations were observed for patients with prostate cancer compared to participants without malignancy. Results showed that there was no correlation between the concentration of the studied metabolites and the cancer grade (Gleason score <7 vs. ≥7) and the age of the patients. Evaluation of biomarkers by ROC (Receiving Operating Characteristics) curve analysis showed that differentiation of prostate cancer patients from participants without malignancy was not enhanced by sarcosine or uracil levels in urine. In contrast to total PSA values, kynurenic acid was found a promising biomarker for the detection of prostate cancer particularly in cases where collection of urine samples was performed after prostatic massage. Sarcosine and uracil in urine samples of patients with prostate cancer were not found as significant biomarkers for the diagnosis of prostate cancer. None of the

  2. The Role of Sarcosine, Uracil, and Kynurenic Acid Metabolism in Urine for Diagnosis and Progression Monitoring of Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Georgios Gkotsos

    2017-02-01

    Full Text Available The aim of this pilot study is to evaluate sarcosine, uracil, and kynurenic acid in urine as potential biomarkers in prostate cancer detection and progression monitoring. Sarcosine, uracil, and kynurenic acid were measured in urine samples of 32 prostate cancer patients prior to radical prostatectomy, 101 patients with increased prostate-specific antigen prior to ultrasonographically-guided prostatic biopsy collected before and after prostatic massage, and 15 healthy volunteers (controls. The results were related to histopathologic data, Gleason score, and PSA (Prostate Specific Antigen. Metabolites were measured after analysis of urine samples with Ultra-High Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS instrumentation. Multivariate, nonparametric statistical tests including receiver operating characteristics analyses, one-way analysis of variance (Kruskal–Wallis test, parametric statistical analysis, and Pearson correlation, were performed to evaluate diagnostic performance. Decreased median sarcosine and kynurenic acid and increased uracil concentrations were observed for patients with prostate cancer compared to participants without malignancy. Results showed that there was no correlation between the concentration of the studied metabolites and the cancer grade (Gleason score <7 vs. ≥7 and the age of the patients. Evaluation of biomarkers by ROC (Receiving Operating Characteristics curve analysis showed that differentiation of prostate cancer patients from participants without malignancy was not enhanced by sarcosine or uracil levels in urine. In contrast to total PSA values, kynurenic acid was found a promising biomarker for the detection of prostate cancer particularly in cases where collection of urine samples was performed after prostatic massage. Sarcosine and uracil in urine samples of patients with prostate cancer were not found as significant biomarkers for the diagnosis of prostate cancer

  3. Theoretical structural and vibrational study of 5-trifluoromethyluracil. A comparison with uracil

    Energy Technology Data Exchange (ETDEWEB)

    Rudyk, Roxana; Ramos, María E.; Checa, María A.; Brandán, Silvia A. [Cátedra de Química General, Instituto de Química Inorgánica, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho 471,(4000), San Miguel de Tucumán, Tucum and #x00E1 (Argentina); Chamorro, Eduardo E. [Facultad de Ciencias Exactas, Universidad Andrés Bello, Avda. República 275, 8370146, Santiago (Chile)

    2014-10-06

    In the present work, a comparative study on the structural and vibrational properties of the 5-trifluoromethyluracil (TFMU) derivative with those corresponding to uracil in gas and aqueous solution phases was performed combining the available H{sup 1}-NMR, C{sup 13}-NMR, F{sup 19}-NMR and FTIR spectra with Density Functional Theory (DFT) calculations. Three stable conformers were theoretically determined in both media by using the hybrid B3LYP/6-31G* method. The solvent effects were simulated by means of the self-consistent reaction field (SCRF) method employing the integral equation formalism variant (IEFPCM). Complete assignments of the vibrational spectra in both phases were performed combining the internal coordinates analysis and the DFT calculations with the Scaled Quantum Mechanics Force Field (SQMFF) methodology. The atomic charges, bond orders, solvation energies, dipole moments, molecular electrostatic potentials and force constants parameters were calculated for the three conformers of TFMU in gas phase and aqueous solution.

  4. Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Toru Ishikawa

    2008-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, including Japan.Although the development of imaging modalities has made the early diagnosis of HCC possible, surgically resectable cases are relatively uncommon because of hepatic function reserve and/or an advanced stage at presentation. Several modalities, such as transcatheter arterial chemoembolization, percutaneous ethanol injection, microwave coagulation therapy and radiofrequency ablation are reportedly useful in treating patients with non-resectable disease. However,unfortunately, many HCC patients have tumor recurrence.The overall prognosis of patients with HCC is very poor,and treatment of the advanced form is still problematic.In this article, we review the clinical efficacy and toxicity of enteric-coated tegafur/uracil in the treatment of patients with advanced non-resectable HCC.

  5. Anomalous high reactivity of formyl and acetone ketyl radicals with uracil and its derivatives

    Science.gov (United States)

    Aravindakumar, C. T.; Jacob, T. A.; Mohan, H.; Mahal, H. S.; Mukherjee, T.; Mittal, J. P.

    1998-05-01

    CO2·- and ( CH3) 2·COH radicals apparently react with uracil and its derivatives, containing two carbonyl groups, with high rate constants ( k=10 10 dm 3 mol -1 s -1). Various mechanistic aspects of such reactions have been probed. The effect of pH and buffer concentration on the initial formation of absorbance points to some keto-enol tautomerism-type fast-reaction between OH - and the substrate, followed by a slower relaxation to the original equilibrium. The radical anions of these compounds react with methyl viologen mainly via an electron transfer reaction with a high rate constant value (4-9)×10 9 dm 3 mol -1 s -1.

  6. Resolution, configurational assignment, and enantiopharmacology at glutamate receptors of 2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) and demethyl-ACPA

    DEFF Research Database (Denmark)

    Johansen, T N; Stensbøl, T B; Nielsen, B;

    2001-01-01

    We have previously described (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) as a potent agonist at the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtype of (S)-glutamic acid (Glu) receptors. We now report the chromatographic resolution...... of ACPA and (RS)-2-amino-3-(3-carboxy-4-isoxazolyl)propionic acid (demethyl-ACPA) using a Sumichiral OA-5000 column. The configuration of the enantiomers of both compounds have been assigned based on X-ray crystallographic analyses, supported by circular dichroism spectra and elution orders on chiral HPLC...... columns. Furthermore, the enantiopharmacology of ACPA and demethyl-ACPA was investigated using radioligand binding and cortical wedge electrophysiological assay systems and cloned metabotropic Glu receptors. (S)-ACPA showed high affinity in AMPA binding (IC(50) = 0.025 microM), low affinity in kainic acid...

  7. [An effective scheme to produce recombinant uracil-DNA glycosylase of Escherichia coli for PCR diagnostics].

    Science.gov (United States)

    Dmitrochenko, A E; Turiianskaia, O M; Gilep, A A; Usanov, S A; Iantsevich, A V

    2014-01-01

    An effective scheme has been developed to produce recombinant uracil-DNA glycosylase of Escherichia coli K12 intended to be used for PCR diagnostics, making it possible to achieve a high yield of the end product using a two-stage purification. The gene encoding this enzyme was cloned into the pCWori vector within the same reading frame with six residues of histidine in the C-erminal sequence. Using this vector and the E. coli DH5alpha, a host-vector expression system has been developed and conditions for protein synthesis have been optimized. To purify the protein, metal affinity chromatography with further dialysis was used to remove imidazole. The enzyme yield was no less than 60 mg of the end protein per 1 L of the culture medium. The concordance between amino acid sequences of the recombinant and native enzymes was proved by peptide mass fingerprinting and mass spectrometry. A rapid test to determine the activity of the enzyme preparation was suggested. It was found that the activity of 1.0 mg of the recombinant protein is no less than 3 x 10(3) units. The recombinant enzyme was most stable at pH 8.0 and an ionic strength of the solution equal to 200 mM; it lost its activity completely for 10 min at 60 degrees C. Storage during 1 h at 20 degrees C resulted in the loss of no more than 30% of activity. In the enzyme preparation, the activity of DNase was absent. The free energy of the unfolding of the protein globule of the recombinant uracil-DNA glycosylase is 23.1 +/- 0.2 kJ/mol. The data obtained indicate that the recombinant enzyme may be recommended for use in PCR diagnostics to prevent the appearance of false positive results caused by pollution of the reaction mixture by products of the preceding reactions.

  8. Synthesis and Antibacterial Activities of 4-Amino-3-( 1-aryl-5-methyl-1,2,3-triazol-4-yl)-5-mercapto-1,2,4- triazoles/2-Amino-5- ( 1- aryl-5- methyl- 1,2,3- triazol-4- yl )- 1,3,4- thiadiazoles and Their Derivatives

    Institute of Scientific and Technical Information of China (English)

    ZHANG,Yan(张艳); SUN,Xiao-Wen(孙小文); HUI,Xin-Ping(惠新平); ZHANG,Zi-Yi(张自义); WANG,Qin(王勤); ZHANG,Qi(张琪)

    2002-01-01

    Treatment of 4-amino-3- (1-aryl-5-methyl-1,2, 3-triazol-4-yl)-5-mercapto-1, 2, 4-triazoles/2-amino-5-( 1-aryi-5-methyl-1, 2,3-triazol-4-yl)-1, 3,4-thiadiazoles with benzaldehyde, acetone and ω-bromoacetophenone was tested and compared. The title compounds Schiff bases, amides, imidazolo[2,1-b]-1,3,4-thiadiazoles and 7H-s-triazolo [3, 4-b ]-1, 3, 4-thiadiazines have been confirmed by elemental analyses, 1H NMR, IR and MS spectra. All the compounds have also been screened for their antibacterial activities against B. subtilis, S. aureus and E. coli.

  9. Potent Methyl Oxidation of 5-Methyl-2′-deoxycytidine by Halogenated Quinoid Carcinogens and Hydrogen Peroxide via a Metal-independent Mechanism

    OpenAIRE

    Shao, Jie; Huang, Chun-Hua; Kalyanaraman, Balaraman; Zhu, Ben-Zhan

    2013-01-01

    Halogenated quinones are a class of carcinogenic intermediates and newly identified chlorination disinfection byproducts in drinking water. We found recently that the highly reactive and biologically important hydroxyl radical (•OH) can be produced by halogenated quinones and H2O2 independent of transition metal ions. However, it is not clear whether these quinoid carcinogens and H2O2 can oxidize the nucleoside 5-methyl-2′-deoxycytidine (5mdC) to its methyl oxidation prod...

  10. Archaeal DNA Polymerase-B as a DNA Template Guardian: Links between Polymerases and Base/Alternative Excision Repair Enzymes in Handling the Deaminated Bases Uracil and Hypoxanthine

    Directory of Open Access Journals (Sweden)

    Javier Abellón-Ruiz

    2016-01-01

    Full Text Available In Archaea repair of uracil and hypoxanthine, which arise by deamination of cytosine and adenine, respectively, is initiated by three enzymes: Uracil-DNA-glycosylase (UDG, which recognises uracil; Endonuclease V (EndoV, which recognises hypoxanthine; and Endonuclease Q (EndoQ, (which recognises both uracil and hypoxanthine. Two archaeal DNA polymerases, Pol-B and Pol-D, are inhibited by deaminated bases in template strands, a feature unique to this domain. Thus the three repair enzymes and the two polymerases show overlapping specificity for uracil and hypoxanthine. Here it is demonstrated that binding of Pol-D to primer-templates containing deaminated bases inhibits the activity of UDG, EndoV, and EndoQ. Similarly Pol-B almost completely turns off EndoQ, extending earlier work that demonstrated that Pol-B reduces catalysis by UDG and EndoV. Pol-B was observed to be a more potent inhibitor of the enzymes compared to Pol-D. Although Pol-D is directly inhibited by template strand uracil, the presence of Pol-B further suppresses any residual activity of Pol-D, to near-zero levels. The results are compatible with Pol-D acting as the replicative polymerase and Pol-B functioning primarily as a guardian preventing deaminated base-induced DNA mutations.

  11. Theoretical Studies on the Binding of Cd~(2+) to Uracil and Its Thio-derivatives%Theoretical Studies on the Binding of Cd~(2+) to Uracil and Its Thio-derivatives

    Institute of Scientific and Technical Information of China (English)

    WANG Min; SA Rong-Jian; WU Ke-Chen; LI Qiao-Hong; WEI Yong-Qin

    2012-01-01

    The interaction of Cd2+ with uracil,2-thiouracil,4-thiouracil and 2,4-dithiouracil have been investigated by the density functional theory(DFT) calculations.For uracil and 2,4-dithiouracil,where the two basic sites are the same,Cd2+ attachment to the heteroatom at position 4 is preferred.However,for the systems where both types of basic centers,a carbonyl and a thiocarbonyl groups,are present,Cd2+ association with sulfur is favorable.The enhanced stability of these enolic and thiol forms comes from Cd2+ interaction with two basic sites simultaneously,which thereby triggers a significant aromatization of the ring.More significantly,the Cd2+ binding energy with uracil and its thio-derivatives is larger than the tautomerization barriers connecting the diketo-like forms with the corresponding enolic-like tautomers.Consequently,when associated with Cd2+,all tautomers are energetically accessible and should be observed in the gas phase.

  12. Different oligomeric states are involved in the allosteric behavior of uracil phosphoribosyltransferase from Escherichia coli

    DEFF Research Database (Denmark)

    Jensen, Kaj Frank; Mygind, Bente

    1996-01-01

    Uracil phosphoribosyltransferase, catalyzing the formation of UMP and pyrophosphate from uracil and 5-phosphoribosyl-a-1-diphosphate (PP RibP), was purified from an overproducing strain of Escherichia coli. GTP was shown to activate the enzyme by reducing Km for PP RibP by about fivefold without...... affecting Vmax. When started by addition of enzyme, the reactions accelerated over an extended period of time, while enzyme solutions incubated first with GTP and PP RibP displayed constant velocities. This indicated that PP RibP and GTP influenced the structure of the enzyme. Gel....... It appears that the smaller form predominates in the absence of substrates, while the larger form predominates in the presence of GTP and PP RibP. Guanosine-3',5'-bis(diphosphate) was found to activate the enzyme much like GTP....

  13. Stability of mutagenic tautomers of uracil and its halogen derivatives: the results of quantum-mechanical investigation

    OpenAIRE

    Hovorun D. M.; Brovarets’ O. O.

    2010-01-01

    Aim. To investigate using the quantum-mechanical methods uracil (Ura) intramolecular tautomerisation and the effect of the thymine (Thy) methyl (Me) group substitution by the halogen on that process. Methods. Non-empirical quantum mechanic, analysis of the electron density by means of Bader’s atom in molecules (AIM) theory and physicochemical kinetics were used. Results. For the first time it has been established that the substitution of thymine Me-group for the halogen (Br, F, Cl) has practi...

  14. A Cost Comparison of Oral Tegafur Plus Uracil/Folinic Acid and Parenteral Fluorouracil for Colorectal Cancer in Canada

    OpenAIRE

    Jean A. Maroun; Carl Asche; Francoise Romeyer; Jayanti Mukherjee; Christine Cripps; Amit Oza; Jamie R. Skillings; Jacques Letarte

    2003-01-01

    Background: Two randomised, controlled trials (n = 1396) comparing (i) intravenous fluorouracil (FU) plus oral folinic acid (leucovorin) and (ii) oral tegafur plus uracil (UFT) plus folinic acid for the treatment of metastatic colorectal carcinoma found both regimens to have equivalent efficacy in terms of survival, tumour response and time to disease progression. The UFT/folinic acid regimen was associated with a better toxicity profile than FU/folinic acid. Objective: To determine the compa...

  15. Synthesis of Polyphosphonates Containing 5-Flouro-N1-furanyl-N3- glyceroalkyl-uracil and Formyl Groups

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    A series of novel polyphosphonates containing 5-flouro- N1-furanyl-N3- glyceroalkyl-uracil and formyl groups was synthesized by the condensation of 3-(w- (1¢-furanyl-5-flourouracil-3-yl) alkoxy)-1, 2-dihydroxy propane with phosphonyl dichloride. The products were characterized by IR, 1H NMR, 31P NMR, , and elemental analysis. The results of bioassay show that compound 8a possesses potential anticancer activity.

  16. BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability

    Science.gov (United States)

    Slupianek, Artur; Falinski, Rafal; Znojek, Pawel; Stoklosa, Tomasz; Flis, Sylwia; Doneddu, Valentina; Pytel, Dariusz; Synowiec, Ewelina; Blasiak, Janusz; Bellacosa, Alfonso; Skorski, Tomasz

    2013-01-01

    Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of CML-CP. Unfortunately, 25% of TKI-naive patients and 50–90% of TKI-responding patients carry CML clones expressing TKI resistant BCR-ABL1 kinase mutants. We reported that CML-CP leukemia stem and progenitor cell populations accumulate high amounts of reactive oxygen species (ROS), which may result in accumulation of uracil derivatives in genomic DNA. Unfaithful and/or inefficient repair of these lesions generates TKI resistant point mutations in BCR-ABL1 kinase. Using an array of specific substrates and inhibitors/blocking antibodies we found that uracil-DNA glycosylase UNG2 were inhibited in BCR-ABL1 –transformed cell lines and CD34+ CML cells. The inhibitory effect was not accompanied by downregulation of nuclear expression and/or chromatin association of UNG2. The effect was BCR-ABL1 kinase-specific because several other fusion tyrosine kinases did not reduce UNG2 activity. Using UNG2-specific inhibitor UGI we found that reduction of UNG2 activity increased the number of uracil derivatives in genomic DNA detected by modified comet assay and facilitated accumulation of ouabain-resistant point mutations in reporter gene Na+/K+ATPase. In conclusion, we postulate that BCR-ABL1 kinase-mediated inhibition of UNG2 contributes to accumulation of point mutations responsible for TKI-resistance causing the disease relapse, and perhaps also other point mutations facilitating malignant progression of CML. PMID:23047475

  17. Multi-photon ionization and fragmentation of uracil: Neutral excited-state ring opening and hydration effects

    Energy Technology Data Exchange (ETDEWEB)

    Barc, B.; Ryszka, M.; Spurrell, J.; Dampc, M.; Limão-Vieira, P.; Parajuli, R.; Mason, N. J.; Eden, S. [Department of Physical Sciences, The Open University, Walton Hall, Milton Keynes MK7 6AA (United Kingdom)

    2013-12-28

    Multi-photon ionization (MPI) of the RNA base uracil has been studied in the wavelength range 220–270 nm, coinciding with excitation to the S{sub 2}(ππ*) state. A fragment ion at m/z = 84 was produced by 2-photon absorption at wavelengths ≤232 nm and assigned to C{sub 3}H{sub 4}N{sub 2}O{sup +} following CO abstraction. This ion has not been observed in alternative dissociative ionization processes (notably electron impact) and its threshold is close to recent calculations of the minimum activation energy for a ring opening conical intersection to a σ(n-π)π* closed shell state. Moreover, the predicted ring opening transition leaves a CO group at one end of the isomer, apparently vulnerable to abstraction. An MPI mass spectrum of uracil-water clusters is presented for the first time and compared with an equivalent dry measurement. Hydration enhances certain fragment ion pathways (particularly C{sub 3}H{sub 3}NO{sup +}) but represses C{sub 3}H{sub 4}N{sub 2}O{sup +} production. This indicates that hydrogen bonding to water stabilizes uracil with respect to neutral excited-state ring opening.

  18. Investigation of aromatase inhibitory activity of metal complexes of 8-hydroxyquinoline and uracil derivatives

    Directory of Open Access Journals (Sweden)

    Prachayasittikul V

    2014-08-01

    Full Text Available Veda Prachayasittikul,1 Ratchanok Pingaew,2 Chanin Nantasenamat,3 Supaluk Prachayasittikul,3 Somsak Ruchirawat,4,5 Virapong Prachayasittikul1 1Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; 2Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, Thailand; 3Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; 4Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 5Chulabhorn Graduate Institute, Bangkok, Thailand Purpose: Estrogens play important roles in the pathogenesis and progression of breast cancer as well as estrogen-related diseases. Aromatase is a key enzyme in the rate-limiting step of estrogen production, in which its inhibition is one strategy for controlling estrogen levels to improve prognosis of estrogen-related cancers and diseases. Herein, a series of metal (Mn, Cu, and Ni complexes of 8-hydroxyquinoline (8HQ and uracil derivatives (4–9 were investigated for their aromatase inhibitory and cytotoxic activities. Methods: The aromatase inhibition assay was performed according to a Gentest™ kit using CYP19 enzyme, wherein ketoconazole and letrozole were used as reference drugs. The cytotoxicity was tested on normal embryonic lung cells (MRC-5 using 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay. Results: Only Cu complexes (6 and 9 exhibited aromatase inhibitory effect with IC50 0.30 and 1.7 µM, respectively. Cytotoxicity test against MRC-5 cells showed that Mn and Cu complexes (5 and 6, as well as free ligand 8HQ, exhibited activity with IC50 range 0.74–6.27 µM. Conclusion: Cu complexes (6 and 9 were found to act as a novel class of aromatase inhibitor. Our findings suggest that these 8HQ–Cu–uracil complexes are promising agents that could be potentially developed as a selective anticancer agent for breast cancer

  19. Diaquabis[2-(5-isopropyl-5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-ylnicotinato]cobalt(II

    Directory of Open Access Journals (Sweden)

    Zhong-Jing Huang

    2010-12-01

    Full Text Available In the title complex, [Co(C13H14N3O32(H2O2], the CoII atom has a distorted octahedral coordination, formed by four N atoms from two (±-2-(5-isopropyl-5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-ylnicotinate ligands and two O atoms from two water molecules. Intramolecular N—H...O and O—H...O hydrogen bonds are present. In the crystal, intermolecular O—H...O hydrogen bonds link the complex molecules into a chain along [010].

  20. Ethylenediammonium bis(5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazol-1-ide: a hydrogen-bond-supported supramolecular ionic assembly

    Directory of Open Access Journals (Sweden)

    Xin Wang

    2008-09-01

    Full Text Available The title compound, C2H10N22+·2C10H9N2O−, is composed of deprotonated 5-methyl-2-phenyl-1H-pyrazol-3(2H-one anions (PMP− and protonated ethylenediamine cations (H2en2+. The ethylenediammonium ion is located on a crystallographic inversion center. The dihedral angle between the phenyl and pyrazole rings is 39.73 (8°. The two components are connected through N—H...O and N—H...N hydrogen bonds, forming an infinite three-dimensional network.

  1. Iodido[5-methyl-1H-benzimidazole-2(3H-thione-κS]bis(triphenylphosphane-κPcopper(I methanol monosolvate

    Directory of Open Access Journals (Sweden)

    Yu-Han Jiang

    2012-10-01

    Full Text Available In the title compound, [CuI(C8H8N2S(C18H15P2]·CH3OH, the coordination environment around the CuI atom is distorted tetrahedral, defined by two P atoms of two triphenylphosphane ligands, one S atom of a 5-methyl-1H-benzimidazole-2(3H-thione ligand and one I atom. The complex molecules and the methanol solvent molecules are connected via N—H...O and O—H...I hydrogen bonds, forming a chain along [010]. An intramolecular N—H...I hydrogen bond is also observed.

  2. The experimental and theoretical gas phase acidities of adenine, guanine, cytosine, uracil, thymine and halouracils

    Science.gov (United States)

    Chen, Edward C. M.; Herder, Charles; Chen, Edward S.

    2006-10-01

    The gas phase acidities GPA (Δ H (298) for deprotonation) of the most stable tautomers of adenine, guanine, cytosine, uracil and thymine are evaluated. New GPA are obtained from electron impact spectra and acid dissociation constants measured in dimethylsulfoxide for A, U and 5-FU. The average experimental GPA are: [N1 sbnd H] C 340(2); T 333(2); U 333(2); 5-FU 329(4); [N9 sbnd H] A 333(1); G 332(4); all in kcal/mol. Only cytosine is a weaker acid than HCl in the gas phase. The most acidic hydrogens in the nucleotides are replaced by the sugar in DNA and RNA. The experimental N3 sbnd H GPA are G 334(4); U 347(2), T 347(4), while the predicted N3 sbnd H 5-FU GPA is 343 kcal/mol. The NH sbnd H GPA are: C 346(4); A 352(2); G 336(4) (all in kcal/mol). These are supported by semi-empirical multiconfiguration configuration interaction calculations. The predicted C8 sbnd H acidities of G and A and the C6 sbnd H of T are about the same, 360(2) kcal/mol. The remaining CH acidities are 370-380 kcal/mol. The 5-halouracils are predicted to be more acidic than HCl.

  3. Trading in cooperativity for specificity to maintain uracil-free DNA.

    Science.gov (United States)

    Szabó, Judit E; Takács, Enikő; Merényi, Gábor; Vértessy, Beáta G; Tóth, Judit

    2016-04-11

    Members of the dUTPase superfamily play an important role in the maintenance of the pyrimidine nucleotide balance and of genome integrity. dCTP deaminases and the bifunctional dCTP deaminase-dUTPases are cooperatively regulated by dTTP. However, the manifestation of allosteric behavior within the same trimeric protein architecture of dUTPases, the third member of the superfamily, has been a question of debate for decades. Therefore, we designed hybrid dUTPase trimers to access conformational states potentially mimicking the ones observed in the cooperative relatives. We studied how the interruption of different steps of the enzyme cycle affects the active site cross talk. We found that subunits work independently in dUTPase. The experimental results combined with a comparative structural analysis of dUTPase superfamily enzymes revealed that subtile structural differences within the allosteric loop and the central channel in these enzymes give rise to their dramatically different cooperative behavior. We demonstrate that the lack of allosteric regulation in dUTPase is related to the functional adaptation to more efficient dUTP hydrolysis which is advantageous in uracil-DNA prevention.

  4. Tegafur-uracil (UFT) plus folinic acid in advanced rectal cancer.

    Science.gov (United States)

    Sanchiz, F; Milla, A

    1994-12-01

    We previously reported positive results to Tegafur-Uracil (UFT) chemotherapy in a group of patients with advanced rectal cancer. We have continued the study and now report the effectiveness of UFT plus folinic acid (FA) in 52 patients with advanced rectal cancer. The therapeutic schedule was UFT, 600 mg/m2/day x 14 days p.o. + FA, 90 mg/m2/day x 14 days p.o. Fifty-two out of a total of 56 patients were evaluated for response and toxicity. A higher incidence of positive responses in patients without previous chemotherapy was appreciated. Twenty-one of the 52 evaluated patients showed a partial response (PR). Responses were strongly correlated with previous chemotherapy (14/20; 70% PR of cases without previous chemotherapy vs 7/32; 22% of cases with previous chemotherapy). All responding patients came forward with a median time to progression of 8.2 months (19.6 months for patients without previous chemotherapy vs 7.7 months for patients with previous chemotherapy, P < 0.01). We concluded that the UFT plus FA could be a treatment of choice for patients with advanced rectal cancer.

  5. Incorporation of dUMP into DNA is a major source of spontaneous DNA damage, while excision of uracil is not required for cytotoxicity of fluoropyrimidines in mouse embryonic fibroblasts.

    Science.gov (United States)

    Andersen, Sonja; Heine, Tina; Sneve, Ragnhild; König, Imbritt; Krokan, Hans E; Epe, Bernd; Nilsen, Hilde

    2005-03-01

    Uracil may arise in DNA as a result of deamination of cytosine or through incorporation of dUMP instead of dTMP during replication. We have studied the steady-state levels of uracil in the DNA of primary cells and mouse embryonic fibroblast (MEF) cell lines from mice deficient in the Ung uracil-DNA glycosylase. The results show that the levels of uracil in the DNA of Ung(-/-) cells strongly depend on proliferation, indicating that the uracil residues originate predominantly from misincorporation during replication. Treatment with 5-fluoro-2'-deoxyuridine (5-FdUrd) or 5-fluorouracil (5-FU) gives rise to a dose-dependent increase of uracil in Ung(-/-) MEFs (up to 1.5-fold) but not in wild-type cells. Interestingly, Ung(-/-) MEFs accumulate AP-sites as well as uracil in response to 5-FdUrd but not to 5-FU. This accumulation of repair intermediates suggests a loss of tightly co-ordinated repair in the absence of Ung, and correlates with stronger inhibition of cell proliferation in response to 5-FdUrd, but not to 5-FU, in Ung(-/-) MEFs compared with wild-type cells. However, other cytotoxic effects of these fluoropyrimidines are comparable in both wild-type and Ung-deficient cells, demonstrating that excision of uracil from DNA by the Ung uracil-DNA glycosylase is not a prerequisite for obtaining cytotoxicity.

  6. Development of calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in cultured neocortical neurons visualized by cobalt staining

    DEFF Research Database (Denmark)

    Jensen, J B; Schousboe, A; Pickering, D S

    1998-01-01

    The developmental expression of calcium (Ca2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in cultured neocortical neurons was evaluated by using cobalt uptake, a histochemical method that identifies cells expressing Ca2+-permeable, non-N-methyl......The developmental expression of calcium (Ca2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in cultured neocortical neurons was evaluated by using cobalt uptake, a histochemical method that identifies cells expressing Ca2+-permeable, non......-N-methyl-D-aspartate (non-NMDA) receptors. At a concentration of 500 microM, AMPA was found to stimulate cobalt uptake only late in development, resulting in staining of 2.7%+/-0.3% of the neurons maintained in culture for 12 days in vitro (DIV). When AMPA receptor desensitization was blocked with 50 microM cyclothiazide......, the developmental profile of cobalt uptake mediated by 25 microM AMPA changed dramatically. The cobalt staining now appeared in young cultures (5 DIV), and the percentage of stained cells increased from 3.4%+/-0.2% at 5 DIV to 21.7%+/-1.6% at 12 DIV. The effect of 200 microM kainate was similar to that seen with 25...

  7. Vibrational spectroscopic investigations, molecular dynamic simulations and molecular docking studies of N‧-diphenylmethylidene-5-methyl-1H-pyrazole-3-carbohydrazide

    Science.gov (United States)

    Pillai, Renjith Raveendran; Menon, Vidya V.; Mary, Y. Shyma; Armaković, Stevan; Armaković, Sanja J.; Panicker, C. Yohannan

    2017-02-01

    FT-IR and FT-Raman spectra of N‧-diphenylmethylidene-5-methyl-1H-pyrazole-3-carbohydrazide were recorded and analyzed. Due to the industrial and biological importance of pyrazole derivatives, we have carried out an extensive quantum chemical study on N‧-diphenylmethylidene-5-methyl-1H-pyrazole-3-carbohydrazide. The theoretical ground state geometry and electronic structure of the title molecule were optimized by DFT/B3LYP/6-311G++(d,p) method and compared with those of the crystal data. The wave numbers obtained are assigned by potential energy distribution. The ring breathing modes of the benzene rings are assigned theoretically at 1009 cm-1 for the mono substituted phenyl rings. The first order hyperpolarizability is comparable with that of similar derivatives and 16 times that of the standard NLO material urea. Conformational analysis was conducted in order to locate all possible conformations of the title compound, followed by investigation of local reactivity properties by MEP and ALIE surfaces. Natural bond orbital analysis has been carried out to analyse the stability of the molecule arising from hyper-conjugative interactions and charge delocalization. Further, reactive properties via autoxidation and hydrolysis mechanisms have been assessed through calculations of bond dissociation energies and radial distribution functions. Docking results confirmed that the compound was a potential inhibitor of CDK2s and were in agreement with the previous reported studies.

  8. Dual targeting of tumor angiogenesis and chemotherapy by endostatin-cytosine deaminase-uracil phosphoribosyltransferase.

    Science.gov (United States)

    Chen, Chun-Te; Yamaguchi, Hirohito; Lee, Hong-Jen; Du, Yi; Lee, Heng-Huan; Xia, Weiya; Yu, Wen-Hsuan; Hsu, Jennifer L; Yen, Chia-Jui; Sun, Hui-Lung; Wang, Yan; Yeh, Edward T H; Hortobagyi, Gabriel N; Hung, Mien-Chie

    2011-08-01

    Several antiangiogenic drugs targeting VEGF/VEGF receptor (VEGFR) that were approved by the Food and Drug Administration for many cancer types, including colorectal and lung cancer, can effectively reduce tumor growth. However, targeting the VEGF signaling pathway will probably influence the normal function of endothelial cells in maintaining homeostasis and can cause unwanted adverse effects. Indeed, emerging experimental evidence suggests that VEGF-targeting therapy induced less tumor cell-specific cytotoxicity, allowing residual cells to become more resistant and eventually develop a more malignant phenotype. We report an antitumor therapeutic EndoCD fusion protein developed by linking endostatin (Endo) to cytosine deaminase and uracil phosphoribosyltransferase (CD). Specifically, Endo possesses tumor antiangiogenesis activity that targets tumor endothelial cells, followed by CD, which converts the nontoxic prodrug 5-fluorocytosine (5-FC) to the cytotoxic antitumor drug 5-fluorouracil (5-FU) in the local tumor area. Moreover, selective targeting of tumor sites allows an increasing local intratumoral concentration of 5-FU, thus providing high levels of cytotoxic activity. We showed that treatment with EndoCD plus 5-FC, compared with bevacizumab plus 5-FU treatment, significantly increased the 5-FU concentration around tumor sites and suppressed tumor growth and metastasis in human breast and colorectal orthotropic animal models. In addition, in contrast to treatment with bevacizumab/5-FU, EndoCD/5-FC did not induce cardiotoxicity leading to heart failure in mice after long-term treatment. Our results showed that, compared with currently used antiangiogenic drugs, EndoCD possesses potent anticancer activity with virtually no toxic effects and does not increase tumor invasion or metastasis. Together, these findings suggest that EndoCD/5-FC could become an alternative option for future antiangiogenesis therapy.

  9. BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability.

    Science.gov (United States)

    Slupianek, A; Falinski, R; Znojek, P; Stoklosa, T; Flis, S; Doneddu, V; Pytel, D; Synowiec, E; Blasiak, J; Bellacosa, A; Skorski, T

    2013-03-01

    Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia in chronic phase (CML-CP). Unfortunately, 25% of TKI-naive patients and 50-90% of patients developing TKI-resistance carry CML clones expressing TKI-resistant BCR-ABL1 kinase mutants. We reported that CML-CP leukemia stem and progenitor cell populations accumulate high amounts of reactive oxygen species, which may result in accumulation of uracil derivatives in genomic DNA. Unfaithful and/or inefficient repair of these lesions generates TKI-resistant point mutations in BCR-ABL1 kinase. Using an array of specific substrates and inhibitors/blocking antibodies we found that uracil DNA glycosylase UNG2 were inhibited in BCR-ABL1-transformed cell lines and CD34(+) CML cells. The inhibitory effect was not accompanied by downregulation of nuclear expression and/or chromatin association of UNG2. The effect was BCR-ABL1 kinase-specific because several other fusion tyrosine kinases did not reduce UNG2 activity. Using UNG2-specific inhibitor UGI, we found that reduction of UNG2 activity increased the number of uracil derivatives in genomic DNA detected by modified comet assay and facilitated accumulation of ouabain-resistant point mutations in reporter gene Na(+)/K(+)ATPase. In conclusion, we postulate that BCR-ABL1 kinase-mediated inhibition of UNG2 contributes to accumulation of point mutations responsible for TKI resistance causing the disease relapse, and perhaps also other point mutations facilitating malignant progression of CML.

  10. Dramatic reduction of sequence artefacts from DNA isolated from formalin-fixed cancer biopsies by treatment with uracil- DNA glycosylase.

    Science.gov (United States)

    Do, Hongdo; Dobrovic, Alexander

    2012-05-01

    Non-reproducible sequence artefacts are frequently detected in DNA from formalinfixed and paraffin-embedded (FFPE) tissues. However, no rational strategy has been developed for reduction of sequence artefacts from FFPE DNA as the underlying causes of the artefacts are poorly understood. As cytosine deamination to uracil is a common form of DNA damage in ancient DNA, we set out to examine whether treatment of FFPE DNA with uracil-DNA glycosylase (UDG) would lead to the reduction of C>T (and G>A) sequence artefacts. Heteroduplex formation in high resolution melting (HRM)-based assays was used for the detection of sequence variants in FFPE DNA samples. A set of samples that gave false positive HRM results for screening for the E17K mutation in exon 4 of the AKT1 gene were chosen for analysis. Sequencing of these samples showed multiple non-reproducible C:G>T:A artefacts. Treatment of the FFPE DNA with UDG prior to PCR amplification led to a very marked reduction of the sequence artefacts as indicated by both HRM and sequencing analysis, indicating that uracil lesions are the major cause of sequence artefacts. Similar results were shown for the BRAF V600 region in the same sample set and EGFR exon 19 in another sample set. UDG treatment specifically suppressed the formation of artefacts in FFPE DNA as it did not affect the detection of true KRAS codon 12 and true EGFR exon 19 and 20 mutations. We conclude that uracil in FFPE DNA leads to a significant proportion of sequence artefacts. These can be minimised by a simple UDG pretreatment which can be readily carried out, in the same tube, as the PCR immediately prior to commencing thermal cycling. HRM is a convenient way of monitoring both the degree of damage and the effectiveness of the UDG treatment. These findings have immediate and important implications for cancer diagnostics where FFPE DNA is used as the primary genetic material for mutational studies guiding personalised medicine strategies and where simple

  11. 5-Methyl-1-[(4-methyl-phen-yl)sulfon-yl]-1H-pyrazol-3-yl 4-methyl-benzene-sulfonate.

    Science.gov (United States)

    Murtaza, Shahzad; Kausar, Naghmana; Tahir, M Nawaz; Tariq, Javaria; Bibi, Samaira

    2012-07-01

    In the title compound, C(18)H(18)N(2)O(5)S(2), the tolyl rings are oriented at a dihedral angle of 16.15 (11)° with respect to one another. The 5-methyl-1H-pyrazol-3-ol ring is roughly planar (r.m.s. deviation = 0.0231 Å) and subtends angles of 73.82 (8) and 89.85 (8)° with the tolyl rings. In the crystal, very weak π-π inter-actions between tolyl groups, with centroid-centroid distances of 4.1364 (19) and 4.0630 (16) Å, together with a C-H⋯π contact generate a three-dimensional network.

  12. Mold Resistance and Leachability of 5-Methyl Carbendazim Fungicide%5-甲基多菌灵的防霉性和抗流失性

    Institute of Scientific and Technical Information of China (English)

    崔爱玲; 黄涛; 翟炜; 程康华

    2013-01-01

    In order to develop carbendazim fungicide for wood-based products,2-carbamatebenzimidazole carbendazim (MBC) was modified to 2-carbamate-5-methyl-benzimidazole (MMBC).Mold resistance and leachability of MMBC were tested.The results showed that mold resistance of MMBC was better than pentachlorophenol sodium (Na-pcp) and leachability was improved compared with MBC.%为开发防霉效果优良的木材用防霉剂,对2-氨基甲酸甲酯苯并咪唑(多菌灵,MBC)进行改性,得到2-氨基甲酸甲酯-5-甲基苯并咪唑(MMBC).经检测MMBC处理材的防霉性和抗流失性,结果表明:MMBC的防霉性优于传统防霉剂五氯酚钠,且流失率较改性前有所降低.

  13. Synthesis and Crystal Structure of Ethyl 5-Amino-1-[(5'-methyl-1'-t-butyl-4'-pyrazolyl)carbonyl]-3- methylthio-1H-pyrazole-4-carboxylate

    Institute of Scientific and Technical Information of China (English)

    李明; 文丽荣; 赵桂龙; 王啸; 杨华铮

    2005-01-01

    The title compound, ethyl 5-amino-1-[(5'-methyl-1'-t-butyl-4'-pyrazolyl)carbonyl] -3-methylthio-1H-pyrazole-4-carboxylate 5, has been synthesized by the treatment of 4 with ethyl 2-cyano-3,3-dimethylthioacrylate, and its crystal structure was determined by X-ray diffraction method. The crystal belongs to monoclinic, space group P21/c with a = 12.194(4), b = 12.909(4), c = 11.607(4) (A), β= 90.183(5)°, V = 1827.2(10) (A)3, Mr = 365.45, Z = 4, Dc = 1.328 g/cm3, μ = 0.203 mm-1, F(000) = 776, R = 0.0586 and wR = 0.1558. Preliminary bioassays indicated that the title compound shows fungicidal and plant growth regulation activities.

  14. Structural and kinetic studies of the allosteric transition in Sulfolobus solfataricus uracil phosphoribosyltransferase: Permanent activation by engineering of the C-terminus

    DEFF Research Database (Denmark)

    Christoffersen, Stig; Kadziola, Anders; Johansson, Eva

    2009-01-01

    Uracil phosphoribosyltransferase catalyzes the conversion of 5-phosphoribosyl- a-1-diphosphate (PRPP) and uracil to uridine monophosphate (UMP) and diphosphate (PPi). The tetrameric enzyme from Sulfolobus solfataricus has a unique type of allosteric regulation by cytidine triphosphate (CTP......) and guanosine triphosphate (GTP). Here we report two structures of the activated state in complex with GTP. One structure (refined at 2.8-Å resolution) contains PRPP in all active sites, while the other structure (refined at 2.9-Å resolution) has PRPP in two sites and the hydrolysis products, ribose-5-phosphate...

  15. Model Uracil-Rich RNAs and Membrane Protein mRNAs Interact Specifically with Cold Shock Proteins in Escherichia coli.

    Science.gov (United States)

    Benhalevy, Daniel; Bochkareva, Elena S; Biran, Ido; Bibi, Eitan

    2015-01-01

    Are integral membrane protein-encoding mRNAs (MPRs) different from other mRNAs such as those encoding cytosolic mRNAs (CPRs)? This is implied from the emerging concept that MPRs are specifically recognized and delivered to membrane-bound ribosomes in a translation-independent manner. MPRs might be recognized through uracil-rich segments that encode hydrophobic transmembrane helices. To investigate this hypothesis, we designed DNA sequences encoding model untranslatable transcripts that mimic MPRs or CPRs. By utilizing in vitro-synthesized biotinylated RNAs mixed with Escherichia coli extracts, we identified a highly specific interaction that takes place between transcripts that mimic MPRs and the cold shock proteins CspE and CspC, which are normally expressed under physiological conditions. Co-purification studies with E. coli expressing 6His-tagged CspE or CspC confirmed that the specific interaction occurs in vivo not only with the model uracil-rich untranslatable transcripts but also with endogenous MPRs. Our results suggest that the evolutionarily conserved cold shock proteins may have a role, possibly as promiscuous chaperons, in the biogenesis of MPRs.

  16. A study of the hydration of deoxydinucleoside monophosphates containing thymine, uracil and its 5-halogen derivatives: Monte Carlo simulation.

    Science.gov (United States)

    Alderfer, J L; Danilov, V I; Poltev, V I; Slyusarchuk, O N

    1999-04-01

    An extensive Monte Carlo simulation of hydration of various conformations of the dinucleoside monophosphates (DNP), containing thymine, uracil and its 5-halogen derivatives has been performed. An anti-anti conformation is the most energetically stable one for each of the DNPs. In the majority of cases the energy preference is determined by water-water interaction. For other dimers conformational energy is the most important factor, or both the factors are of nearly equal importance. The introduction of the methyl group into the 5-position of uracil ring most noticeably influences the conformational energy and leads to the decrease of its stabilizing contribution to the total interaction energy. The introduction of halogen atoms increases the relative content of anti-syn and syn-anti conformations of DNPs as compared to the parent ones due to the formation of an energetically more favorable water structure around these conformations. A correlation is observed between the Monte Carlo results for the halogenated DNPs and their experimental photoproduct distribution. The data obtained demonstrates a sequence dependence in the photochemistry of the halogenated dinucleoside monophosphates.

  17. Selectively improving nikkomycin Z production by blocking the imidazolone biosynthetic pathway of nikkomycin X and uracil feeding in Streptomyces ansochromogenes

    Directory of Open Access Journals (Sweden)

    Yang Haihua

    2009-11-01

    Full Text Available Abstract Background Nikkomycins are a group of peptidyl nucleoside antibiotics and act as potent inhibitors of chitin synthases in fungi and insects. Nikkomycin X and Z are the main components produced by Streptomyces ansochromogenes. Of them, nikkomycin Z is a promising antifungal agent with clinical significance. Since highly structural similarities between nikkomycin Z and X, separation of nikkomycin Z from the culture medium of S. ansochromogenes is difficult. Thus, generating a nikkomycin Z selectively producing strain is vital to scale up the nikkomycin Z yields for clinical trials. Results A nikkomycin Z producing strain (sanPDM was constructed by blocking the imidazolone biosynthetic pathway of nikkomycin X via genetic manipulation and yielded 300 mg/L nikkomycin Z and abolished the nikkomycin X production. To further increase the yield of nikkomycin Z, the effects of different precursors on its production were investigated. Precursors of nucleoside moiety (uracil or uridine had a stimulatory effect on nikkomycin Z production while precursors of peptidyl moiety (L-lysine and L-glutamate had no effect. sanPDM produced the maximum yields of nikkomycin Z (800 mg/L in the presence of uracil at the concentration of 2 g/L and it was approximately 2.6-fold higher than that of the parent strain. Conclusion A high nikkomycin Z selectively producing was obtained by genetic manipulation combined with precursors feeding. The strategy presented here might be applicable in other bacteria to selectively produce targeted antibiotics.

  18. SYNTHESIS, CHARACTERIZATION AND BIOCIDAL ACTIVITY OF NOVEL HALOGENATED - 4-[(SUBSTITUTED-BENZOTHIAZOL-2-YL HYDRAZONO]-2-(SUBSTITUTED-PHENYL-5-METHYL /ETHOXY -2,4-DIHYDRO-PYRAZOL-3-ONE DERIVATIVES Synthese, Charakterisierung und biozide Aktivität NOVEL HALOGENIERTEN - 4 - [(substituiertes-benzothiazol-2-YL hydrazono] -2 -(Substituiertes Phenyl-5-Methyl / ETHOXY -2,4-DIHYDRO-pyrazol-3-ONE DERIVATE

    Directory of Open Access Journals (Sweden)

    V. Khatri, K. Sharma, V. Sareen, D. Shinde and S. Sareen

    2012-04-01

    Full Text Available Some new 4-[(substituted-benzothiazol-2-ylhydrazono]-2-(substituted-phenyl-5- methyl/ethoxy-2,4-dihydro-pyrazol-3-one(4 have been synthesized by reacting substituted 2- amino benzothiazol (1 with acetoacetic ester and malonic ester (2. 2-[(substituted-benzothiazol- 2-ylhydrazono]-3-oxo-butyric acid ethyl ester and 2-[(substituted-benzothiazol-2- ylhydrazono]- malonic acid diethyl ester (3 react with different hydrazines to give the title compounds(4. These compounds are evaluated for their antifungal and insecticidal activity. The structures of all these compounds have been confirmed by IR, 1H NMR, mass spectra and elemental analysis data.

  19. Reaction of Ketene Dithioacetals with Pyrazolylcarbohydrazide:Synthesis and Biological Activities of Ethyl 5-Amino-1-(5'-methyl-1'-t-butyl-4'-pyrazolyl)carbonyl-3-methylthio-1H-pyrazole-4-carboxylate

    Institute of Scientific and Technical Information of China (English)

    LI Ming李明; WEN Li-Rong文丽荣; FU Wei-Jun付维军; ZHAO Gui-Long赵桂龙; HU Fang-Zhong胡方中; YANG Hua-Zheng杨华铮

    2004-01-01

    The title compound, C16-H23N5O3S, ethyl 5-amino-1-(5'-methyl-1'-t-butyl-4'-pyrazolyl)carbonyl-3-methylthio1H-pyrazole-4-carboxylate (5) has been synthesized by the treatment of ethyl 2-cyano-3,3-dimethylthioacrylate with 1-t-butyl-5-methyl-4-hydrazinocarbonylpyrazole (4) in refluxed ethanol. The possible mechanism of the above reaction was also discussed. The results of biological test show that the title compound has fungicidal and plant growth regulation activities.

  20. Synthesis and anti-HIV-1 activity of 1-substiuted 6-(3-cyanobenzoyl) and [(3-cyanophenyl)fluoromethyl]-5-ethyl-uracils

    DEFF Research Database (Denmark)

    Loksha, Yasser M; Pedersen, Erik B; Loddo, Roberta;

    2009-01-01

    1-Substiuted 6-(3-cyanobenzoyl) and [(3-cyanophenyl)fluoromethyl]-5-ethyl-uracils were synthesized and evaluated in cell-based assays against HIV-1 wild-type and its clinically relevant non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants. Some of the synthesized compounds sho...

  1. Uracil excision by endogenous SMUG1 glycosylase promotes efficient Ig class switching and impacts on A:T substitutions during somatic mutation.

    Science.gov (United States)

    Dingler, Felix A; Kemmerich, Kristin; Neuberger, Michael S; Rada, Cristina

    2014-07-01

    Excision of uracil introduced into the immunoglobulin loci by AID is central to antibody diversification. While predominantly carried out by the UNG uracil-DNA glycosylase as reflected by deficiency in immunoglobulin class switching in Ung(-/-) mice, the deficiency is incomplete, as evidenced by the emergence of switched IgG in the serum of Ung(-/-) mice. Lack of switching in mice deficient in both UNG and MSH2 suggested that mismatch repair initiated a backup pathway. We now show that most of the residual class switching in Ung(-/-) mice depends upon the endogenous SMUG1 uracil-DNA glycosylase, with in vitro switching to IgG1 as well as serum IgG3, IgG2b, and IgA greatly diminished in Ung(-/-) Smug1(-/-) mice, and that Smug1 partially compensates for Ung deficiency over time. Nonetheless, using a highly MSH2-dependent mechanism, Ung(-/-) Smug1(-/-) mice can still produce detectable levels of switched isotypes, especially IgG1. While not affecting the pattern of base substitutions, SMUG1 deficiency in an Ung(-/-) background further reduces somatic hypermutation at A:T base pairs. Our data reveal an essential requirement for uracil excision in class switching and in facilitating noncanonical mismatch repair for the A:T phase of hypermutation presumably by creating nicks near the U:G lesion recognized by MSH2.

  2. Non-canonical uracil processing in DNA gives rise to double-strand breaks and deletions: relevance to class switch recombination.

    Science.gov (United States)

    Bregenhorn, Stephanie; Kallenberger, Lia; Artola-Borán, Mariela; Peña-Diaz, Javier; Jiricny, Josef

    2016-04-01

    During class switch recombination (CSR), antigen-stimulated B-cells rearrange their immunoglobulin constant heavy chain (CH) loci to generate antibodies with different effector functions. CSR is initiated by activation-induced deaminase (AID), which converts cytosines in switch (S) regions, repetitive sequences flanking the CH loci, to uracils. Although U/G mispairs arising in this way are generally efficiently repaired to C/Gs by uracil DNA glycosylase (UNG)-initiated base excision repair (BER), uracil processing in S-regions of activated B-cells occasionally gives rise to double strand breaks (DSBs), which trigger CSR. Surprisingly, genetic experiments revealed that CSR is dependent not only on AID and UNG, but also on mismatch repair (MMR). To elucidate the role of MMR in CSR, we studied the processing of uracil-containing DNA substrates in extracts of MMR-proficient and -deficient human cells, as well as in a system reconstituted from recombinant BER and MMR proteins. Here, we show that the interplay of these repair systems gives rise to DSBs in vitro and to genomic deletions and mutations in vivo, particularly in an S-region sequence. Our findings further suggest that MMR affects pathway choice in DSB repair. Given its amenability to manipulation, our system represents a powerful tool for the molecular dissection of CSR.

  3. Allosteric regulation of the GTP activated and CTP inhibited uracil phosphoribosyltransferase from the thermophilic archaeon Sulfolobus solfataricus

    DEFF Research Database (Denmark)

    Jensen, Kaj Frank; Arent, Susan; Larsen, Sine;

    2005-01-01

    The upp gene, encoding uracil phosphoribosyltransferase (UPRTase) from the thermoacidophilic archaeon Sulfolobus solfataricus, was cloned and expressed in Escherichia coli. The enzyme was purified to homogeneity. It behaved as a tetramer in solution and showed optimal activity at pH 5.5 when...

  4. Photoelectron spectrum of valence anions of uracil and first-principles calculations of excess electron binding energies

    Science.gov (United States)

    Bachorz, Rafał A.; Klopper, Wim; Gutowski, Maciej; Li, Xiang; Bowen, Kit H.

    2008-08-01

    The photoelectron spectrum (PES) of the uracil anion is reported and discussed from the perspective of quantum chemical calculations of the vertical detachment energies (VDEs) of the anions of various tautomers of uracil. The PES peak maximum is found at an electron binding energy of 2.4 eV, and the width of the main feature suggests that the parent anions are in a valence rather than a dipole-bound state. The canonical tautomer as well as four tautomers that result from proton transfer from an NH group to a C atom were investigated computationally. At the Hartree-Fock and second-order Møller-Plesset perturbation theory levels, the adiabatic electron affinity (AEA) and the VDE have been converged to the limit of a complete basis set to within +/-1 meV. Post-MP2 electron-correlation effects have been determined at the coupled-cluster level of theory including single, double, and noniterative triple excitations. The quantum chemical calculations suggest that the most stable valence anion of uracil is the anion of a tautomer that results from a proton transfer from N1H to C5. It is characterized by an AEA of 135 meV and a VDE of 1.38 eV. The peak maximum is as much as 1 eV larger, however, and the photoelectron intensity is only very weak at 1.38 eV. The PES does not lend support either to the valence anion of the canonical tautomer, which is the second most stable anion, and whose VDE is computed at about 0.60 eV. Agreement between the peak maximum and the computed VDE is only found for the third most stable tautomer, which shows an AEA of ~-0.1 eV and a VDE of 2.58 eV. This tautomer results from a proton transfer from N3H to C5. The results illustrate that the characteristics of biomolecular anions are highly dependent on their tautomeric form. If indeed the third most stable anion is observed in the experiment, then it remains an open question why and how this species is formed under the given conditions.

  5. In vitro and in vivo antiherpetic effects of (1R,2R)-1-(5'-methylful-3'-yl)propane-1,2,3-triol.

    Science.gov (United States)

    Sasaki, Kohei; Hayashi, Kyoko; Matsuya, Yuji; Sugimoto, Kenji; Lee, Jung-Bum; Kurosaki, Fumiya; Hayashi, Toshimitsu

    2016-04-01

    In this study, we demonstrated the in vitro and in vivo antiherpetic activities of a stable furan derivative, (1R,2R)-1-(5'-methylful-3'-yl)propane-1,2,3-triol (MFPT), which had originally been isolated from Streptomyces sp. strain FV60. In the present study, we synthesized MFPT from (5-methylfuran-3-yl)methanol in 6 steps for use in the experiments. MFPT showed potent in vitro antiviral activities against two acyclovir (ACV)-sensitive (KOS and HF) strains and an ACV-resistant (A4-3) strain of herpes simplex virus type 1 (HSV-1) and an ACV-sensitive HSV type 2 (HSV-2) UW 268 strain, their selectivity indices ranging from 310 to 530. By intravaginal application of MFPT to mice, the virus yields decreased dose-dependently against the three strains of HSV-1 and HSV-2. When MFPT was applied at a dose of 1.0 mg/day, the lesion scores, as clinical signs manifested by viral infection, were extensively suppressed in HSV-1-infected mice, whereas the lesion scores in HSV-2-infected mice were not markedly decreased. Interestingly, MFPT exerted an inhibitory effect against ACV-resistant HSV-1 in mice to a similar degree as in ACV-sensitive HSV-1-infected mice. Therefore, the compound might have potential for developing a topical antiviral agent that could be also applied to the infections caused by ACV-resistant viruses.

  6. The chemokine growth-related gene product β protects rat cerebellar granule cells from apoptotic cell death through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors

    Science.gov (United States)

    Limatola, Cristina; Ciotti, Maria Teresa; Mercanti, Delio; Vacca, Fabrizio; Ragozzino, Davide; Giovannelli, Aldo; Santoni, Angela; Eusebi, Fabrizio; Miledi, Ricardo

    2000-01-01

    Cultured cerebellar granule neurons are widely used as a cellular model to study mechanisms of neuronal cell death because they undergo programmed cell death when switched from a culture medium containing 25 mM to one containing 5 mM K+. We have found that the growth-related gene product β (GROβ) partially prevents the K+-depletion-induced cell death, and that the neuroprotective action of GROβ on granule cells is mediated through the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type of ionotropic glutamate receptors. GROβ-induced survival was suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione, which is a specific antagonist of AMPA/kainate receptors; it was not affected by the inhibitor of N-methyl-d-aspartate receptors, 2-amino-5-phosphonopentanoic acid, and was comparable to the survival of granule cells induced by AMPA (10 μM) treatment. Moreover, GROβ-induced neuroprotection was abolished when granule cells were treated with antisense oligonucleotides specific for the AMPA receptor subunits, which significantly reduced receptor expression, as verified by Western blot analysis with subunit-specific antibodies and by granule cell electrophysiological sensitivity to AMPA. Our data demonstrate that GROβ is neurotrophic for cerebellar granule cells, and that this activity depends on AMPA receptors. PMID:10811878

  7. Induction of tolerance to poison ivy urushiol in the guinea pig by epicutaneous application of the structural analog 5-methyl-3-n-pentadecylcatechol.

    Science.gov (United States)

    Stampf, J L; Benezra, C; Byers, V; Castagnoli, N

    1986-05-01

    Previous studies have established that epicutaneous application of 5-methyl-3-n-pentadecylcatechol (5-Me-PDC), a synthetic analog of a poison ivy urushiol component, leads to immune tolerance to 3-n-pentadecylcatechol (PDC) in mice. The induction of tolerance by 5-Me-PDC may be mediated by a protein conjugate formed via selective reaction of thiol nucleophiles present on the carrier macromolecule with the corresponding o-quinone derived from the parent catechol. In order to examine further the tolerogenic properties of 5-Me-PDC, we have extended our studies to the guinea pig, the generally accepted experimental species for the study of contact allergy. The results have established that specific immune tolerance to poison ivy urushiol is induced following 2 epicutaneous applications of the PDC analog. Furthermore, we were able to show that the treated animals remained tolerant for at least 6 weeks, a period of time comparable to that observed following the intravenous administration of the O,O-bis-acetyl derivative of PDC. The data point to the possibility of developing a therapeutically effective topical tolerogen for poison ivy contact dermatitis.

  8. Potential of 5-methyl 1-H benzotriazole to suppress the dissolution of α-aluminum bronze in sulfide-polluted salt water

    Energy Technology Data Exchange (ETDEWEB)

    Nazeer, Ahmed Abdel; Ashour, E.A. [National Research Centre, Electrochemistry Laboratory, Dokki, Cairo 12622 (Egypt); Allam, Nageh K., E-mail: nageh.allam@aucegypt.edu [National Research Centre, Electrochemistry Laboratory, Dokki, Cairo 12622 (Egypt); Energy Materials Laboratory, Physics Department, School of Sciences and Engineering, The American University in Cairo, P.O. Box 74, New Cairo 11835 (Egypt)

    2014-03-01

    This work investigates the inhibition effect of 5-methyl 1-H benzotriazole (MBT) on the dissolution behavior of α-aluminum bronze in clean and sulfide-polluted salt water using potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), electrochemical frequency modulation (EFM) and scanning electron microscopy (SEM) techniques. The inhibition efficiency increases with the increasing MBT concentration and decreases with the increasing temperature. The adsorption process of MBT is spontaneous and follows Langmuir adsorption isotherm model. MBT possesses excellent inhibiting effect for the corrosion of α-Al-bronze, which acts as a mixed type inhibitor. Thermodynamic and kinetic parameters for the adsorption process were determined. The presence of sulfide ions (2 ppm) decreases the inhibition efficiency of MBT against the corrosion of Al-bronze alloy in chloride solutions from 94.7% to 89% as also confirmed via SEM images. The results obtained from the different techniques were in good agreement, which prove the validity of these tools in the measurements of the tested inhibitor. - Highlights: • MBT is an excellent mixed corrosion inhibitor for bronze. • There is a competitive adsorption between MBT and sulfide ions to adsorb on bronze surface. • The adsorption of MBT is spontaneous and follows Langmuir model. • CPE decreases significantly with the increasing MBT concentration.

  9. Theoretical molecular structure, vibrational frequencies and NMR investigations of 2-[(1E-2-aza-2-(5-methyl(2-pyridylethenyl]-4-bromobenzen-1-ol

    Directory of Open Access Journals (Sweden)

    Cemal Parlak

    2012-08-01

    Full Text Available The normal mode frequencies and corresponding vibrational assignments, 1H and 13C NMR chemical shifts and structural parameters (bond lengths, bond and dihedral angles of 2-[(1E-2-aza-2-(5-methyl(2-pyridylethenyl]-4-bromobenzen-1-ol (2mpe-4bb Schiff base compound have been theoretically examined by means of Hartree-Fock (HF and Becke-3-Lee-Yang-Parr (B3LYP density functional methods with 6-31G(d and 6-311++G(d,p basis sets. Furthermore, reliable vibrational assignments have made on the basis of potential energy distribution (PED calculated and the thermodynamics functions, highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO of 2mpe-4bb have been predicted. Theoretical results have been successfully compared with available experimental data in the literature. Regarding the calculations, 2mpe-4bb prefers enol-imine form and DFT method is superior to HF approach except for predicting bond lengths.DOI: http://dx.doi.org/10.4314/bcse.v26i2.11

  10. Synthesis and Crystal Structure of 5-Methyl- 2-phenyl-4-[(2-p-bromophenylamino)- furylmethylene]-3(2H)-one

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yong; LI Jin-Zhou; ZHANG Heng-Qiang

    2008-01-01

    A novel 4-heterocyclic acylpyrazolone-based Schiff base compound 5-methyl- 2-phenyl-4-[(2-p-bromophenylamino)-furylmethylene]-3(2H)-one (C21H16N3O2Br) has been syn- thesized by the reaction of 1-phenyl-3-methyl-4-(α-furoyl)-pyrazolone-5 (HPMαFP) and p-bro- moaniline. Elemental analysis, IR spectra and X-ray single-crystal diffraction were carried out to determine the composition and crystal structure of the compound. Crystal data: triclinic system, space group P(1), a = 9.0936(3), b = 9.8067(4), c = 11.6863(4) (A),α = 102.512(10), β = 90.9630(10), γ = 114.327(10)°, Mr = 422.28, Z = 2, F(000) = 428.0, V = 920.46(11) (A)3, Dc = 1.524 g/cm3, μ = 2.254mm-1, R = 0.0476 and wR = 0.1318 for 9389 independent reflections (Rint = 0.0122) and 3281 observed reflections (I > 2σ(I)). Structural analysis indicates that the compound exists in an amine-one form.

  11. Synthesis and crystal Structure of 2[1-(1,1-dimethylethyl)-5-methyl-1-H-pyrazol-4-ylcarbonyl]-N-Phenyldrazinecarbothioamide

    Institute of Scientific and Technical Information of China (English)

    李明; 文丽荣; 付维军; 赵桂龙; 杨华铮

    2004-01-01

    The crystal structure of 2[1-(1,1-dimethylethyl)-5-methyl-1-H-pyrazol-4-ylcar-bonyl]-N-phenyldrazinecarbothioamide ([C16H21N5OS]·CH3COCH3,C19H27N5O2S,Mr=389.52) has been determined by single-crystal X-ray diffraction.The crystal belongs to tetragonal,space group I41/a with a=23.960(4),b=23.960(4),c=16.120(5)A,V=9254(4)A3,Z=16,Dc=1.118 g/cm3,μ=0.161 mm-1,F(000)=3328,R=0.0660 and wR=0.1305 for 3878 unique reflections with 1653 observed ones (I > 2σ(I)).The intermolecular hydrogen bond between N(3)-H(3B)…O(1),N(5)-H(5A)…S(1) and N(4)-H(4D)…O(2) has been observed.

  12. Synthesis and Crystal Structure of 1-(1'-t- Butyl-5'-methyl-4-pyrazolyl-carbonyl)- 3,5-dimethyl-1H-yl-pyrazole

    Institute of Scientific and Technical Information of China (English)

    文丽荣; 付维军; 李明; 赵桂龙; 胡方中; 杨华铮

    2004-01-01

    The crystal structure of 1-(1'-t-butyl-5'-methyl-4'-pyrazolylcarbonyl)-3,5-dimeth yl-1H-yl-pyrazole ([C14H20N4O]2, Mr = 520.68) has been determined by single-crystal X-ray diffraction analysis. The crystal belongs to triclinic, space group P1 with a = 11.049(4), b = 11.313(4), c = 13.964(5) A, a = 69.085(6), β = 75.962(6), γ = 62.245(6)°, V = 1436.7(9)A3, Z = 2, Dc= 1.204 g/cm3,t = 0.079 mm-1, F(000) = 560, R = 0.0790 and wR = 0.1416 for 4729 unique reflections with 2635 observed ones (I > 2σ(I)). The results indicate that the pyrazole rings display aromaticity. The four pyrazole moieties are approximately coplanar in each case. The dihedral angles between planes 1 and 2, 3 and 4 are 40.99 and 10.77°, respectively.

  13. High sensitivity of amide V bands in uracil and its derivatives to the strengths of hydrogen bonding

    Science.gov (United States)

    Bandekar, Jagdeesh; Zundel, Georg

    Bands due to CO, CH and NH out-of-plane bending modes have been identified and studied as a function of temperature in the cis-amide uracil and its derivatives. Only the bands due to NH out-of-plane bending modes, the so-called amide V bands, are found to be sensitive to the strengths of hydrogen bonds. This sensitivity is found to be as great as that of NH stretching bands. It is shown that the amide V bands could be used, among other things, to detect the possibility and/or extent of hydrogen bonding in Hoogsteen-type base-pairs. This provides a very simple way to detect the presence of undesirable uncomplexed bases in the study of base-paired complexes. These results point to the need to understand better the origin of amide V bands.

  14. PORTA-ENXERTOS, CITOCININAS, RETARDANTES DE CRESCIMENTO E URACIL NA FERTILIDADE DE GEMAS DE VIDEIRAS APIRÊNICAS

    Directory of Open Access Journals (Sweden)

    PLÍNIO SALGADO FONSECA DE MELO

    2012-01-01

    Full Text Available The growth retardants Paclobutrazol (PBZ and Cycocel (CCC had been used, in spraying, associates or not with two cytokinins: Benziladenina (BAP and Thidiazuron (TDZ, and a nitrogenous base, the Uracil, with the purpose of studying its effect in the bud fertility of the 'Superior Seedless', grafted on the 'Harmony' and IAC-766 'Campinas', and of the 'Crimson Seedless' and 'Thompson Seedless', grafted on the 'Harmony', in the conditions of the São Francisco Valley, Brazil. It was observed that the separately use of the products had not promoted significant differences in the studied of the bud fertility, but, the association of the growth retardants with the TDZ it induce the 'Thompson Seedless' to a bigger productivity, and that the expression of the bud fertility of the 'Seedless Superior' benefits on to being grafted on the 'Harmony' rootstock.

  15. Automated quantum chemistry based molecular dynamics simulations of electron ionization induced fragmentations of the nucleobases Uracil, Thymine, Cytosine, and Guanine.

    Science.gov (United States)

    Grimme, Stefan; Bauer, Christopher Alexander

    2015-01-01

    The gas-phase decomposition pathways of electron ionization (EI)-induced radical cations of the nucleobases uracil, thymine, cytosine, and guanine are investigated by means of mixed quantum-classical molecular dynamics. No preconceived fragmentation channels are used in the calculations. The results compare well to a plethora of experimental and theoretical data for these important biomolecules. With our combined stochastic and dynamic approach, one can access in an unbiased way the energetically available decomposition mechanisms. Additionally, we are able to separate the EI mass spectra of different tautomers of cytosine and guanine. Our method (previously termed quantum chemistry electron ionization mass spectra) reproduces free nucleobase experimental mass spectra well and provides detailed mechanistic in-sight into high-energy unimolecular decomposition processes.

  16. Imaging [18F]FAU [1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) uracil] in dogs.

    Science.gov (United States)

    Sun, Haihao; Collins, Jerry M; Mangner, Thomas J; Muzik, Otto; Shields, Anthony F

    2003-01-01

    We have studied the biodistribution of [(18)F]FAU [(1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)uracil], which previous work has shown is incorporated into DNA and functions as an inhibitor of DNA synthesis. It is being tested as a potential antineoplastic agent and imaging agent for PET. We have produced [(18)F]FAU and injected the tracer into 3 normal dogs and imaged them for up to 4 hours and removed tissues along with blood and urine samples for HPLC and activity analysis. The results showed that [(18)F]FAU evenly distributed to most of organs. In sharp contrast to our prior experience with thymidine and its analogs, marrow had less retention of [(18)F]FAU than the non-proliferating tissues.

  17. 2-Amino-4,4a-dihydro-4a,7-dimethyl-3H-phenoxazin-3-one as an unexpected product from reduction of 5-methyl-2-nitrophenol

    NARCIS (Netherlands)

    Jansze, S.M.; Saggiomo, V.; Marcelis, A.T.M.; Lutz, M.; Velders, A.H.

    2015-01-01

    When attempting to synthesize symmetric 2,2'-dihydroxy-4,4'-dimethyl-azobenzene from 5-methyl-2-nitrophenol by reductive methods based on two literature procedures, an unexpected product was isolated in 30% yield. Full analysis by mass spectrometry, NMR spectroscopy, and single-crystal X-ray structu

  18. Synthesis of 3- [ 1- (4-Ethoxyphenyl)-5-methyl-1,2,3-triazol-4-yl ]-6- substituted- s-triazolo [ 3,4- b ] -1,3,4-thiadiazoles

    Institute of Scientific and Technical Information of China (English)

    DONG Heng-Shan; WANG Bin

    2003-01-01

    @@ Several 3- [ 1- (4-ethoxyphenyl)-5-methyl- 1,2, 3-triazol-4-yl ]-6-substituted-s-triazolo [ 3,4- b ]- 1,3,4-thiadia zoles have been synthesized and the structures of these compounds were established by MS, IR and 1H NMR spectral data.

  19. A facile route to 5-methyl-5H-indeno[1,2-c]quinolones via palladium-catalyzed cyclization of 2-alkynylbromobenzenes with N,N-dimethyl-2-alkynylanilines.

    Science.gov (United States)

    Pan, Xiaolin; Luo, Yong; Kuang, Yunyan; Li, Guangming

    2014-08-21

    A tandem reaction catalyzed by palladium is developed to provide a facile and simple route for the synthesis of 5-methyl-5H-indeno[1,2-c]quinolones, which can introduce diversity and complexity into the products from readily available starting materials. This transformation proceeds well with good functional group tolerance.

  20. Multiple Decay Mechanisms and 2D‐UV Spectroscopic Fingerprints of Singlet Excited Solvated Adenine‐Uracil Monophosphate

    Science.gov (United States)

    Li, Quansong; Giussani, Angelo; Segarra‐Martí, Javier; Nenov, Artur; Rivalta, Ivan; Voityuk, Alexander A.; Mukamel, Shaul; Roca‐Sanjuán, Daniel

    2016-01-01

    Abstract The decay channels of singlet excited adenine uracil monophosphate (ApU) in water are studied with CASPT2//CASSCF:MM potential energy calculations and simulation of the 2D‐UV spectroscopic fingerprints with the aim of elucidating the role of the different electronic states of the stacked conformer in the excited state dynamics. The adenine 1La state can decay without a barrier to a conical intersection with the ground state. In contrast, the adenine 1Lb and uracil S(U) states have minima that are separated from the intersections by sizeable barriers. Depending on the backbone conformation, the CT state can undergo inter‐base hydrogen transfer and decay to the ground state through a conical intersection, or it can yield a long‐lived minimum stabilized by a hydrogen bond between the two ribose rings. This suggests that the 1Lb, S(U) and CT states of the stacked conformer may all contribute to the experimental lifetimes of 18 and 240 ps. We have also simulated the time evolution of the 2D‐UV spectra and provide the specific fingerprint of each species in a recommended probe window between 25 000 and 38 000 cm−1 in which decongested, clearly distinguishable spectra can be obtained. This is expected to allow the mechanistic scenarios to be discerned in the near future with the help of the corresponding experiments. Our results reveal the complexity of the photophysics of the relatively small ApU system, and the potential of 2D‐UV spectroscopy to disentangle the photophysics of multichromophoric systems. PMID:27113273

  1. Multiple Decay Mechanisms and 2D-UV Spectroscopic Fingerprints of Singlet Excited Solvated Adenine-Uracil Monophosphate.

    Science.gov (United States)

    Li, Quansong; Giussani, Angelo; Segarra-Martí, Javier; Nenov, Artur; Rivalta, Ivan; Voityuk, Alexander A; Mukamel, Shaul; Roca-Sanjuán, Daniel; Garavelli, Marco; Blancafort, Lluís

    2016-05-23

    The decay channels of singlet excited adenine uracil monophosphate (ApU) in water are studied with CASPT2//CASSCF:MM potential energy calculations and simulation of the 2D-UV spectroscopic fingerprints with the aim of elucidating the role of the different electronic states of the stacked conformer in the excited state dynamics. The adenine (1) La state can decay without a barrier to a conical intersection with the ground state. In contrast, the adenine (1) Lb and uracil S(U) states have minima that are separated from the intersections by sizeable barriers. Depending on the backbone conformation, the CT state can undergo inter-base hydrogen transfer and decay to the ground state through a conical intersection, or it can yield a long-lived minimum stabilized by a hydrogen bond between the two ribose rings. This suggests that the (1) Lb , S(U) and CT states of the stacked conformer may all contribute to the experimental lifetimes of 18 and 240 ps. We have also simulated the time evolution of the 2D-UV spectra and provide the specific fingerprint of each species in a recommended probe window between 25 000 and 38 000 cm(-1) in which decongested, clearly distinguishable spectra can be obtained. This is expected to allow the mechanistic scenarios to be discerned in the near future with the help of the corresponding experiments. Our results reveal the complexity of the photophysics of the relatively small ApU system, and the potential of 2D-UV spectroscopy to disentangle the photophysics of multichromophoric systems.

  2. Molecular dynamics simulation reveals conformational switching of water-mediated uracil-cytosine base-pairs in an RNA duplex.

    Science.gov (United States)

    Schneider, C; Brandl, M; Sühnel, J

    2001-01-26

    A 4 ns molecular dynamics simulation of an RNA duplex (r-GGACUUCGGUCC)(2 )in solution with Na+ and Cl- as counterions was performed. The X-ray structure of this duplex includes two water-mediated uracil-cytosine pairs. In contrast to the other base-pairs in the duplex the water-mediated pairs switch between different conformations. One conformation corresponds to the geometry of the water-mediated UC pairs in the duplex X-ray structure with water acting both as hydrogen-bond donor and acceptor. Another conformation is close to that of a water-mediated UC base-pair found in the X-ray structure of the 23 S rRNA sarcin/ricin domain. In this case the oxygen of the water molecule is linked to two-base donor sites. For a very short time also a direct UC base-pair and a further conformation that is similar to the one found in the RNA duplex structure but exhibits an increased H3(U)...N3(C) distance is observed. Water molecules with unusually long residence times are involved in the water-mediated conformations. These results indicate that the dynamic behaviour of the water-mediated UC base-pairs differs from that of the duplex Watson-Crick and non-canonical guanine-uracil pairs with two or three direct hydrogen bonds. The conformational variability and increased flexibility has to be taken into account when considering these base-pairs as RNA building blocks and as recognition motifs. Copyright 2001 Academic Press.

  3. Epstein-Barr virus encoded nuclear protein EBNA-3 binds a novel human uridine kinase/uracil phosphoribosyltransferase

    Directory of Open Access Journals (Sweden)

    Klein George

    2002-08-01

    Full Text Available Abstract Background Epstein-Barr virus (EBV infects resting B-lymphocytes and transforms them into immortal proliferating lymphoblastoid cell lines (LCLs in vitro. The transformed immunoblasts may grow up as immunoblastic lymphomas in immuno-suppressed hosts. Results In order to identify cellular protein targets that may be involved in Epstein-Barr virus mediated B-cell transformation, human LCL cDNA library was screened with one of the transformation associated nuclear antigens, EBNA-3 (also called EBNA-3A, using the yeast two-hybrid system. A clone encoding a fragment of a novel human protein was isolated (clone 538. The interaction was confirmed using in vitro binding assays. A full-length cDNA clone (F538 was isolated. Sequence alignment with known proteins and 3D structure predictions suggest that F538 is a novel human uridine kinase/uracil phosphoribosyltransferase. The GFP-F538 fluorescent fusion protein showed a preferentially cytoplasmic distribution but translocated to the nucleus upon co-expression of EBNA-3. A naturally occurring splice variant of F538, that lacks the C-terminal uracil phosphoribosyltransferase part but maintain uridine kinase domain, did not translocate to the nucleus in the presence of EBNA3. Antibody that was raised against the bacterially produced GST-538 protein showed cytoplasmic staining in EBV negative Burkitt lymphomas but gave a predominantly nuclear staining in EBV positive LCL-s and stable transfected cells expressing EBNA-3. Conclusion We suggest that EBNA-3 by direct protein-potein interaction induces the nuclear accumulation of a novel enzyme, that is part of the ribonucleotide salvage pathway. Increased intranuclear levels of UK/UPRT may contribute to the metabolic build-up that is needed for blast transformation and rapid proliferation.

  4. Poly[(5-methyl-5-allyloxycarbonyl-trimethylene carbonate)-co-(5,5-dimethyl-trimethylene carbonate)] with grafted polyethylenimine as biodegradable polycations for efficient gene delivery.

    Science.gov (United States)

    He, Feng; Wang, Chang-Fang; Jiang, Tao; Han, Bing; Zhuo, Ren-Xi

    2010-11-08

    In this paper, biodegradable polycations based on polycarbonates with grafted polyethylenimine (PEI) were synthesized as a nonviral vector for gene delivery. Immobilized porcine pancreas lipase (IPPL) was employed to perform the copolymerization of 5-methyl-5-allyloxy carbonyl-trimethylenecarbonate (MAC) with 5,5-dimethyl-trimethylene carbonate (DTC). The DTC molar percent X was equal to 6.7, 12.5, and 45.4, respectively. The resulting copolymers with different compositions (P(MAC-co-DTCx) underwent additional allyl epoxidation and thereby grafted by low molecular weight PEI1800. The MWs of P(MAC-co-DTCx)-g-PEI, measured by GPC-MALLS, were 219800, 179100, and 51700 g/mol with polydispersities of 1.5, 1.4, and 1.2, respectively. Physicochemical properties of these vectors were characterized and the DNA loading was evaluated. P(MAC-co-DTCx)-g-PEI could form nanosized particles (less than 100 nm) with pDNA. The three P(MAC-co-DTCx)-g-PEI/DNA polyplexes had similar buffer capabilities that were better than that of PEI25K and PMAC-g-PEI. Despite a slightly lower DNA binding ability, the PEI-grafted polycarbonates, especially P(MAC-co-DTC45.4)-g-PEI, presented apparently low cytotoxicity and much higher gene transfection efficiency in comparison with PEI25K in 293T cells. Moreover, preincubation of P(MAC-co-DTC6.7)-g-PEI showed a quickly weakening DNA binding capacity, while a suitable degradation rate of vectors would facilitate the efficient release of pDNA from polyplexes after cellular uptake and also reduce cell cytotoxicity. The results of this study demonstrated the promise of P(MAC-co-DTCx)-g-PEI copolymers for efficient gene delivery.

  5. RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Canton, T; Böhme, G A; Boireau, A; Bordier, F; Mignani, S; Jimonet, P; Jahn, G; Alavijeh, M; Stygall, J; Roberts, S; Brealey, C; Vuilhorgne, M; Debono, M W; Le Guern, S; Laville, M; Briet, D; Roux, M; Stutzmann, J M; Pratt, J

    2001-10-01

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists are of potential interest for the treatment of certain acute and chronic neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we describe the synthesis and pharmacological properties of 9-carboxymethyl-4-oxo-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-phosphonic acid (RPR 119990). The compound displaced [3H]AMPA from rat cortex membranes with a K(i) of 107 nM. In oocytes expressing human recombinant AMPA receptors, RPR 119990 depressed ion flux with a K(B) of 71 nM. The antagonist properties of this compound were confirmed on rat native AMPA receptors in cerebella granule neurons in culture and in hippocampal slices where it antagonized electrophysiological responses with IC50 values of 50 and 93 nM, respectively. RPR 119990 antagonized hippocampal evoked responses in vivo, demonstrating brain penetration at active concentrations. RPR 119990 is a potent anticonvulsant in the supramaximal electroshock in the mouse with an ED50 of 2.3 mg/kg 1 h post s.c. administration, giving it a workably long action. Pharmacokinetic studies show good passage into the plasma after subcutaneous administration, whereas brain penetration is low but with slow elimination. This compound was found active in a transgenic mouse model of familial amyotrophic lateral sclerosis (SOD1-G93A) where it was able to improve grip muscle strength and glutamate uptake from spinal synaptosomal preparations, and prolong survival with a daily dose of 3 mg/kg s.c.

  6. Potent methyl oxidation of 5-methyl-2'-deoxycytidine by halogenated quinoid carcinogens and hydrogen peroxide via a metal-independent mechanism.

    Science.gov (United States)

    Shao, Jie; Huang, Chun-Hua; Kalyanaraman, Balaraman; Zhu, Ben-Zhan

    2013-07-01

    Halogenated quinones are a class of carcinogenic intermediates and are newly identified chlorination disinfection by-products in drinking water. We found recently that the highly reactive and biologically important hydroxyl radical ((•)OH) can be produced by halogenated quinones and H2O2 independent of transition metal ions. However, it is not clear whether these quinoid carcinogens and H2O2 can oxidize the nucleoside 5-methyl-2'-deoxycytidine (5mdC) to its methyl oxidation products and, if so, what the underlying molecular mechanism is. Here we show that three methyl oxidation products, 5-(hydroperoxymethyl)-, 5-(hydroxymethyl)-, and 5-formyl-2'-deoxycytidine, could be produced when 5mdC was treated with tetrachloro-1,4-benzoquinone (TCBQ) and H2O2. The formation of the oxidation products was markedly inhibited by typical (•)OH scavengers and under anaerobic conditions. Analogous effects were observed with other halogenated quinones and the classic Fenton system. Based on these data, we propose that the oxidation of 5mdC by TCBQ/H2O2 might be through the following mechanism: (•)OH produced by TCBQ/H2O2 may first abstract hydrogen from the methyl group of 5mdC, leading to the formation of 5-(2'-deoxycytidylyl)methyl radical, which may combine with O2 to form the peroxyl radical. The unstable peroxyl radical transforms into the corresponding hydroperoxide 5-(hydroperoxymethyl)-2'-deoxycytidine, which reacts with TCBQ and results in the formation of 5-(hydroxymethyl)-2'-deoxycytidine and 5-formyl-2'-deoxycytidine. This is the first report that halogenated quinoid carcinogens and H2O2 can induce potent methyl oxidation of 5mdC via a metal-independent mechanism, which may partly explain their potential carcinogenicity. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Selective extraction, separation and speciation of iron in different samples using 4-acetyl-5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid

    Energy Technology Data Exchange (ETDEWEB)

    Sacmaci, Serife [Erciyes University, Department of Chemistry, Faculty of Arts and Sciences, TR-38039 Kayseri (Turkey)], E-mail: sacmaci@erciyes.edu.tr; Kartal, Senol [Erciyes University, Department of Chemistry, Faculty of Arts and Sciences, TR-38039 Kayseri (Turkey)

    2008-08-08

    A method for speciation, preconcentration and separation of Fe(II) and Fe(III) in different matrices was developed using solvent extraction and flame atomic absorption spectrometry. 4-Acetyl-5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (AMPC) was used as a new complexing reagent for Fe(III). The Fe(III)-AMPC complex was extracted into methyl isobutyl ketone (MIBK) phase in the pH range 1.0-2.5, and Fe(II) ion remained in aqueous phase at all pH. The chemical composition of the Fe(III)-AMPC complex was determined by the Job's method. The optimum conditions for quantitative recovery of Fe(III) were determined as pH 1.5, shaking time of 2 min, 1.64 x 10{sup -4} mol L{sup -1} AMPC reagent and 10 mL of MIBK. Furthermore, the influences of diverse metal ions were investigated. The level of Fe(II) was calculated by difference of total iron and Fe(III) concentrations. The detection limit based on the 3{sigma} criterion was found to be 0.24 {mu}g L{sup -1} for Fe(III). The recoveries were higher than 95% and relative standard deviation was less than 2.1% (N = 8). The validation of the procedure was performed by the analysis of two certified standard reference materials. The presented method was applied to the determination of Fe(II) and Fe(III) in tap water, lake water, river water, sea water, fruit juice, cola, and molasses samples with satisfactory results.

  8. Synthesis, structural characterization and theoretical approach of 3-(2,6-dichlorobenzyl)-5-methyl-N-nitro-1,3,5-oxadiazinan-4-imine.

    Science.gov (United States)

    Ni, Haiwei; Zhang, Yu; Zhang, Fang; Zhao, Jianying; Wu, Liubi; Chu, Xiaozhong

    2015-03-05

    3-(2,6-Dichlorobenzyl)-5-methyl-N-nitro-1,3,5-oxadiazinan-4-imine (DNOI) was synthesized and characterized by X-ray diffraction, FT-IR, FT-Raman and UV-Vis spectra. The X-ray diffraction study showed that DNOI has a one dimensional configuration, due to the intermolecular C9H⋯O1 and N4H⋯O2 hydrogen bonds. The benzene ring and the oxadiazine rings are tilted with respect to each other by 63.07° (C3N1C5C6). Vibrational spectra and electronic spectra measurements were made for the compound. Optimized geometrical structure and harmonic vibrational frequencies were computed with DFT (B3LYP, B3P86, and M062X) methods using 6-311++G(d,p) basis set. Assignments of the observed spectra were proposed. The equilibrium geometries computed by all of the methods were compared with X-ray diffraction results. The absorption spectra of the title compound were computed both in gas phase and in CH3OH solution using TD-B3LYP/6-311++G(d,p) and PCM-B3LYP/6-311++G(d,p) approaches, respectively. The calculated results provide a good description of positions of the bands maxima in the observed electronic spectrum. Temperature dependence of thermodynamic parameters in the range of 100-1000K were determined, entropy, heat capacity and enthalpy changes were increasing with temperature increasing, while for Gibbs free energy is decreasing with temperature increasing. The bond orbital occupancies, contribution from parent natural bond orbital (NBO), the natural atomic hybrids was calculated and discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Role of spinal cord alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in complete Freund's adjuvant-induced inflammatory pain

    Directory of Open Access Journals (Sweden)

    Shih Ming-Hung

    2008-12-01

    Full Text Available Abstract Spinal cord α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs mediate acute spinal processing of nociceptive and non-nociceptive information, but whether and how their activation contributes to the central sensitization that underlies persistent inflammatory pain are still unclear. Here, we examined the role of spinal AMPARs in the development and maintenance of complete Freund's adjuvant (CFA-induced persistent inflammatory pain. Intrathecal application of two selective non-competitive AMPAR antagonists, CFM-2 (25 and 50 μg and GYKI 52466 (50 μg, significantly attenuated mechanical and thermal hypersensitivities on the ipsilateral hind paw at 2 and 24 h post-CFA injection. Neither CFM-2 nor GYKI 52466 affected the contralateral basal responses to thermal and mechanical stimuli. Locomotor activity was not altered in any of the drug-treated animals. CFA-induced inflammation did not change total expression or distribution of AMPAR subunits GluR1 and GluR2 in dorsal horn but did alter their subcellular distribution. The amount of GluR2 was markedly increased in the crude cytosolic fraction and decreased in the crude membrane fraction from the ipsilateral L4–5 dorsal horn at 24 h (but not at 2 h post-CFA injection. Conversely, the level of GluR1 was significantly decreased in the crude cytosolic fraction and increased in the crude membrane fraction from the ipsilateral L4–5 dorsal horn at 24 h (but not at 2 h post-CFA injection. These findings suggest that spinal AMPARs might participate in the central spinal mechanism of persistent inflammatory pain.

  10. Effect of Pd(II and Ni(II coordination compounds with 4-amino-3-mercapto-5-methyl-1,2,4-triazole on the mitochondrial dehydrogenases activity

    Directory of Open Access Journals (Sweden)

    S. I. Orysyk

    2015-02-01

    Full Text Available Pd(II and Ni(II complex compounds: [Pd(AMMT2]Cl2 (1, [Pd(AMMT4]Cl2 (2 and [Ni(AMMT2(H2O2](NO32 (3 with 4-amino-3-mercapto-5-methyl-1,2,4-triazole (AMMT have been synthesized. The spectral characteristics of 1, 2 were studied by 1H (13C NMR and UV-Vis spectroscopy. X-ray diffraction studies established that all complexes contain the AMMT molecule, which are coordinated to the central metal ion in the thione tautomeric form. At the ratio M : L = 1 : 2 ligand is coordinated in bidentate chelate manner by the nitrogen of amino- and sulfur of mercapto group (compounds 1, 3. But the molar ratio M : L = 1 : 4 leads to monodentate coordination of AMMT molecules only by sulfur of mercaptogroup (complex 2. Vacant coordination sites of the metal ion are occupied by water molecules (complex 3. The screening of complexes 1−3 and starting compounds [АММТ, K2PdCl4 (4, Ni(NO32∙6H2O (5] by their mitochondrial dehydrogenase activity have been performed by us for the first time, resulting in established that the Pd(II complexes (1, 2, Pd(II salt (4 and AMMT normalize the activity of mitochondrial dehydrogenases of cancer HeLa cells, identified by MTT-test. In contrast, the Ni(II complex (3 and Ni(II salt (5 do not stimulate the activity of mitochondrial dehydrogenases. It has been found, that all investigated compounds do not affect on the cell cycle and the level of apoptotic cells as well as do not show a toxic effect. Thus, these results indicate that AMMT and Pd(II complexes may be used as modifiers of mitochondrial respiration, which dysfunction is particularly evident in the tumor cells.

  11. Ubiquinone-0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone) as effective catalyzer of ascorbate and epinephrine oxidation and damager of neuroblastoma cells.

    Science.gov (United States)

    Roginsky, V A; Bruchelt, G; Bartuli, O

    1998-01-01

    The kinetics of ascorbate (AscH ) and epinephrine (EP) oxidation in the presence of 2,3-dimethoxy-5-methyl-1,4-benzoquinone (UQ) were studied in 0.05 M phosphate buffer, pH 7.4, at 37 degrees C by using a Clark electrode and ESR techniques. UQ at nanomolar concentrations displayed a pronounced catalytic effect on AscH oxidation which exceeded that of all reported organic catalysts tested in this system. The process was accompanied by the intensive oxygen consumption and increase in the steady-state concentration of the ascorbyl radical Asc.-. The rate of oxygen consumption (R[OX]) was maximal at the moment of reagent mixing ((R[OX]0) and then reduced over a few minutes until a steady-state level ((R[OX])SS) was achieved. (R[OX])0 was found to be proportional to [UQ][AscH-] without regard to the concentrations of the individual reagents; (R[OX])SS was directly related to [UQ] at a given concentration of AscH-. The difference between (R[OX])0 and (R[OX])SS decreased as [AscH-] decreased. The presence of a lipid phase (sodium dodecylsulphate micelles) only moderately decreased UQ activity as a catalyst of AscH- oxidation. Adding micromolar concentrations of UQ induced the acceleration of EP autoxidation. The capability of UQ to catalyze the oxidation of EP exceeded by approximately 25 times that of adrenochrome, a quinoid product of EP oxidation. These catalytic properties of UQ allowed us to predict its pronounced cytotoxicity, especially in the presence of AscH- and to cells of the sympathetic nervous system which are rich in catecholamines. This possibility was confirmed by experiments with human neuroblastoma cells in culture. The capability of UQ to injure neuroblastoma cell line SK-N-SH exceeded that of well-known neurotoxic agents 6-hydroxydopamine and menadione.

  12. Neo-adjuvant chemoradiotherapy by 5-fluoro-uracil and oxaliplatine for the locally evolved rectum cancer: study of the toxicity and the histological response; Chimioradiotherapie neoadjuvante par 5-fluoro-uracile et oxaliplatine pour les cancers du rectum localement evolues: etude de la toxicite et de la reponse histologique

    Energy Technology Data Exchange (ETDEWEB)

    Le Scodan, R.; Miranda, O.; Henni, M.; Durdux, C.; Housset, M. [HEGP, Dept. de Radiotherapie, 75 - Paris (France); Landi, B. [HEGP, Dept. de Gastroenterologie, 75 - Paris (France); Berger, A. [HEGP, Dept. Chirurgie Viscerale, 75 - Paris (France); Dousset, B. [Hopital Cochin, Dept. de Chirurgie Viscerale, 75 - Paris (France); Brezault, C. [Hopital Cochin, Dept. Gastroenterologie, 75 - Paris (France); Cote, J.F. [HEGP, Dept. d' anatomopathologie, 75 - Paris (France)

    2006-11-15

    The neo-adjuvant chemoradiotherapy by 5-fluoro-uracil and oxaliplatine, for the locally evolved rectum cancers, has a certain efficiency in term of histological response with an acceptable acute toxicity. The study of prediction factors to the response to chemoradiotherapy is in progress. (N.C.)

  13. mtSSB may sequester UNG1 at mitochondrial ssDNA and delay uracil processing until the dsDNA conformation is restored

    DEFF Research Database (Denmark)

    Wollen Steen, Kristian; Doseth, Berit; westbye, Marianne;

    2012-01-01

    Single-strand DNA binding proteins protect DNA from nucleolytic damage, prevent formation of secondary structures and prevent premature reannealing of DNA in DNA metabolic transactions. In eukaryotes, the nuclear single-strand DNA binding protein RPA is essential for chromosomal DNA replication...... excision of uracil and oxidative demethylation of 3meC in single-stranded DNA by UNG1 and ABH1, respectively, whereas excision by NEIL1 was partially inhibited. mtSSB also effectively inhibited nicking of single-stranded DNA by APE1 and ABH1 and partially inhibited the lyase activity of NEIL1. Finally we...... identified a putative surface motif in mtSSB that may recruit UNG1 to DNA-bound mtSSB. We suggest that the massive amount of mtSSB in mitochondria effectively prevents processing of uracil and other types of damaged bases to avoid introduction of nicks in single-stranded mtDNA formed during replication...

  14. Visual and light scattering spectrometric method for the detection of melamine using uracil 5‧-triphosphate sodium modified gold nanoparticles

    Science.gov (United States)

    Liang, Lijiao; Zhen, Shujun; Huang, Chengzhi

    2017-02-01

    A highly selective method was presented for colorimetric determination of melamine using uracil 5‧-triphosphate sodium modified gold nanoparticles (UTP-Au NPs) in this paper. Specific hydrogen-bonding interaction between uracil base (U) and melamine resulted in the aggregation of AuNPs, displaying variations of localized surface plasmon resonance (LSPR) features such as color change from red to blue and enhanced localized surface plasmon resonance light scattering (LSPR-LS) signals. Accordingly, the concentration of melamine could be quantified based on naked eye or a spectrometric method. This method was simple, inexpensive, environmental friendly and highly selective, which has been successfully used for the detection of melamine in pretreated liquid milk products with high recoveries.

  15. Synthesis of novel 1H-1,2,3-triazole tethered C-5 substituted uracil-isatin conjugates and their cytotoxic evaluation

    KAUST Repository

    Kumar, Kewal

    2012-12-01

    The present manuscript describes the synthesis of uracil-isatin hybrids via azide-alkyne cycloadditions and their cytotoxic evaluation against three human cancer cell lines viz. HeLa (cervix), MCF-7 (breast) and DU145 (prostate) using MTT assay. The evaluation studies revealed the dependence of cytotoxicity on C-5 substituents of both uracil and isatin as well as the alkyl chain length with compounds 6g and 6k showing IC50 values 18.21 and 13.90 μM respectively against DU145 cell lines. Most of the synthesized conjugates exhibited considerable selectivity against MCF-7 and DU145 cell lines. © 2012 Elsevier Masson SAS. All rights reserved.

  16. CNDO/SCF molecular orbital structural studies and charge transfer complex formation between 4,4’-dimethoxydiquinone and uracil

    Directory of Open Access Journals (Sweden)

    Anwar S. El-Shahawy

    2004-12-01

    Full Text Available Through CNDO/SCF molecular orbital calculations, the structure of 4,4’-dimethoxy- diquinone (DQ has been discussed and compared with some related compounds. The electron transfer between DQ and uracil was studied in ethanol as an interaction medium. The ionization potentials and the electron affinities of the studied molecules have been calculated in addition to their charge densities giving the columbic potential energy of the donor and acceptor. The experimental charge transfer band lies at 500 nm. The electronic transitions have been calculated for the singlet and triplet transitions in uracil and DQ molecules using the SCF eigenvectors of the two HOMO’s, ψn-1 and ψ n, and the two LUMO’s, ψ n+1 and ψ n+2, using CI theory. The calculated electronic transitions are compared with those of the experimental data to verify the non-planar structure of the DQ molecule.

  17. Synthesis of novel 1H-1,2,3-triazole tethered C-5 substituted uracil-isatin conjugates and their cytotoxic evaluation.

    Science.gov (United States)

    Kumar, Kewal; Sagar, Sunil; Esau, Luke; Kaur, Mandeep; Kumar, Vipan

    2012-12-01

    The present manuscript describes the synthesis of uracil-isatin hybrids via azide-alkyne cycloadditions and their cytotoxic evaluation against three human cancer cell lines viz. HeLa (cervix), MCF-7 (breast) and DU145 (prostate) using MTT assay. The evaluation studies revealed the dependence of cytotoxicity on C-5 substituents of both uracil and isatin as well as the alkyl chain length with compounds 6g and 6k showing IC(50) values 18.21 and 13.90 μM respectively against DU145 cell lines. Most of the synthesized conjugates exhibited considerable selectivity against MCF-7 and DU145 cell lines. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  18. Identification of ozonation by-products of 4- and 5-methyl-1H-benzotriazole during the treatment of surface water to drinking water.

    Science.gov (United States)

    Müller, Alexander; Weiss, Stefan C; Beisswenger, Judith; Leukhardt, H Georg; Schulz, Wolfgang; Seitz, Wolfram; Ruck, Wolfgang K L; Weber, Walter H

    2012-03-01

    During the treatment of surface water to drinking water, ozonation is often used for disinfection and to remove organic trace substances, whereby oxidation by-products can be formed. Here we use the example of tolyltriazole to describe an approach for identifying relevant oxidation by-products in the laboratory and subsequently detecting them in an industrial-scale process. The identification process involves ozonation experiments with pure substances at laboratory level (concentration range mg L(-1)). The reaction solutions from different ozone contact times were analyzed by high performance liquid chromatography - quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) in full scan mode. Various approaches were used to detect the oxidation by-products: (i) target searches of postulated oxidation by-products, (ii) comparisons of chromatograms (e.g., UV/VIS) of the different samples, and (iii) color-coded abundance time courses (kinetic) of all detected compounds were illustrated in a kind of a heat map. MS/MS, H/D exchange, and derivatization experiments were used for structure elucidation for the detected by-product. Due to the low contaminant concentrations (ng L(-1)-range) of contaminants in the untreated water, the conversion of results from laboratory experiments to an industrial-scale required the use of HPLC-MS/MS with sample enrichment (e.g., solid phase extraction.) In cases where reference substances were not available or oxidation by-products without clear structures were detected, reaction solutions from laboratory experiments were used to optimize the analytical method to detect ng L(-1) in the samples of the industrial processes. We exemplarily demonstrated the effectiveness of the methodology with the industrial chemicals 4- and 5-methyl-1H-benzotriazole (4- and 5-MBT) as an example. Moreover, not only did we identify several oxidation by-products in the laboratory experiments tentatively, but also detected three of the eleven reaction

  19. Sulfanilic acid functionalized mesoporous SBA-15: A water-tolerant solid acid catalyst for the synthesis of uracil fused spirooxindoles as antioxidant agents

    Indian Academy of Sciences (India)

    Robabeh Baharfar; Razieh Azimi

    2015-08-01

    Incorporating sulfanilic acid as a hydrophobic Brønsted acid inside the nanospaces of SBA-15 led to a water-tolerant solid acid catalyst, SBA-15-PhSO 3 H, which showed excellent catalytic performance in synthesis of uracil-fused spirooxindoles in aqueous ethanol. The synthesized compounds were evaluated for their antioxidant activity by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging assay.

  20. Synthesis of Polyphosphonates Containing 5—Flouro—N1—furanyl—N3—glyceroalkyl—uracil and Formyl Groups

    Institute of Scientific and Technical Information of China (English)

    LiBAI; RuYuCHEN; 等

    2002-01-01

    A series of novel polyphosphonates containing 5-flouro-N1-furanyl-N3-glyceroalkyl-uracil and formyl groups was synthesized by the condensation of 3-(ω-(1′-furanyl-5-flourouracil-3-yl) alkoxy)-1,2-dihydroxy propane with phosphonyl dichloride. The products were characterized by IR,1H NMR,31P NMR, M,and elemental analysis. The results of bioassay show that compound 8a possesses potential anticancer activity.

  1. Preparation of nucleoside-pyridine hybrids and pyridine attached acylureas from an unexpected uracil ring-opening and pyridine ring-forming sequence

    Institute of Scientific and Technical Information of China (English)

    Xue Sen Fan; Xia Wang; Xin Ying Zhang; Dong Feng; Ying Ying Qu

    2009-01-01

    Novel pyrimidine nucleoside-3,5-dicyanopyridine hybrids (4) or pyridine attached acylureas (5) were selectively and efficiently prepared from the reaction of 2'-deoxyuridin-5-yl-methylene malonortitrile (1), malononitrile (2) and thiophenol (3) or from an unexpected uracil ring-opening and pyridine ring-forming sequence via the reaction of 1 and 3. It is the first time such a sequence has ever been reported.

  2. Folate deficiency increases mtDNA and D-1 mtDNA deletion in aged brain of mice lacking uracil-DNA glycosylase.

    Science.gov (United States)

    Kronenberg, Golo; Gertz, Karen; Overall, Rupert W; Harms, Christoph; Klein, Jeanette; Page, Melissa M; Stuart, Jeffrey A; Endres, Matthias

    2011-04-01

    Strong epidemiological and experimental evidence links folate deficiency and resultant hyperhomocysteinemia with cognitive decline and neurodegeneration. Here, we tested the hypothesis that uracil misincorporation contributes to mitochondrial pathology in aged brain following folate deprivation. In a 2 × 2 design, 14-month-old mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls were subjected to a folate-deficient versus a regular diet for six weeks. Folate-deficient feeding significantly enhanced mtDNA content and overall abundance of the D-1 mtDNA deletion in brain of Ung-/-, but not of wild-type mice. Independent of folate status, the frequency of the D-1 mtDNA deletion in mtDNA was significantly increased in Ung-/- mice. The rate of mitochondrial biogenesis as assessed at six weeks of the experimental diet by mRNA expression levels of transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and of mitochondrial transcription factor A (Tfam) was not affected by either Ung-/- genotype or short-term folate deficiency. Similarly, citrate synthase (CS) activity in the brain did not differ across experimental groups. By contrast, independent of genotype, lactate dehydrogenase (LDH) activity was significantly reduced in folate-deficient animals. Our results suggest that impaired uracil excision repair causes an increase in mitochondrial mutagenesis in aged brain along with a compensatory increase in mtDNA content in response to low folate status. Folate deficiency may contribute to neurodegeneration via mtDNA damage.

  3. Doubly differential distribution of electron emission in ionization of uracil in collisions with 3.5-MeV/u bare C ions

    Science.gov (United States)

    Agnihotri, A. N.; Nandi, S.; Kasthurirangan, S.; Kumar, A.; Galassi, M. E.; Rivarola, R. D.; Champion, C.; Tribedi, L. C.

    2013-03-01

    We report the energy and angular distribution of the electron emission from an RNA base molecule uracil in collisions with 3.5-MeV/u bare C ions. The absolute double differential cross sections (DDCS) are measured for emission energy between a few to 600 eV. The angular distributions are compared to those obtained for the O2 molecule in the same experiment. The single differential cross sections (SDCS) are also deduced. The energy and angular distributions of the DDCS and SDCS are compared with the state-of-the-art quantum-mechanical models based on continuum distorted wave-eikonal initial state (CDW-EIS) and correct boundary first Born (CB1) approximations which use a suitable molecular wave function for uracil. The models, however, give substantial deviations from the observed energy and angular distributions of the DDCS as well as SDCS. The CDW-EIS calculations are closer to the data compared to the CB1. In the case of uracil a large difference in the forward-backward emission of electrons was observed in comparison to that in collisions with an oxygen molecule.

  4. Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio.

    Science.gov (United States)

    Thomas, F; Hennebelle, I; Delmas, C; Lochon, I; Dhelens, C; Garnier Tixidre, C; Bonadona, A; Penel, N; Goncalves, A; Delord, J P; Toulas, C; Chatelut, E

    2016-02-01

    Despite the growing evidence that dihydropyrimidine dehydrogenase deficiency (DPD, encoded by the DPYD gene) confers a higher risk of developing severe toxicity, most patients are not screened for DPD deficiency before fluoropyrimidine treatment. We report here the genetic and phenotypic analyses of DPD in a family related to a patient who died after a first cycle of 5-fluorouracil and in 15 additional retrospective patients having a partial DPD deficiency (as measured by plasma dihydrouracil/uracil ratio). The patient with lethal toxicity was found to be a compound heterozygote for two DPYD mutations: a novel 8-bp duplication (c.168_175dupGAATAATT, p.Phe59Ter) and c.1679T>G (Ile560Ser). The patient's dihydrouracil/uracil ratio indicates complete DPD deficiency. The novel mutation was found in two members of the patient's family. Deleterious DPYD mutations were identified in 9 out of the 15 patients. The relationship between genotype and dihydrouracil/uracil values in the 22 patients of the present study was significant (P = 0.01).

  5. A New Approach to Ethyl 1-Aroyl/Aroylmethyl-5-methyl-3-methylthiopyrazole-4-carboxylates: High Regioselectivity in Alkylation and Acylation Reactions between N-1 and N-2 of a Pyrazole Derivative

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Two series, totalizing twelve, of new compounds, ethyl 1-aroyl/aroylmethyl-5-methyl-3-methylthiopyrazole-4-carboxylates 5/6, have been synthesized via highly regioselective acylation and alkylation of ethyl 3-methyl-5-methylthio-1H- pyrazole-4-carboxylate 2a with aroyl chloride 3and alpha-tosyloxysubstitutedacetophenones 4. Unexpected structures of the product have been unambiguously determined by both X-ray crystallographic analysis and 2D NMR.

  6. FeCl3/SiO2 NPs as a robust and efficient catalyst for the synthesis of 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones

    Directory of Open Access Journals (Sweden)

    Esmaeil Afkhami

    2016-09-01

    Full Text Available A four-component reaction of phenylhydrazines, ethyl acetoacetate, aldehydes and β-naphthol has been achieved in the presence of FeCl3/SiO2 nanoparticles as a highly effective heterogeneous catalyst to produce 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones in good to excellent yields, short reaction times, mild reaction conditions and the employment of a cost-effective catalyst.

  7. Uracil DNA glycosylase counteracts APOBEC3G-induced hypermutation of hepatitis B viral genomes: excision repair of covalently closed circular DNA.

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    Kouichi Kitamura

    Full Text Available The covalently closed circular DNA (cccDNA of the hepatitis B virus (HBV plays an essential role in chronic hepatitis. The cellular repair system is proposed to convert cytoplasmic nucleocapsid (NC DNA (partially double-stranded DNA into cccDNA in the nucleus. Recently, antiviral cytidine deaminases, AID/APOBEC proteins, were shown to generate uracil residues in the NC-DNA through deamination, resulting in cytidine-to-uracil (C-to-U hypermutation of the viral genome. We investigated whether uracil residues in hepadnavirus DNA were excised by uracil-DNA glycosylase (UNG, a host factor for base excision repair (BER. When UNG activity was inhibited by the expression of the UNG inhibitory protein (UGI, hypermutation of NC-DNA induced by either APOBEC3G or interferon treatment was enhanced in a human hepatocyte cell line. To assess the effect of UNG on the cccDNA viral intermediate, we used the duck HBV (DHBV replication model. Sequence analyses of DHBV DNAs showed that cccDNA accumulated G-to-A or C-to-T mutations in APOBEC3G-expressing cells, and this was extensively enhanced by UNG inhibition. The cccDNA hypermutation generated many premature stop codons in the P gene. UNG inhibition also enhanced the APOBEC3G-mediated suppression of viral replication, including reduction of NC-DNA, pre-C mRNA, and secreted viral particle-associated DNA in prolonged culture. Enhancement of APOBEC3G-mediated suppression by UNG inhibition was not observed when the catalytic site of APOBEC3G was mutated. Transfection experiments of recloned cccDNAs revealed that the combination of UNG inhibition and APOBEC3G expression reduced the replication ability of cccDNA. Taken together, these data indicate that UNG excises uracil residues from the viral genome during or after cccDNA formation in the nucleus and imply that BER pathway activities decrease the antiviral effect of APOBEC3-mediated hypermutation.

  8. Successful treatment of multiple lung metastases of hepatocellular carcinoma by combined chemotherapy with docetaxel, cisplatin and tegafur/uracil

    Institute of Scientific and Technical Information of China (English)

    Atsunori Tsuchiya; Michitaka Imai; Hiroteru Kamimura; Tadayuki Togashi; Kouji Watanabe; Kei-ichi Seki; Toru Ishikawa; Hironobu Ohta; Toshiaki Yoshida; Tomoteru Kamimura

    2009-01-01

    We report the successful treatment of multiple lung metastases after hepatic resection for hepatocellular carcinoma (HCC) with combined docetaxel, cisplatin (CDDP), and enteric-coated tegafur/uracil (UFT-E). A 68-year-old man was diagnosed with multiple lung metastases of HCC 7 mo after partial hepatectomy for HCC. Oral UFT-E was given daily and docetaxel and CDDP were given intra-arterially (administered just before the bronchial arteries) every 2 wk via a subcutaneous injection port. One month after starting chemotherapy, levels of tumor marker, protein induced by vitamin K absence Ⅱ (PIVKA-Ⅱ), decreased rapidly, and after a further month, chest X-ray and computed tomography revealed the complete disappearance of multiple liver metastases. Two years after the combined chemotherapy, HCC recurred in the liver and was treated but no pulmonary recurrence occurred. In the absence of a standardized highly effective therapy, this combined chemotherapy with docetaxel, CDDP and UFT-E may be an attractive option for multiple lung metastases of HCC.

  9. Stability of mutagenic tautomers of uracil and its halogen derivatives: the results of quantum-mechanical investigation

    Directory of Open Access Journals (Sweden)

    Hovorun D.M.

    2010-07-01

    Full Text Available Aim. To investigate using the quantum-mechanical methods uracil (Ura intramolecular tautomerisation and the effect of the thymine (Thy methyl (Me group substitution by the halogen on that process. Methods. Non-empirical quantum mechanic, analysis of the electron density by means of Bader’s atom in molecules (AIM theory and physicochemical kinetics were used. Results. For the first time it has been established that the substitution of thymine Me-group for the halogen (Br, F, Cl has practically no effect on the main physico-chemical characteristics of intramolecular tautomerisation. At the same time, the energy of Ura tautomerisation increases for 3,08 kcal/mol in comparison with corresponding value for Thy under standard conditions. Conclusions. So, Thy, unlike Ura, is obviously able, as a canonical DNA nucleotide base, to provide together with Ade, Gua and Cyt an acceptable mutability degree of the genome from the point of view of its adaptation reserve. Mutagenic action of the Ura halogen derivatives is not directly associated with their tautomerisation.

  10. Meta-analysis of five studies on tegafur plus uracil (UFT) as post-operative adjuvant chemotherapy for breast cancer.

    Science.gov (United States)

    Kasumi, Fujio; Yoshimoto, Masataka; Uchino, Junichi; Abe, Rikiya; Nomura, Yasuo; Sugimachi, Keizo; Nakazato, Hiroaki; Abe, Osahiko

    2003-01-01

    Meta-analysis of 5 studies on postoperative breast cancer cases (2 studies on surgery alone vs. tegafur plus uracil (UFT) and 3 studies on tamoxifen (TAM) alone vs. TAM + UFT) were carried out to evaluate the anticancer drug UFT in oral postoperative adjuvant chemotherapy. Of the 1973 patients enrolled, 1898 were eligible and 75 were excluded (exclusion rate 3.8%). There was no bias in major background factors in either the UFT-treated (965) or non-UFT-treated (933) groups. The reduction in the odds of death and the odds of recurrence were 17 +/- 17% (p = 0.33) and 21 +/- 11% (p = 0.060), respectively. Multivariate analysis using Cox's proportional hazards model emphasized the effectiveness of UFT treatment for suppression of recurrence compared with non-treatment with UFT (p = 0.038). Suppression of recurrence was remarkable in the group treated with UFT for 2 years. (the reduction in the odds of recurrence: 23 +/- 11%, p = 0.048) Stratified analysis was applied concerning recurrence, and improved results were obtained in premenopausal cases (the reduction in the odds of recurrence: 33 +/- 11%, p = 0.019). These results suggested that UFT treatment for 2 years was effective as postoperative adjuvant chemotherapy for stage I - IIIA breast cancer for the prolongation of the recurrence-free survival period. Copyright 2003 S. Karger AG, Basel

  11. An extended version of Boyd's force field method applicable to heteroatomic molecules. Part 1. Adenine and uracil

    Science.gov (United States)

    Espinosa-Müller, A. W.; Bravo, A. N.

    The force field method developed by Boyd is extended to include molecules containing atoms other than C and H (e.g., N, O, P, S, Cl, Br,…). A new set of force field parameters is determined in order to redefine the potential energy functions that govern the dynamics of the internal (valence coordinates) degrees of freedom of a molecule. It is shown that the minimum of the partial potential energy surface is significantly affected by electrostatic intramolecular interactions. In this regard the non-bonded interactions appears to be less important than the dipole-dipole type interactions for a given interatomic distance when heteroatoms are present in the molecular framework. The reliability of the extended method as regards minimized structure, vibrational spectra and thermodynamic properties has been checked for more than 20 polyatomic molecules. From the correlation between calculated and experimental properties it is concluded that the method has good potential for further applications on polyatomic molecules with increasing size and topological compexities such as adenine and uracil.

  12. Phase II study of preoperative radiation plus concurrent daily tegafur-uracil (UFT with leucovorin for locally advanced rectal cancer

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    Calais Gilles

    2011-03-01

    Full Text Available Abstract Background Considerable variation in intravenous 5-fluorouracil (5-FU metabolism can occur due to the wide range of dihydropyrimidine dehydrogenase (DPD enzyme activity, which can affect both tolerability and efficacy. The oral fluoropyrimidine tegafur-uracil (UFT is an effective, well-tolerated and convenient alternative to intravenous 5-FU. We undertook this study in patients with locally advanced rectal cancer to evaluate the efficacy and tolerability of UFT with leucovorin (LV and preoperative radiotherapy and to evaluate the utility and limitations of multicenter staging using pre- and post-chemoradiotherapy ultrasound. We also performed a validated pretherapy assessment of DPD activity and assessed its potential influence on the tolerability of UFT treatment. Methods This phase II study assessed preoperative UFT with LV and radiotherapy in 85 patients with locally advanced T3 rectal cancer. Patients with potentially resectable tumors received UFT (300 mg/m/2/day, LV (75 mg/day, and pelvic radiotherapy (1.8 Gy/day, 45 Gy total 5 days/week for 5 weeks then surgery 4-6 weeks later. The primary endpoints included tumor downstaging and the pathologic complete response (pCR rate. Results Most adverse events were mild to moderate in nature. Preoperative grade 3/4 adverse events included diarrhea (n = 18, 21% and nausea/vomiting (n = 5, 6%. Two patients heterozygous for dihydropyrimidine dehydrogenase gene (DPYD experienced early grade 4 neutropenia (variant IVS14+1G > A and diarrhea (variant 2846A > T. Pretreatment ultrasound TNM staging was compared with postchemoradiotherapy pathology TN staging and a significant shift towards earlier TNM stages was observed (p Conclusion Preoperative chemoradiotherapy using UFT with LV plus radiotherapy was well tolerated and effective and represents a convenient alternative to 5-FU-based chemoradiotherapy for the treatment of resectable rectal cancer. Pretreatment detection of DPD deficiency should

  13. Theoretical study of the hydroxyl radical addition to uracil and photochemistry of the formed U6OH• adduct.

    Science.gov (United States)

    Francés-Monerris, Antonio; Merchán, Manuela; Roca-Sanjuán, Daniel

    2014-03-20

    Hydroxyl radical ((•)OH) is produced in biological systems by external or endogenous agents. It can damage DNA/RNA by attacking pyrimidine nucleobases through the addition to the C5═C6 double bond. The adduct resulting from the attachment at the C5 position prevails in the experimental measurements, although the reasons for this preference remain unclear. The first aim of this work is therefore to shed light on the comprehension of this important process. Thus, the thermal (•)OH addition to the C5═C6 double bond of uracil has been studied theoretically by using DFT, MP2, and the multiconfigurational CASPT2//CASSCF methodologies. The in-vacuo results obtained with the latter protocol plus the analysis of solvent effects support the experimental observation. A significant lower barrier height is predicted for the C5 pathway with respect to that of the C6 route. In contrast to the C5 adduct, the C6 adduct is able to absorb visible light. Hence, the second aim of the work is to study the photochemistry of this species using the CASPT2//CASSCF methodology within the framework of the photochemical reaction path approach (PRPA). The nonradiative decay to the ground state of this compound has been characterized. A photoreactive character is predicted for the C6 adduct in the excited states according to the presence of excited-state minima along the main decay channel. Finally, a new mechanism of photodissociation has been explored, which implies the photoinduced regeneration of the canonical nucleobase by irradiating with visible light, being therefore relevant in RNA protection against damage by reactive oxygen species.

  14. Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs.

    Science.gov (United States)

    Lipani, Luca; Odadzic, Dalibor; Weizel, Lilia; Schwed, Johannes-Stephan; Sadek, Bassem; Stark, Holger

    2014-10-30

    The histamine H3 receptor (H3R) plays a role in cognitive and memory processes and is involved in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. Therefore, several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. However, many other promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity accompanied with low solubility. Analysis of previous potential H3R selective antagonists/inverse agonists, e.g. pitolisant, revealed promising results concerning physicochemical properties and drug-likeness. Herein, a series of new hH3R ligands 8-20 consisting of piperidin-1-yl or piperidin-1-yl-propoxyphenyl coupled to different uracil, thymine, and 5,6-dimethyluracil related moieties, were synthesized, evaluated on their binding properties at the hH3R and the estimation of different physicochemical and drug-likeness properties. Due to the coupling to various positions at pyrimidine-2,4-(1H,3H)-dione, affinity at hH3Rs and drug-likeness parameters have been improved. For instance, compound 9 showed in addition to high affinity at the hH3R (pKi (hH3R) = 8.14) clog S, clog P, LE, LipE, and drug-likeness score values of -4.36, 3.47, 0.34, 4.63, and 1.54, respectively. Also, the methyl substituted analog 17 (pKi (hH3R) = 8.15) revealed LE, LipE and drug-likeness score values of -3.29, 2.47, 0.49, 5.52, and 1.76, respectively.

  15. Structures of protonated thymine and uracil and their monohydrated gas-phase ions from ultraviolet action spectroscopy and theory.

    Science.gov (United States)

    Pedersen, Sara Øvad; Byskov, Camilla Skinnerup; Turecek, Frantisek; Brøndsted Nielsen, Steen

    2014-06-19

    The strong UV chromophores thymine (Thy) and uracil (Ura) have identical heteroaromatic rings that only differ by one methyl substituent. While their photophysics has been elucidated in detail, the effect on the excited states of base protonation and single water molecules is less explored. Here we report gas-phase absorption spectra of ThyH(+) and UraH(+) and monohydrated ions and demonstrate that the substituent is not only responsible for spectral shifts but also influences the tautomer distribution, being different for bare and monohydrated ions. Spectra interpretation is aided by calculations of geometrical structures and transition energies. The lowest free-energy tautomer (denoted 178, enol-enol form) accounts for 230-280 nm (ThyH(+)) and 225-270 nm (UraH(+)) bands. ThyH(+) hardly absorbs above 300 nm, whereas a discernible band is measured for UraH(+) (275-320 nm), ascribed to the second lowest free-energy tautomer (138, enol-keto form) comprising a few percent of the UraH(+) population at room temperature. Band widths are similar to those measured of cold ions in support of very short excited-state lifetimes. Attachment of a single water increases the abundance of 138 relative to 178, 138 now clearly present for ThyH(+). 138 resembles more the tautomer present in aqueous solution than 178 does, and 138 may indeed be a relevant transition structure. The band of ThyH(+)(178) is unchanged, that of UraH(+)(178) is nearly unchanged, and that of UraH(+)(138) blue-shifts by about 10 nm. In stark contrast to protonated adenine, more than one solvating water molecule is required to re-establish the absorption of ThyH(+) and UraH(+) in aqueous solution.

  16. Classical trajectory Monte Carlo model calculations for ionization of the uracil molecule by impact of heavy ions

    Science.gov (United States)

    Sarkadi, L.

    2016-09-01

    The ionization of the uracil molecule induced by heavy-ion impact has been investigated using the classical trajectory Monte Carlo (CTMC) method. Assuming the validity of the independent-particle model approximation, the collision problem is solved by considering the three-body dynamics of the projectile, an active electron and the molecule core. The interaction of the molecule core with the other two particles is described by a multi-center potential built from screened atomic potentials. The cross section differential with respect to the energy and angle of the electrons ejected in the ionization process has been calculated for an impact of 3.5 MeV u-1 {{{C}}}6+ ions. Total electron emission cross sections (TCS) are presented for {{{C}}}q+ (q=0-6) and {{{O}}}6+ projectiles as a function of the impact energy in the range from 10 keV u-1 to 10 MeV u-1. The dependence of the TCS on the charge state of the projectile has been investigated for 2.5 MeV u-1 {{{O}}}q+ (q=4-8) and {{{F}}}q+ (q=5-9) ions. The results of the calculations are compared with available experimental data and the predictions of other theoretical models: the first Born approximation with correct boundary conditions (CB1), the continuum-distorted-wave-eikonal-initial-state approach (CDW-EIS), and the combined classical-trajectory Monte Carlo-classical over-the-barrier model (CTMC-COB).

  17. The methyl- and aza-substituent effects on nonradiative decay mechanisms of uracil in water: a transient absorption study in the UV region.

    Science.gov (United States)

    Hua, XinZhong; Hua, LinQiang; Liu, XiaoJun

    2016-05-18

    The nonradiative decay dynamics of photo-excited uracil (Ura) and its derivatives, i.e., thymine (5-methyluracil, Thy), 6-methyluracil (6-MU) and 6-azauracil (6-AU) in water, has been studied using a femtosecond transient absorption method. The molecules are populated in the lowest (1)ππ* state by a pump pulse at 266 nm, and a broadband continuum in the deep UV region is then employed as the probe. The extension of the continuous UV probe down to 250 nm enables us to investigate comprehensively the population dynamics of the ground states for those molecules and to uncover the substituent effects on nonradiative decay dynamics of uracil. Vibrational cooling in the ground states of Ura, Thy and 6-MU has been directly observed for the first time, providing solid evidence of the ultrafast (1)ππ* → S0 decay. In combination with the ground state bleaching signals, it is consolidated that their lowest (1)ππ* state decays via two parallel pathways, i.e., (1)ππ* → S0 and (1)ππ* → (1)nπ*. Moreover, the contribution of the (1)ππ* → (1)nπ* channel is found to be much smaller for Thy or 6-MU than for Ura. Different from methyl-substitution, the initial (1)ππ* state of the aza-substituent 6-AU decays primarily to the (1)nπ* state, while the (1)ππ* → S0 channel can be negligible. Our study provides a comprehensive understanding of the substituent effects on the excited-state dynamics of uracil in water.

  18. Vibrational spectra of the ML/sub 2/Cl/sub 2/ complexes (M=Zn,Cd,Co,Ni; L=5-methyl-1-phenylhexahydro-1,3-5-triazine-2-thion)

    Energy Technology Data Exchange (ETDEWEB)

    Zakharova, O.S.; Dobreva, D.D.; Ignatova, L.A.; Kravchenko, V.V.; Petrov, K.I. (Moskovskij Inst. Tonkoj Khimicheskoj Tekhnologii (USSR))

    1984-01-01

    IR absorption spectra of the complexes ML/sub 2/Cl/sub 2/ (M=Zn, Cd, Co, Ni, L=5 - methyl-1-phenylhexahydro-1, 3, 5-triazine-2-thion) in the range from 4000 to 200 cm/sup -1/ and Raman laser spectra of the complexes ML/sub 2/Cl/sub 2/ (M=Zn, Cd) in crystal state are recorded. Qualitative interpretation of vibrational frequencies in the spectra has been carried out. It is established that ligand molecules are coordinated via sulphur atom. The structure of the complexes is briefly outlined.

  19. Diaquabis[2-(5-isopropyl-5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl-κN3nicotinato-κN]manganese(II

    Directory of Open Access Journals (Sweden)

    Peng Gao

    2010-12-01

    Full Text Available In the title compound, [Mn(C13H14N3O32(H2O2], the MnII ion is coordinated by four N atoms from two (±-2-(5-isopropyl-5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-ylnicotinate ligands and two water molecules in a distorted octahedral environment. Intermolecular O—H...O hydrogen bonds lead to a chain along [010]. Intramolecular N—H...O and O—H...O hydrogen bonds are observed.

  20. The respective N-hydroxypyrazole analogues of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid

    DEFF Research Database (Denmark)

    Clausen, Rasmus P; Hansen, Kasper B; Calí, Patrizia

    2004-01-01

    We have determined the pharmacological activity of N-hydroxypyrazole analogues (3a and 4a) of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA), as well as substituted derivatives of these two compounds. The pharmacological...... partial agonism to antagonism with increasing substituent size, substitution abolishes affinity for mglu1 and mglu4 receptors. Ligand- and receptor-based modelling approaches assist in explaining these pharmacological trends among the metabotropic receptors and suggest a mechanism of partial agonism...

  1. Effects of vaccinia virus uracil DNA glycosylase catalytic site and deoxyuridine triphosphatase deletion mutations individually and together on replication in active and quiescent cells and pathogenesis in mice

    Directory of Open Access Journals (Sweden)

    Moss Bernard

    2008-12-01

    Full Text Available Abstract Background Low levels of uracil in DNA result from misincorporation of dUMP or cytosine deamination. Vaccinia virus (VACV, the prototype poxvirus, encodes two enzymes that can potentially reduce the amount of uracil in DNA. Deoxyuridine triphosphatase (dUTPase hydrolyzes dUTP, generating dUMP for biosynthesis of thymidine nucleotides while decreasing the availability of dUTP for misincorporation; uracil DNA glycosylase (UNG cleaves uracil N-glycosylic bonds in DNA initiating base excision repair. Studies with actively dividing cells showed that the VACV UNG protein is required for DNA replication but the UNG catalytic site is not, whereas the dUTPase gene can be deleted without impairing virus replication. Recombinant VACV with an UNG catalytic site mutation was attenuated in vivo, while a dUTPase deletion mutant was not. However, the importance of the two enzymes for replication in quiescent cells, their possible synergy and roles in virulence have not been fully assessed. Results VACV mutants lacking the gene encoding dUTPase or with catalytic site mutations in UNG and double UNG/dUTPase mutants were constructed. Replication of UNG and UNG/dUTPase mutants were slightly reduced compared to wild type or the dUTPase mutant in actively dividing cells. Viral DNA replication was reduced about one-third under these conditions. After high multiplicity infection of quiescent fibroblasts, yields of wild type and mutant viruses were decreased by 2-logs with relative differences similar to those observed in active fibroblasts. However, under low multiplicity multi-step growth conditions in quiescent fibroblasts, replication of the dUTPase/UNG mutant was delayed and 5-fold lower than that of either single mutant or parental virus. This difference was exacerbated by 1-day serial passages on quiescent fibroblasts, resulting in 2- to 3-logs lower titer of the double mutant compared to the parental and single mutant viruses. Each mutant was more

  2. Elucidating collision induced dissociation products and reaction mechanisms of protonated uracil by coupling chemical dynamics simulations with tandem mass spectrometry experiments.

    Science.gov (United States)

    Molina, Estefanía Rossich; Ortiz, Daniel; Salpin, Jean-Yves; Spezia, Riccardo

    2015-12-01

    In this study we have coupled mixed quantum-classical (quantum mechanics/molecular mechanics) direct chemical dynamics simulations with electrospray ionization/tandem mass spectrometry experiments in order to achieve a deeper understanding of the fragmentation mechanisms occurring during the collision induced dissociation of gaseous protonated uracil. Using this approach, we were able to successfully characterize the fragmentation pathways corresponding to ammonia loss (m/z 96), water loss (m/z 95) and cyanic or isocyanic acid loss (m/z 70). Furthermore, we also performed experiments with isotopic labeling completing the fragmentation picture. Remarkably, fragmentation mechanisms obtained from chemical dynamics simulations are consistent with those deduced from isotopic labeling.

  3. Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small cell lung cancer-specific cytotoxicity and tumor growth delay

    DEFF Research Database (Denmark)

    Christensen, Camilla L; Gjetting, Torben; Poulsen, Thomas Tuxen

    2010-01-01

    Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine...... deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug. Experimental design: The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter insulinoma-associated 1 (INSM1...

  4. Synthesis of New 1,2,3-Triazole Derivatives of Uracil and Thymine with Potential Inhibitory Activity against Acidic Corrosion of Steels

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    Mario A. Romero-Romo

    2013-04-01

    Full Text Available Ten 1,4-disubstituted 1,2,3-triazoles were synthesized from one of 1-(azido-methylbenzene, 1-(azidomethyl-4-fluorobenzene, 1-(azidomethyl-4-chlorobenzene, 1-(azidomethyl-4-bromobenzene or 1-(azidomethyl-4-iodobenzene, generated in situ from sodium azide and the corresponding benzyl halide, and dipropargyl uracil or dipropargyl thymine. Optimal experimental conditions were established for the conventional click chemistry. The corrosion inhibiting properties of some of these compounds, which were determined by means of an electrochemical technique, are also presented.

  5. New insights on the role of the gamma-herpesvirus uracil-DNA glycosylase leucine loop revealed by the structure of the Epstein-Barr virus enzyme in complex with an inhibitor protein.

    Science.gov (United States)

    Géoui, Thibault; Buisson, Marlyse; Tarbouriech, Nicolas; Burmeister, Wim Pascal

    2007-02-09

    Epstein-Barr virus (EBV) is a human gamma-herpesvirus. Within its 86 open reading frame containing genome, two enzymes avoiding uracil incorporation into DNA can be found: uracil triphosphate hydrolase and uracil-DNA glycosylase (UNG). The latter one excises uracil bases that are due to cytosine deamination or uracil misincorporation from double-stranded DNA substrates. The EBV enzyme belongs to family 1 UNGs. We solved the three-dimensional structure of EBV UNG in complex with the uracil-DNA glycosylase inhibitor protein (Ugi) from bacteriophage PBS-2 at a resolution of 2.3 A by X-ray crystallography. The structure of EBV UNG encoded by the BKRF3 reading frame shows the excellent global structural conservation within the solved examples of family 1 enzymes. Four out of the five catalytic motifs are completely conserved, whereas the fifth one, the leucine loop, carries a seven residue insertion. Despite this insertion, catalytic constants of EBV UNG are similar to those of other UNGs. Modelling of the EBV UNG-DNA complex shows that the longer leucine loop still contacts DNA and is likely to fulfil its role of DNA binding and deformation differently than the enzymes with previously solved structures. We could show that despite the evolutionary distance of EBV UNG from the natural host protein, bacteriophage Ugi binds with an inhibitory constant of 8 nM to UNG. This is due to an excellent specificity of Ugi for conserved elements of UNG, four of them corresponding to catalytic motifs and a fifth one corresponding to an important beta-turn structuring the catalytic site.

  6. 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

    Directory of Open Access Journals (Sweden)

    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.

  7. Sulfolobus acidocaldarius UDG Can Remove dU from the RNA Backbone: Insight into the Specific Recognition of Uracil Linked with Deoxyribose

    Directory of Open Access Journals (Sweden)

    Gang-Shun Yi

    2017-01-01

    Full Text Available Sulfolobus acidocaldarius encodes family 4 and 5 uracil-DNA glycosylase (UDG. Two recombinant S. acidocaldarius UDGs (SacUDG were prepared and biochemically characterized using oligonucleotides carrying a deaminated base. Both SacUDGs can remove deoxyuracil (dU base from both double-stranded DNA and single-stranded DNA. Interestingly, they can remove U linked with deoxyribose from single-stranded RNA backbone, suggesting that the riboses on the backbone have less effect on the recognition of dU and hydrolysis of the C-N glycosidic bond. However, the removal of rU from DNA backbone is inefficient, suggesting strong steric hindrance comes from the 2′ hydroxyl of ribose linked to uracil. Both SacUDGs cannot remove 2,2′-anhydro uridine, hypoxanthine, and 7-deazaxanthine from single-stranded DNA and single-stranded DNA. Compared with the family 2 MUG, other family UDGs have an extra N-terminal structure consisting of about 50 residues. Removal of the 46 N-terminal residues of family 5 SacUDG resulted in only a 40% decrease in activity, indicating that the [4Fe-4S] cluster and truncated secondary structure are not the key elements in hydrolyzing the glycosidic bond. Combining our biochemical and structural results with those of other groups, we discussed the UDGs’ catalytic mechanism and the possible repair reactions of deaminated bases in prokaryotes.

  8. Sulfolobus acidocaldarius UDG Can Remove dU from the RNA Backbone: Insight into the Specific Recognition of Uracil Linked with Deoxyribose.

    Science.gov (United States)

    Yi, Gang-Shun; Wang, Wei-Wei; Cao, Wei-Guo; Wang, Feng-Ping; Liu, Xi-Peng

    2017-01-18

    Sulfolobus acidocaldarius encodes family 4 and 5 uracil-DNA glycosylase (UDG). Two recombinant S. acidocaldarius UDGs (SacUDG) were prepared and biochemically characterized using oligonucleotides carrying a deaminated base. Both SacUDGs can remove deoxyuracil (dU) base from both double-stranded DNA and single-stranded DNA. Interestingly, they can remove U linked with deoxyribose from single-stranded RNA backbone, suggesting that the riboses on the backbone have less effect on the recognition of dU and hydrolysis of the C-N glycosidic bond. However, the removal of rU from DNA backbone is inefficient, suggesting strong steric hindrance comes from the 2' hydroxyl of ribose linked to uracil. Both SacUDGs cannot remove 2,2'-anhydro uridine, hypoxanthine, and 7-deazaxanthine from single-stranded DNA and single-stranded DNA. Compared with the family 2 MUG, other family UDGs have an extra N-terminal structure consisting of about 50 residues. Removal of the 46 N-terminal residues of family 5 SacUDG resulted in only a 40% decrease in activity, indicating that the [4Fe-4S] cluster and truncated secondary structure are not the key elements in hydrolyzing the glycosidic bond. Combining our biochemical and structural results with those of other groups, we discussed the UDGs' catalytic mechanism and the possible repair reactions of deaminated bases in prokaryotes.

  9. RutR is the uracil/thymine-sensing master regulator of a set of genes for synthesis and degradation of pyrimidines.

    Science.gov (United States)

    Shimada, Tomohiro; Hirao, Kiyo; Kori, Ayako; Yamamoto, Kaneyoshi; Ishihama, Akira

    2007-11-01

    Using the genomic SELEX, a total of six Escherichia coli DNA fragments have been identified, which formed complexes with transcription factor RutR. The RutR regulon was found to include a large number of genes encoding components for not only degradation of pyrimidines but also transport of glutamate, synthesis of glutamine, synthesis of pyrimidine nucleotides and arginine, and degradation of purines. DNase I footprinting indicated that RutR recognizes a palindromic sequence of TTGACCAnnTGGTCAA. The RutR box in P1 promoter of carAB encoding carbamoyl phosphate synthetase, a key enzyme of pyrimidine synthesis, overlaps with the PepA (CarP) repressor binding site, implying competition between RutR and PepA. Adding either uracil or thymine abolished RutR binding in vitro to the carAB P1 promoter. Accordingly, in the rutR-deletion mutant or in the presence of uracil, the activation in vivo of carAB P1 promoter was markedly reduced. Northern blot analysis of the RutR target genes indicated that RutR represses the Gad system genes involved in glutamate-dependent acid resistance and allantoin degradation. Altogether we propose that RutR is the pyrimidine sensor and the master regulator for a large set of the genes involved in the synthesis and degradation of pyrimidines.

  10. Nucleic acid related compounds. 65. New syntheses of 1-(beta-D-arabinofuranosyl)-5(E)-(2-iodovinyl)uracil (IVAraU) from vinylsilane precursors. Radioiodine uptake as a marker for thymidine kinase positive herpes viral infections

    Energy Technology Data Exchange (ETDEWEB)

    Robins, M.J.; Manfredini, S.; Wood, S.G.; Wanklin, R.J.; Rennie, B.A.; Sacks, S.L. (Department of Chemistry, Brigham Young University, Provo, UT (USA))

    1991-07-01

    (Trimethylsilyl)acetylene was coupled with 1-(2,3,5-tri-O-acetyl-beta-D- arabinofuranosyl)-5-iodouracil to give 1- (2,3,5-tri-O-acetyl-beta-D-arabinofuranosyl)-5-(2-(trimethylsilyl)eth yny l) uracil. Lindlar hydrogenation of 4 gave 1-(2,3,4-tri-O-acetyl-beta-D-arabinofuranosyl)-5(Z)-(2- (trimethylsilyl)vinyl)uracil. Treatment of 5 with iodine monochloride (or sodium iodide/phenyliodine(III) dichloride) in benzene gave 1-(2,3,5-tri-O-acetyl-beta-D-arabinofuranosyl)-5(E)-(2-iodovinyl)uracil (7), whereas polar solvents favored the (Z)-iodovinyl isomer 8. Deacetylation of 7 gave 1-(beta-D-arabinofuranosyl)-5(E)-(2-iodovinyl)uracil (IVAraU, 9). A microscale in situ synthesis with Na{asterisk}I gave ({asterisk}I)IVAraU. Treatment of HSV-infected cells with (125I)IVAraU resulted in virus-dependent uptake associated with nucleoside phosphorylation by wild type or acyclovir-resistant DNA polymerase mutants (but not with TK-HSV-1 mutants). Uptake was virus-inoculum dependent and was detectable within 4 h postinfection. The process was not completely reversible. Virus-specified uptake of (125I)IVAraU may allow automated in vitro detection of HSV isolates.

  11. Synthesis, characterization and investigation of electrochemical and spectroelectrochemical properties of non-peripherally tetra-5-methyl-1,3,4-thiadiazole substituted copper(II) iron(II) and oxo-titanium (IV) phthalocyanines

    Science.gov (United States)

    Demirbaş, Ümit; Akyüz, Duygu; Akçay, Hakkı Türker; Barut, Burak; Koca, Atıf; Kantekin, Halit

    2017-09-01

    In this study novel substituted phthalonitrile (3) and non-peripherally tetra 5-Methyl-1,3,4-thiadiazole substituted copper(II) (4), iron(II) (5) and oxo-titanium (IV) (6) phthalocyanines were synthesized. These novel compounds were fully characterized by FT-IR, 1H NMR, UV-vis and MALDI-TOF mass spectroscopic techniques. Voltammetric and in situ spectroelectrochemical measurements were performed for metallo-phthalocyanines (4-6). TiIVOPc and FeIIPc showed metal-based and ligand-based electron transfer reactions while CuIIPc shows only ligand-based electron transfer reaction. Voltammetric measurements indicated that the complexes have reversible, diffusion controlled and one-electron redox reactions. The assignments of the redox processes and color of the electrogenerated species of the complexes were determined with in-situ spectroelectrochemical and electrocolorimetric measurements. These measurements showed that the complexes can be used as the electrochromic materials for various display technologies.

  12. Crystal structure of N-(7-di­bromo­methyl-5-methyl-1,8-naphthyridin-2-yl)benzamide–pyrrolidine-2,5-dione (1/1)

    Science.gov (United States)

    Wang, Bang Zhong; Zhou, Jun Ping; Zhou, Yong; Luo, Jian Song; Yang, Jun Jie; Chi, Shao M.ing

    2017-01-01

    The title compound, C17H13Br2N3O·C4H5NO2, is a co-crystal of N-(7-di­bromo­methyl-5-methyl-1,8-naphthyridin-2-yl)benzamide and pyrrolidine-2,5-dione (succinimide). The benzamide mol­ecule exhibits pseudo-mirror symmetry, with an r.m.s. deviation of the non-H atoms of 0.09 Å (except for the two Br atoms). The angle between the least-squares planes of the two mol­ecules is 26.2 (2)°. In the crystal, the two mol­ecules are mutually linked by N—H⋯O and N—H⋯N hydrogen bonds. The packing is consolidated by C—H⋯(O,N) hydrogen bonds and π–π stacking inter­actions. PMID:28083121

  13. A DFT/TD DFT study of the structure and spectroscopic properties of 5-methyl-2-(8-quinolinyl)benzoxazole and its complexes with Zn(II) ion.

    Science.gov (United States)

    Guzow, Katarzyna; Milewska, Magda; Czaplewski, Cezary; Wiczk, Wiesław

    2010-02-01

    The structure and spectroscopic properties of 5-methyl-2-(8-quinolinyl)benzoxazole and its complexes with Zn(II) ion were studied using a DFT and TD DFT methods with def2-TZVP basis set. It was shown that the type of functional used (B3-LYP or pbe0) implemented in TURBOMOLE package does not have essential influence on the geometry (small differences in bond length, valence and dihedral angles) of studied compounds in both ground and excited states. However, significant differences were obtained for the position of vertical absorption and emission transition but not for the oscillator strength of transition. Application of pbe0 functional seems to reproduce better the experimental spectrum.

  14. Synthesis, Crystal Structure and Biological Activities of 3-[2-(4-Fluoro-phenyl)-ethyl]-5-methyl-4-hydroxyl-4-methyl-7-methylsulfanyl-3,4-dihydro-pyrido[4,3-d]pyrimidine-8-carbonitrile

    Institute of Scientific and Technical Information of China (English)

    MO Wen-Yan; HE Hong-Wu

    2007-01-01

    The title compound, 3-[2-(4-fluoro-phenyl)-ethyl]-5-methyl-4-hydroxyl-4-methyl-7-methylsulfanyl-3,4-dihydro-pyrido[4,3-d]pyrimidine-8-carbonitrile, has been prepared and detemined by single-crystal X-ray diffraction. The crystal belongs to the triclinic system, space group P1- with a = 6.8754(8), b = 10.2617(12), c = 13.3491(16)(A), α = 93.163(2), β = 96.704(2), γ =102.421(2)°, V= 910.35(19) (A)3, Z = 2, Mr = 370.44, Dc = 1.351 g/cm3,μ = 0.203 mm-1, F(000) =388, the final R = 0.0573 and wR = 0.1497. X-ray analysis reveals that the pyridine and pyrimidine rings are almost coplanar.

  15. 5-methyl-tetrahydrofolate and the S-adenosylmethionine cycle in C57BL/6J mouse tissues: gender differences and effects of arylamine N-acetyltransferase-1 deletion.

    Directory of Open Access Journals (Sweden)

    Katey L Witham

    Full Text Available Folate catabolism involves cleavage of the C(9-N(10 bond to form p-aminobenzoylgluamate (PABG and pterin. PABG is then acetylated by human arylamine N-acetyltransferase 1 (NAT1 before excretion in the urine. Mice null for the murine NAT1 homolog (Nat2 show several phenotypes consistent with altered folate homeostasis. However, the exact role of Nat2 in the folate pathway in vivo has not been reported. Here, we examined the effects of Nat2 deletion in male and female mice on the tissue levels of 5-methyl-tetrahydrofolate and the methionine-S-adenosylmethionine cycle. We found significant gender differences in hepatic and renal homocysteine, S-adenosylmethionine and methionine levels consistent with a more active methionine-S-adenosylmethionine cycle in female tissues. In addition, methionine levels were significantly higher in female liver and kidney. PABG was higher in female liver tissue but lower in kidney compared to male tissues. In addition, qPCR of mRNA extracted from liver tissue suggested a significantly lower level of Nat2 expression in female animals. Deletion of Nat2 affected liver 5- methyl-tetrahydrofolate in female mice but had little effect on other components of the methionine-S-adenosylmethionine cycle. No N-acetyl-PABG was observed in any tissues in Nat2 null mice, consistent with the role of Nat2 in PABG acetylation. Surprisingly, tissue PABG levels were similar between wild type and Nat2 null mice. These results show that Nat2 is not required to maintain tissue PABG homeostasis in vivo under normal conditions.

  16. Insights into the mechanisms of ifosfamide encephalopathy: drug metabolites have agonistic effects on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and induce cellular acidification in mouse cortical neurons.

    Science.gov (United States)

    Chatton, J Y; Idle, J R; Vågbø, C B; Magistretti, P J

    2001-12-01

    Therapeutic value of the alkylating agent ifosfamide has been limited by major side effects including encephalopathy. Although the underlying biochemical processes of the neurotoxic side effects are still unclear, they could be attributed to metabolites rather than to ifosfamide itself. In the present study, the effects of selected ifosfamide metabolites on indices of neuronal activity have been investigated, in particular for S-carboxymethylcysteine (SCMC) and thiodiglycolic acid (TDGA). Because of structural similarities of SCMC with glutamate, the Ca(2+)(i) response of single mouse cortical neurons to SCMC and TDGA was investigated. SCMC, but not TDGA, evoked a robust increase in Ca(2+)(i) concentration that could be abolished by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but only partly diminished by the N-methyl-D-aspartate receptor antagonist 10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK=801). Cyclothiazide (CYZ), used to prevent AMPA/kainate receptor desensitization, potentiated the response to SCMC. Because activation of AMPA/kainate receptors is known to induce proton influx, the intracellular pH (pH(i)) response to SCMC was investigated. SCMC caused a concentration-dependent acidification that was amplified by CYZ. Since H(+)/monocarboxylate transporter (MCT) activity leads to similar cellular acidification, we tested its potential involvement in the pH(i) response. Application of the lactate transport inhibitor quercetin diminished the pH(i) response to SCMC and TDGA by 43 and 51%, respectively, indicating that these compounds may be substrates of MCTs. Taken together, this study indicates that hitherto apparently inert ifosfamide metabolites, in particular SCMC, activate AMPA/kainate receptors and induce cellular acidification. Both processes could provide the biochemical basis of the observed ifosfamide-associated encephalopathy.

  17. Enhancement of Antitumor Effect of Tegafur/Uracil (UFT) plus Leucovorin by Combined Treatment with Protein-Bound Polysaccharide, PSK, in Mouse Models

    Institute of Scientific and Technical Information of China (English)

    Ryoji Katoh; Mitsuru Ooshiro

    2007-01-01

    We evaluated the antitumor effect of combined therapy with tegafur/uracil (UFT) plus leucovorin (LV) (UFT/LV)and protein-bound polysaccharide, PSK, in three mouse models of transplantable tumors. UFT/LV showed antitumor effect against Meth A sarcoma, and the antitumor effect was enhanced when PSK given concomitantly.UFT/LV showed antitumor effect to Lewis lung carcinoma and PSK alone also showed antitumor effect at high dose, but a combination of UFT/LV and PSK resulted in no enhanced antitumor effect. Colon 26 carcinoma was weakly responsive to UFT/LV, and no enhancement of antitumor effect was found even PSK was used in combination. In conclusion, while the effect of PSK varies depending on tumor, combined use of UFT/LV and PSK may be expected to augment the antitumor effect.

  18. Assessing solvent effects on the singlet excited state lifetime of uracil derivatives: A femtosecond fluorescence upconversion study in alcohols and D{sub 2}O

    Energy Technology Data Exchange (ETDEWEB)

    Gustavsson, Thomas [Laboratoire Francis Perrin, CEA/DSM/DRECAM/SPAM - CNRS URA 2453, CEA/Saclay, F-91191 Gif-sur-Yvette (France)], E-mail: thomas.gustavsson@cea.fr; Banyasz, Akos [Laboratoire Francis Perrin, CEA/DSM/DRECAM/SPAM - CNRS URA 2453, CEA/Saclay, F-91191 Gif-sur-Yvette (France); Sarkar, Nilmoni [Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, WB (India); Markovitsi, Dimitra [Laboratoire Francis Perrin, CEA/DSM/DRECAM/SPAM - CNRS URA 2453, CEA/Saclay, F-91191 Gif-sur-Yvette (France); Improta, Roberto [Dipartimento di Chimica, Universita Federico II, Complesso Universitario Monte S. Angelo, Via Cintia, I-80126 Napoli (Italy); Istituto Biostrutture e Bioimmagini/CNR, V. Mezzocannone 6 - 80134 Napoli (Italy)

    2008-06-23

    The excited state lifetimes of uracil, thymine and 5-fluorouracil have been measured using femtosecond UV fluorescence upconversion in various protic and aprotic polar solvents. The fastest decays are observed in acetonitrile and the slowest in aqueous solution while those observed in alcohols are intermediate. No direct correlation with macroscopic solvent parameters such as polarity or viscosity is found, but hydrogen bonding is one key factor affecting the fluorescence decay. It is proposed that the solvent modulates the relative energy of two close-lying electronically excited states, the bright {pi}{pi}* and the dark n{pi}* states. This relative energy gap controls the non-radiative relaxation of the {pi}{pi}* state through a conical intersection close to the Franck-Condon region competing with the ultrafast internal conversion to the ground state. In addition, an inverse isotope effect is observed in D{sub 2}O where the decays are faster than in H{sub 2}O.

  19. Development of Diversified Methods for Chemical Modification of the 5,6-Double Bond of Uracil Derivatives Depending on Active Methylene Compounds

    Directory of Open Access Journals (Sweden)

    Kosaku Hirota

    2012-05-01

    Full Text Available The reaction of 5-halogenouracil and uridine derivatives 1 and 7 with active methylene compounds under basic conditions produced diverse and selective C-C bond formation products by virtue of the nature of the carbanions. Three different types of reactions such as the regioselective C-C bond formation at the 5- and 6-positions of uracil and uridine derivatives (products 2, 5, 8, 17, 20 and 21, and the formation of fused heterocycle derivatives 2,4-diazabicyclo[4.1.0]heptane (15 and 2,4-diazabicyclo-[4.1.0]nonane (16 via dual C-C bond formations at both the 5- and 6-positions were due to the different active methylene compounds used as reagents.

  20. Cisplatin, tegafur-uracil and leucovorin plus mitomycin C: an acceptably effective and toxic regimen for patients with recurrent or metastatic nasopharyngeal carcinoma

    Directory of Open Access Journals (Sweden)

    Chia-Hsun Hsieh

    2013-10-01

    Full Text Available Background: This prospective phase II clinical trial evaluated the efficacy and toxicity of cisplatin, oral tegafur-uracil, leucovorin, and mitomycin C in patients with recurrent or metastatic nasopharyngeal carcinoma. Methods: Patients with histologically proven non-keratinizing or undifferentiated nasopharyngeal carcinoma were prospectively enrolled from April 2002 to June 2005. Cisplatin 50 mg/m 2 on day 1, 22 and mitomycin C 6 mg/m 2 on day 1 were administered. Oral tegafur-uracil 300 mg/m 2 /day and oral leucovorin 60 mg/day were given on day 1-14 and day 22-35, respectively. Each cycle was repeated every 6 weeks. Primary and secondary endpoints are response rate and toxic profiles with survivals, respectively. Results: Twenty-two patients with the median age of 47 (35-69 years were enrolled in the study. Sixteen (72.7% patients had undifferentiated nasopharyngeal carcinoma. The regimen was well-tolerated by all patients with the exception of one patient (4.6% who experienced grade IV anorexia, and two patients (9.1% who had grade IV vomiting. There was no treatment-related death. The overall response rate was 59.1%, including 3 (13.6% complete remissions. The median duration of response was 15.9 months, the median time to tumor progression was 10.0 months, and the median overall survival was 16.0 months. Conclusion: This outpatient chemotherapy regimen is acceptably effective and toxic among patients with recurrent or metastatic nasopharyngeal carcinoma.

  1. Structural and biophysical analysis of interactions between cod and human uracil-DNA N-glycosylase (UNG) and UNG inhibitor (Ugi)

    Energy Technology Data Exchange (ETDEWEB)

    Assefa, Netsanet Gizaw [UiT The Arctic University of Norway, 9037 Tromsø (Norway); Niiranen, Laila [UiT The Arctic University of Norway, 9037 Tromsø (Norway); University of Turku, FIN-20014 Turku (Finland); Johnson, Kenneth A.; Leiros, Hanna-Kirsti Schrøder; Smalås, Arne Oskar; Willassen, Nils Peder [UiT The Arctic University of Norway, 9037 Tromsø (Norway); Moe, Elin, E-mail: elin.moe@uit.no [UiT The Arctic University of Norway, 9037 Tromsø (Norway); Universidade Nova de Lisboa, Avenida da Republica (EAN), 2780-157 Oeiras (Portugal)

    2014-08-01

    A structural and biophysical study of the interactions between cod and human uracil-DNA N-glycosylase (UNG) and their inhibitor Ugi is presented. The stronger interaction between cod UNG and Ugi can be explained by a greater positive electrostatic surface potential. Uracil-DNA N-glycosylase from Atlantic cod (cUNG) shows cold-adapted features such as high catalytic efficiency, a low temperature optimum for activity and reduced thermal stability compared with its mesophilic homologue human UNG (hUNG). In order to understand the role of the enzyme–substrate interaction related to the cold-adapted properties, the structure of cUNG in complex with a bacteriophage encoded natural UNG inhibitor (Ugi) has been determined. The interaction has also been analyzed by isothermal titration calorimetry (ITC). The crystal structure of cUNG–Ugi was determined to a resolution of 1.9 Å with eight complexes in the asymmetric unit related through noncrystallographic symmetry. A comparison of the cUNG–Ugi complex with previously determined structures of UNG–Ugi shows that they are very similar, and confirmed the nucleotide-mimicking properties of Ugi. Biophysically, the interaction between cUNG and Ugi is very strong and shows a binding constant (K{sub b}) which is one order of magnitude larger than that for hUNG–Ugi. The binding of both cUNG and hUNG to Ugi was shown to be favoured by both enthalpic and entropic forces; however, the binding of cUNG to Ugi is mainly dominated by enthalpy, while the entropic term is dominant for hUNG. The observed differences in the binding properties may be explained by an overall greater positive electrostatic surface potential in the protein–Ugi interface of cUNG and the slightly more hydrophobic surface of hUNG.

  2. Quantitative assessment of the effect of uracil-DNA glycosylase on amplicon DNA degradation and RNA amplification in reverse transcription-PCR

    Directory of Open Access Journals (Sweden)

    Kleiboeker Steven B

    2005-04-01

    Full Text Available Abstract Although PCR and RT-PCR provided a valuable approach for detection of pathogens, the high level of sensitivity of these assays also makes them prone to false positive results. In addition to cross-contamination with true positive samples, false positive results are also possible due to "carry-over" contamination of samples with amplicon DNA generated by previous reactions. To reduce this source of false positives, amplicon generated by reactions in which dUTP was substituted for dTTP can be degraded by uracil DNA glycosylase (UNG. UNG does not degrade RNA but will cleave contaminating uracil-containing DNA while leaving thymine-containing DNA intact. The availability of heat-labile UNG makes use of this approach feasible for RT-PCR. In this study, real-time RT-PCR was used to quantify UNG degradation of amplicon DNA and the effect of UNG on RNA detection. Using the manufacturers' recommended conditions, complete degradation of DNA was not observed for samples containing 250 copies of amplicon DNA. Doubling the UNG concentration resulted in degradation of the two lowest concentrations of DNA tested, but also resulted in an increase of 1.94 cycles in the CT for RNA detection. To improve DNA degradation while minimizing the effect on RNA detection, a series of time, temperature and enzyme concentrations were evaluated. Optimal conditions were found to be 0.25 U UNG per 25 μl reaction with a 20 min, 30°C incubation prior to RT-PCR. Under these conditions, high concentrations of amplicon DNA could be degraded while the CT for RNA detection was increased by 1.2 cycles.

  3. Methyl 4-(butyrylamino-5-methyl-2-nitrobenzoate

    Directory of Open Access Journals (Sweden)

    Cheng Yao

    2008-04-01

    Full Text Available The title compound, C13H16N2O5, is useful as an intermediate in the field of agrochemicals. Intramolecular C—H...O hydrogen bonds result in the formation of one six- and one five-membered nearly planar ring; the six-membered ring is also nearly coplanar with the adjacent benzene ring. In the crystal structure, intermolecular C—H...O hydrogen bonds link the molecules.

  4. Platinum(IV) coordination compounds containing 5-methyl-1,2,4-triazolo[1,5- a]pyrimidin-7(4 H)-one as nonleaving ligand. Molecular and cytotoxicity in vitro characterization

    Science.gov (United States)

    Łakomska, Iwona; Fandzloch, Marzena; Wojtczak, Andrzej; Szłyk, Edward

    2011-08-01

    Novel platinum(IV) coordination compounds with 5-methyl-1,2,4-triazolo[1,5- a]pyrimidin-7(4 H)-one (HmtpO): cis- trans-[PtCl 2(OH) 2(NH 3)(HmtpO)] ( 1), cis- trans-[PtCl 5(HmtpO)][(CH 3) 2NH 2] ( 2) have been prepared and structurally characterized by spectroscopic methods ( 1H, IR and X-ray crystallography ( 2)). The X-ray results indicate that the local geometry around the platinum(IV) centre approximates a typical octahedral arrangement with nitrogen atom N3 of the HmtpO and three chloride atoms in equatorial positions. The remaining two axial positions are occupied by two chlorides. The preliminary assessment of antitumor properties of ( 1) was performed as an in vitro antiproliferative activity against HL-60 human acute promyelocytic leukemia and HCV29T bladder cancer. The cis- trans-[PtCl 2(OH) 2(NH 3)(HmtpO)] ( 1) exhibits higher cytotoxic activity against HL-60 (IC 50 = 6.4 μM) than cisplatin.

  5. Normal coordinate analysis and vibrational spectroscopy (FT-IR and FT-Raman) studies of 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide using density functional method.

    Science.gov (United States)

    Shahidha, R; Muthu, S; Elamurugu Porchelvi, E; Govindarajan, M

    2014-11-11

    Vibrational spectral analysis of 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide is (5MN4TPI4C) molecule was carried out using FT-IR and FT-Raman spectroscopic techniques. The equilibrium geometry, harmonic vibrational wavenumbers, various bonding features have been computed using density functional B3LYP method with 6-311G(d,p) as basis set. The assignments of the vibrational spectra have been carried out with the aid of normal coordinate analysis (NCA) following the scaled quantum mechanical force field methodology (SQMFFM). Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The non-linear optical (NLO) behavior of 5MN4TPI4C has been studied by determination of the electric dipole moment (μ) and hyperpolarizability (β) by using B3LYP/6-311G(d,p) method. The molecular orbital compositions and their contributions to the chemical bonding are studied by Total density of energy states (TDOS), sum of α and β electron (αβDOS) density of states. Thermodynamic properties (heat capacity, entropy and enthalpy) of the title compound at different temperatures are calculated.

  6. Crystal Structure, Spectral Studies, and Hirshfeld Surfaces Analysis of 5-Methyl-5H-dibenzo[b,f]azepine and 5-(4-Methylbenzyl-5H-dibenzo[b,f]azepine

    Directory of Open Access Journals (Sweden)

    Madan Kumar Shankar

    2014-01-01

    Full Text Available The compounds, 5-methyl-5H-dibenzo[b,f]azepine (1 and 5-(4-methylbenzyl-5H-dibenzo[b,f]azepine (2, were synthesized and characterized by spectral studies, and finally confirmed by single crystal X-ray diffraction method. The compound 1 crystallizes in the orthorhombic crystal system in Pca21 space group, having cell parameters a=11.5681 (18 Å, b=11.8958 (18 Å, c=8.0342 (13 Å, and Z=4 and V=1105.6 (3 Å3. And the compound 2 crystallizes in the orthorhombic crystal system and space group Pbca, with cell parameters a=16.5858 (5 Å, b=8.4947 (2 Å, c=23.1733 (7 Å, and Z=8 and V=3264.92 (16 Å3. The azepine ring of both molecules 1 and 2 adopts boat conformation with nitrogen atom showing maximum deviations of 0.483 (2 Å and 0.5025 (10 Å, respectively. The C–H⋯π short contacts were observed. The dihedral angle between fused benzene rings to the azepine motif is 47.1 (2° for compound 1 and 52.59 (6° for compound 2, respectively. The short contacts were analyzed and Hirshfeld surfaces computational method for both molecules revealed that the major contribution is from C⋯H and H⋯H intercontacts.

  7. Expression of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) GluR2/3 receptors in the developing rat pineal gland.

    Science.gov (United States)

    Kaur, C; Sivakumar, V; Ling, E A

    2005-10-01

    The expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type glutamate (GluR2/3) receptors and N-methyl-D-aspartate receptor subtype 1 (NMDAR1) was carried out by immunohistochemistry, double immunofluorescence and real-time RT-PCR analysis in the pineal glands of 1-day to 6-wk-old rats in the present study. GluR2/3 immunopositive cells were distributed throughout the pineal gland and showed branching processes in all age groups. The NMDAR1 immunoreactivity, however, was observed in fewer branched cells. A constitutive mRNA expression of NMDAR1, GluR2 and GluR3 was detected in the pineal glands of various ages and showed no significant difference between the age groups studied. Immunohistochemical and double immunofluorescence results showed that the GluR2/3 were mainly expressed and co-localized with OX-42-positive microglia/macrophages and the glial fibrillary acidic protein (GFAP)-positive astrocytes. Co-localization of NMDAR1 with OX-42- and GFAP-positive cells was much less. The expression of these receptors on the glial cells suggests that they may be involved in the development and growth of the pineal gland in the early postnatal period (1 day to 3 wk) and subsequently in the regulation of melatonin synthesis.

  8. Effects of (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline on glutamate transporter 1 and cysteine/glutamate exchanger as well as ethanol drinking behavior in male, alcohol-preferring rats.

    Science.gov (United States)

    Aal-Aaboda, Munaf; Alhaddad, Hasan; Osowik, Francis; Nauli, Surya M; Sari, Youssef

    2015-06-01

    Alcohol consumption is largely associated with alterations in the extracellular glutamate concentrations in several brain reward regions. We recently showed that glutamate transporter 1 (GLT-1) is downregulated following chronic exposure to ethanol for 5 weeks in alcohol-preferring (P) rats and that upregulation of the GLT-1 levels in nucleus accumbens and prefrontal cortex results, in part, in attenuating ethanol consumption. Cystine glutamate antiporter (xCT) is also downregulated after chronic ethanol exposure in P rats, and its upregulation could be valuable in attenuating ethanol drinking. This study examines the effect of a synthetic compound, (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), on ethanol drinking and expressions of GLT-1 and xCT in the amygdala and the hippocampus of P rats. P rats were exposed to continuous free-choice access to water, 15% and 30% ethanol, and food for 5 weeks, after which they received treatments of MS-153 or vehicle for 5 days. The results show that MS-153 treatment significantly reduces ethanol consumption. It was revealed that GLT-1 and xCT expressions were downregulated in both the amygdala and the hippocampus of ethanol-vehicle-treated rats (ethanol-vehicle group) compared with water-control animals. MS-153 treatment upregulated GLT-1 and xCT expressions in these brain regions. These findings demonstrate an important role for MS-153 in these glutamate transporters for the attenuation of ethanol-drinking behavior.

  9. Tweaking subtype-selectivity and agonist efficacy at (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in a small series of BnTetAMPA analogues

    DEFF Research Database (Denmark)

    Wang, Shuang-Yan; Larsen, Younes; Navarrete, Cristina V.

    2016-01-01

    A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp...... electrophysiology at the four homomeric AMPA receptors expressed in Xenopus laevis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three ligands (6, 7, and 8) in complex...... with the agonist binding domain (ABD) of GluA2 show that they induce full domain closure despite their low agonist efficacies. Trp767 in GluA2 ABD could be an important determinant for partial agonism of this compound series at AMPA receptors, since agonist efficacy also correlated with the location of the Trp767...

  10. Lanthanide complexes containing 5-methyl-1,2,4-triazolo[1,5-a] pyrimidin-7(4H)-one and their therapeutic potential to fight leishmaniasis and Chagas disease.

    Science.gov (United States)

    Caballero, Ana B; Rodríguez-Diéguez, Antonio; Salas, Juan M; Sánchez-Moreno, Manuel; Marín, Clotilde; Ramírez-Macías, Inmaculada; Santamaría-Díaz, Noelia; Gutiérrez-Sánchez, Ramón

    2014-09-01

    In the last years, numerous and significant advances in lanthanide coordination chemistry have been achieved. The unique chemical nature of these metal ions which is conferred by their f-electrons has led to a wide range of coordination compounds with interesting structural, physical and also biological properties. Consequently, lanthanide complexes have found applications mainly in catalysis, gas adsorption, photochemistry and as diagnostic tools. However, research on their therapeutic potential and the understanding of their mechanism of action is still taking its first steps, and there is a distinct lack of research in the parasitology field. In the present work, we describe the synthesis and physical properties of seven new lanthanide complexes with the anionic form of the bioactive ligand 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO), namely [Ln(mtpO)3(H2O)6]·9H2O (Ln=La(III), Nd(III), Eu(III), Gd(III), Tb(III), Dy(III) and Er(III)). In addition, results on the in vitro antiproliferative activity against Leishmania spp. and Trypanosoma cruzi are described. The high activity of the new compounds against parasite proliferation and their low cytotoxicity against reference host cell lines show a great potential of this type of compounds to become a new generation of highly effective and non-toxic antiparasitic agents to fight the so considered neglected diseases leishmaniasis and Chagas disease.

  11. The stress hormone corticosterone increases synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors via serum- and glucocorticoid-inducible kinase (SGK) regulation of the GDI-Rab4 complex.

    Science.gov (United States)

    Liu, Wenhua; Yuen, Eunice Y; Yan, Zhen

    2010-02-26

    Corticosterone, the major stress hormone, plays an important role in regulating neuronal functions of the limbic system, although the cellular targets and molecular mechanisms of corticosteroid signaling are largely unknown. Here we show that a short treatment of corticosterone significantly increases alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission and AMPAR membrane trafficking in pyramidal neurons of prefrontal cortex, a key region involved in cognition and emotion. This enhancing effect of corticosterone is through a mechanism dependent on Rab4, the small GTPase-controlling receptor recycling between early endosome and plasma membrane. Guanosine nucleotide dissociation inhibitor (GDI), which regulates the cycle of Rab proteins between membrane and cytosol, forms an increased complex with Rab4 after corticosterone treatment. Corticosterone also triggers an increased GDI phosphorylation at Ser-213 by the serum- and glucocorticoid-inducible kinase (SGK). Moreover, AMPAR synaptic currents and surface expression and their regulation by corticosterone are altered by mutating Ser-213 on GDI. These results suggest that corticosterone, via SGK phosphorylation of GDI at Ser-213, increases the formation of GDI-Rab4 complex, facilitating the functional cycle of Rab4 and Rab4-mediated recycling of AMPARs to the synaptic membrane. It provides a potential mechanism underlying the role of corticosteroid stress hormone in up-regulating excitatory synaptic efficacy in cortical neurons.

  12. Poly(ADP-Ribose)Polymerase 1 (PARP-1) Activation and Ca(2+) Permeable α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) Channels in Post-Ischemic Brain Damage: New Therapeutic Opportunities?

    Science.gov (United States)

    Gerace, Elisabetta; Pellegrini-Giampietro, Domenico E; Moroni, Flavio; Mannaioni, Guido

    2015-01-01

    A significant number of laboratories observed that poly (ADP-ribose) polymerase (PARP) inhibitors, administered a few hours after ischemic or traumatic brain injury, may drastically reduce the subsequent neurological damage. It has also been shown that PARP inhibitors, administered for 24 hours to rats with permanent middle cerebral artery occlusion (MCAO), may reduce the number of dying neurons for a long period after surgery, thus suggesting that these agents could reduce the delayed brain damage and the neurological and cognitive impairment (dementia) frequently observed a few months after a stroke. In organotypic hippocampal slices exposed to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG), an alkylating agent able to activate PARP, a selective and delayed degeneration of the CA1 pyramidal cells which was anatomically similar to that observed after a short period of oxygen and glucose deprivation (OGD) has been described. Biochemical and electrophysiological approaches showed that MNNG exposure caused an increased expression and function of the calcium permeable α-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) channels in the CA1 but not in the CA3 hippocampal region. PARP inhibitors prevented this increase and reduced CA1 cell death. The AMPA receptor antagonist 2,3-dihydroxy-6- nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione or the selective Ca(2+) permeable AMPA channel blocker 1-Naphthyl acetyl spermine (NASPM), also reduced the MNNG-induced CA1 pyramidal cell death. Since activation of PARP-1 facilitate the expression of Ca(2+) permeable channels and the subsequent delayed cell death, PARP inhibitors administered a few hours after a stroke may not only reduce the early post-ischemic brain damage but also the late neuronal death frequently occurring after severe stroke.

  13. Linking supply to demand: the neuronal monocarboxylate transporter MCT2 and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptor GluR2/3 subunit are associated in a common trafficking process.

    Science.gov (United States)

    Pierre, Karin; Chatton, Jean-Yves; Parent, Annabelle; Repond, Cendrine; Gardoni, Fabrizio; Di Luca, Monica; Pellerin, Luc

    2009-05-01

    MCT2 is the major neuronal monocarboxylate transporter (MCT) that allows the supply of alternative energy substrates such as lactate to neurons. Recent evidence obtained by electron microscopy has demonstrated that MCT2, like alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, is localized in dendritic spines of glutamatergic synapses. Using immunofluorescence, we show in this study that MCT2 colocalizes extensively with GluR2/3 subunits of AMPA receptors in neurons from various mouse brain regions as well as in cultured neurons. It also colocalizes with GluR2/3-interacting proteins, such as C-kinase-interacting protein 1, glutamate receptor-interacting protein 1 and clathrin adaptor protein. Coimmunoprecipitation of MCT2 with GluR2/3 and C-kinase-interacting protein 1 suggests their close interaction within spines. Parallel changes in the localization of both MCT2 and GluR2/3 subunits at and beneath the plasma membrane upon various stimulation paradigms were unraveled using an original immunocytochemical and transfection approach combined with three-dimensional image reconstruction. Cell culture incubation with AMPA or insulin triggered a marked intracellular accumulation of both MCT2 and GluR2/3, whereas both tumor necrosis factor alpha and glycine (with glutamate) increased their cell surface immunolabeling. Similar results were obtained using Western blots performed on membrane or cytoplasm-enriched cell fractions. Finally, an enhanced lactate flux into neurons was demonstrated after MCT2 translocation on the cell surface. These observations provide unequivocal evidence that MCT2 is linked to AMPA receptor GluR2/3 subunits and undergoes a similar translocation process in neurons upon activation. MCT2 emerges as a novel component of the synaptic machinery putatively linking neuroenergetics to synaptic transmission.

  14. Ca2+-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors and dopamine D1 receptors regulate GluA1 trafficking in striatal neurons.

    Science.gov (United States)

    Tukey, David S; Ziff, Edward B

    2013-12-06

    Regulation of striatal medium spiny neuron synapses underlies forms of motivated behavior and pathological drug seeking. A primary mechanism for increasing synaptic strength is the trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) into the postsynapse, a process mediated by GluA1 AMPAR subunit phosphorylation. We have examined the role of converging glutamate and dopamine inputs in regulating biochemical cascades upstream of GluA1 phosphorylation. We focused on the role of Ca(2+)-permeable AMPARs (CPARs), which lack the GluA2 AMPAR subunit. Under conditions that prevented depolarization, stimulation of CPARs activated neuronal nitric oxide synthase and production of cGMP. CPAR-dependent cGMP production was sufficient to induce synaptic insertion of GluA1, detected by confocal microscopy, through a mechanism dependent on GluA1 Ser-845 phosphorylation. Dopamine D1 receptors, in contrast, stimulate GluA1 extra synaptic insertion. Simultaneous activation of dopamine D1 receptors and CPARs induced additive increases in GluA1 membrane insertion, but only CPAR stimulation augmented CPAR-dependent GluA1 synaptic insertion. This incorporation into the synapse proceeded through a sequential two-step mechanism; that is, cGMP-dependent protein kinase II facilitated membrane insertion and/or retention, and protein kinase C activity was necessary for synaptic insertion. These data suggest a feed-forward mechanism for synaptic priming whereby an initial stimulus acting independently of voltage-gated conductance increases striatal neuron excitability, facilitating greater neuronal excitation by a subsequent stimulus.

  15. CX717 as a positive allosteric modulator of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptor: research advances%AMPA受体正向变构调节剂CX717研究进展

    Institute of Scientific and Technical Information of China (English)

    贺艺超; 肖典; 齐倩倩; 赵国明; 周辛波

    2013-01-01

    α-氨基-3-羟基-5-甲基-4-异噁唑丙酸(AMPA)受体是离子型谷氨酸受体的一种亚型,分布于中枢神经系统的突触后膜,介导大多数快速兴奋性神经传递.CX717是由美国Cortex制药公司研制的苯甲酰胺类AMPA受体正向调节剂,能够降低AMPA受体失活或降敏的速度从而提高突触的活性,与阿尔茨海默病、帕金森病、抑郁症和注意力缺陷多动症等疾病的治疗密切相关.本文主要综述CX717在化学结构、药代动力学、毒理学和药效学方面的研究进展.%α-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptor,a subtype of ionotropic glutamate receptors in the postsynaptic membrane of the central nervous system (CNS),mediates most of the fast excitatory neurotransmission.CX717 developed by Cortex Pharmaceuticals Company of the USA belongs to the benzamide series of AMPA receptor positive modulators.It can reduce the speed of AMPA receptor inactivation or desensitization,thereby enhancing synaptic activity,and is closely related to the treatment of Alzheimer's disease,Parkinson's disease,depression and attention deficit hyperactivity disorder(ADHD).This article reviews the latest research of CX717 regarding its structure,pharmacokinetics,toxicology and pharmacodynamics.

  16. Involvement of p38 MAPK and ATF-2 signaling pathway in anti-inflammatory effect of a novel compound bis[(5-methyl)2-furyl](4-nitrophenyl)methane on lipopolysaccharide-stimulated macrophages.

    Science.gov (United States)

    Udompong, Sarinporn; Mankhong, Sakulrat; Jaratjaroonphong, Jaray; Srisook, Klaokwan

    2017-09-01

    Activated macrophages produce various pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) and cyclooxygenase (COX)-2-derived prostaglandin E2 (PGE2) during inflammatory response. However, overproduction of NO and PGE2 appears to be involved in pathogenesis of various inflammatory diseases. Therefore, inhibition of NO and PGE2 production might be useful for the treatment of inflammatory-related diseases. In this study, the bis[(5-methyl)2-furyl](4-nitrophenyl)methane or BFNM was evaluated for the anti-inflammatory activity and mechanism of action in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage. BFNM inhibited NO and PGE2 production in a concentration-dependent manner and down-regulated the expression of iNOS and COX-2 at mRNA and protein levels. BFNM suppressed nuclear translocation of NF-κB p65 subunit only very slightly, and failed to decrease NF-κB DNA binding activity. In contrast, the compound significantly reduced phosphorylation of p38 MAPK and ATF-2, a component of AP-1 known to be involved in the transcriptional regulation of iNOS and COX-2, in a dose-dependent manner in LPS-induced cells. Collectively, these results suggest that BFNM has an anti-inflammatory effect in RAW 264.7 macrophages, at least in part, by suppression of NO and PGE2 production. The inhibitory effect of BFNM is mediated mainly via the p38 MAPK/ATF-2 signaling pathway. Thus, BFNM would be a lead compound for the development of novel anti-inflammatory agents. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Resonance Raman Intensities Demonstrate that C5 Substituents Affect the Initial Excited-State Structural Dynamics of Uracil More than C6 Substituents.

    Science.gov (United States)

    Teimoory, Faranak; Loppnow, Glen R

    2016-05-04

    Resonance Raman derived initial excited-state structural dynamics provide insight into the photochemical mechanisms of pyrimidine nucleobases, in which the photochemistry appears to be dictated by the C5 and C6 substituents. The absorption and resonance Raman spectra and excitation profiles of 5,6-dideuterouracil were measured to further test this photochemical dependence on the C5 and C6 substituents. The resulting set of excited-state reorganization energies of the observed internal coordinates were calculated and compared to those of other 5- and 6-substituted uracils. The results show that the initial excited-state dynamics along the C5C6 stretch responds to changes in mass at C5 and C6 in the same manner but that the in-plane bends at C5 and C6 are more sensitive to substituents at the C5 position than at the C6 position. In addition, the presence of two deuterium substituents at C5 and C6 decreases the initial excited-state structural dynamics along these in-plane bends, in contrast to what is observed in the presence of two CH3 groups on C5 and C6. The results are discussed in the context of DNA nucleobase photochemistry.

  18. Structural and Energetic Impact of Non-Natural 7-Deaza-8-Azaadenine and its 7-Substituted Derivatives on H-Bonding Potential with Uracil in RNA Molecules

    KAUST Repository

    Chawla, Mohit

    2015-09-21

    Non-natural (synthetic) nucleobases, including 7-ethynyl- and 7-triazolyl-8-aza-7-deazaadenosine, have been introduced in RNA molecules for targeted applications, and have been characterized experimentally. However, no theoretical characterization of the impact of these modifications on the structure and energetics of the corresponding H-bonded base pair is available. To fill this gap, we performed quantum mechanics calculations, starting with the analysis of the impact of the 8-aza-7-deaza modification of the adenosine skeleton, and we moved then to analyze the impact of the specific substituents on the modified 8-aza-7-deazaadenosine. Our analysis indicates that, despite of these severe structural modifications, the H-bonding properties of the modified base pair gratifyingly replicate those of the unmodified base pair. Similar behavior is predicted when the same skeleton modifications are applied to guanosine when paired to cytosine. To stress further the H-bonding pairing in the modified adenosine-uracil base pair, we explored the impact of strong electron donor and electron withdrawing substituents on the C7 position. Also in this case we found minimal impact on the base pair geometry and energy, confirming the validity of this modification strategy to functionalize RNAs without perturbing its stability and biological functionality.

  19. Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan.

    Science.gov (United States)

    Nakayama, Takahiro; Noguchi, Shinzaburo

    2010-01-01

    In Japan, the history of postoperative chemotherapy for breast cancer started with 5-fluorouracil (5-FU), launched in the 1980s. Currently, oral fluoropyrimidine-based regimens indicated for the treatment of breast cancer in Japan include tegafur plus uracil (UFT); tegafur, gimeracil, and oteracil (TS-1); doxifluridine; and capecitabine. In particular, UFT represents an important option for long-term treatment because of minimal adverse events and the potential for long-term maintenance of effective plasma concentrations of 5-FU to inhibit micrometastasis after surgery. Therefore, various clinical studies of postoperative adjuvant chemotherapy with UFT have been conducted in patients with completely resected tumors. Recent studies have shown that UFT prolongs survival after tumor resection in patients with gastric cancer, colorectal cancer, and lung cancer. In patients with breast cancer, large clinical trials of UFT-based postoperative chemotherapy conducted in Japan have shown that UFT is useful for the treatment of intermediate-risk patients with no lymph node metastasis. This paper reviews the results of clinical studies of UFT conducted in Japan to assess the therapeutic usefulness of this oral 5-FU. The types of patients most likely to benefit from UFT are discussed on the basis of currently available evidence and a global consensus of treatment recommendations. The optimal timing of endocrine therapy and strategies for postoperative adjuvant chemotherapy with UFT in patients with breast cancer are also discussed.

  20. Preliminary results of phase I trial of oral uracil/tegafur (UFT, leucovorin plus irinotecan and radiation therapy for patients with locally recurrent rectal cancer

    Directory of Open Access Journals (Sweden)

    Fukunaga Mutsumi

    2006-11-01

    Full Text Available Abstract Background Surgical attempts for locally recurrent rectal cancer often fail due to local re-recurrence and distant metastasis. Preoperative chemoradiation may enhance better local control and survival. The aim of this study was to assess the safety of oral uracil and tegafur (UFT plus leucovorin (LV, and irinotecan combined with radiation and determine the maximum-tolerated dose (MTD and dose limiting toxicity (DLT of the triple drug regimen. Patients and methods Patients with locally recurrent rectal cancer received escalating doses of irinotecan on days 1, 8, 15, and 22 (starting at 30 mg/m2, with 10 mg increments between consecutive cohorts and fixed doses of UFT (300 mg/m2 plus LV (75 mg/day on days 3 to 7, 10 to 14, 17 to 21, and 24 to 28. Radiation was given 5 days per week totaling 40 to 50 Gy (2Gy/day. Results Six patients were treated at the starting dose, and 2 received the full scheduled chemoradiotherapy. The other 4 patients had grade 3 diarrhea and diarrhea was the DLT. One patient had partial response and he had subsequently radical surgical resection. Median progression free survival for local recurrence was 320 days. Conclusion Irinotecan plus UFT/LV with concomitant radiotherapy in patients with locally recurrent rectal cancer was not feasible due to diarrhea in this setting. Modification of the treatment is needed.

  1. The Unusual Presentation of Gastric Adenocarcinoma as a Testicular Mass: A Favorable Response to Docetaxel and Cisplatin Plus Oral Tegafur/Uracil and Leucovorin

    Directory of Open Access Journals (Sweden)

    Kai-Chung Yang

    2010-02-01

    Full Text Available Gastric cancer is one of the most common malignancies in the world. The routes of metastasis include direct extension, lymphatics, and peritoneal or hematogenous spread. Testicular metastasis is rare. We present here a 23-year-old gastric cancer patient who first presented with right-side testis swelling and pain. Diagnosis of metastatic adenocarcinoma was made after right-side orchiectomy. Gastric adenocarcinoma with ascites and peritoneal seeding was found after esophagogastroscopy and abdominal computed tomography. The patient received chemotherapy consisting of docetaxel 36 mg/m2 and cisplatin 30 mg/m2 on day 1 and day 8, plus oral tegafur/uracil 300 mg/m2/day and leucovorin 90 mg/day on day 1 to day 14 in a 21-day cycle, and he had a partial response to the chemotherapy. Metastatic tumors, especially gastric adenocarcinoma, should be considered in the differential diagnosis of patients presenting with testicular mass and they may respond well to chemotherapy.

  2. Ionization and fragmentation of RNA base molecule uracil in collisions with carbon ions of energies between 100 keV and 60 MeV

    Science.gov (United States)

    Tribedi, L. C.; Agnihotri, A. N.; Kasthurirangan, S.; Kumar, A.; Champion, C.; Rivarola, R.

    2012-11-01

    We report here the first measurement of absolute single ionization cross-section of uracil (C4H4N2O2, m=112) in collisions with highly charged C ions of energy ranging between 100 keV to 60 MeV i.e. in the range of Bragg peak which is relevant for high energy hadron therapy. An ECR based low energy accelerator along with a 14 MV Pelletron accelerator were used to obtain a wide range of energies. Energy and charge state (representing perturbation strength) dependence of io-nization cross-section has been studied using a ToF mass spectrometer. In the low energy range, cross-section increases with energy and then saturates while in the high energy range it decreases with energy. Ionization cross-section found to increase linearly with charge-state. The CTMC and CDW-EIS models are used to compare with the data. The complementary experiment was also carried out to measure the low energy electron emission spectrum at different angles.

  3. Polymeric Cd(II), trinuclear and mononuclear Ni(II) complexes of 5-methyl-4-phenyl-1,2,4-triazole-3-thione: Synthesis, structural characterization, thermal behaviour, fluorescence properties and antibacterial activity

    Science.gov (United States)

    Bharty, M. K.; Paswan, S.; Dani, R. K.; Singh, N. K.; Sharma, V. K.; Kharwar, R. N.; Butcher, R. J.

    2017-02-01

    Syntheses of a polymeric Cd(II) complex, [Cd(mptt)2]n (1), a trinuclear Ni(II) complex, [Ni3(μ-mptt)4(μ-H2O)2(H2O)2(ttfa)2]·3H2O (2) and a mononuclear Ni(II) complex [Ni(mptt)2(en)2] (3) have been performed using the ligand 5-methyl-4-phenyl-1,2,4-triazole-3-thione (Hmptt) and nickel(II)/cadmium(II) salts {ttfa = thenoyltrifluroacetonate). The ligand and the complexes have been characterized by various physicochemical methods in addition to their single crystal X-ray structure. The Cd centre in complex 1 adopts a distorted tetrahedral geometry with one sulfur atom and two mptt ligands provide three nitrogen atoms from three triazole units. The sulfur atom of the ligand binds covalently and overall the ligand acts as uninigative N,S/N,N bidentate moiety. The polymeric structure of complex 1 results from the N atoms of the neighboring triazole units coordinating with the Cd(II) centre. The three Ni(II) centres in the trinuclear Ni(II) complex 2 form a linear arrangement and all have six coordinated arrangements. The middle Ni(II) binds with four deprotonated triazole ring nitrogens and two water molecules form two bridges. The terminal Ni(II) centres bind through two thenoyl oxygens, two triazole nitrogens and water molecules that formed bridges with the middle Ni centre. In complex 3, the nickel(II) centre is covalently bonded through two deprotonated triazole ring nitrogens from two ligand moieties and other four sites are occupied by four nitrogens from two bidentate en ligands. Thermogravimetric analyses (TGA) of the complexes indicated for NiO as the final residue. The bioefficacy of the ligand and complexes 2 and 3 have been examined against the growth of bacteria to evaluate their anti-microbial potential. Complex 2 showed high antibacterial activity as compared to the ligand and complex 3. Complexes 1, 2 and 3 are fluorescent materials with maximum emissions at 425, 421 and 396 nm at an excitation wavelength of 323, 348 and 322 nm, respectively.

  4. X-ray structures of uridine phosphorylase from Vibrio cholerae in complexes with uridine, thymidine, uracil, thymine, and phosphate anion: Substrate specificity of bacterial uridine phosphorylases

    Science.gov (United States)

    Prokofev, I. I.; Lashkov, A. A.; Gabdulkhakov, A. G.; Balaev, V. V.; Seregina, T. A.; Mironov, A. S.; Betzel, C.; Mikhailov, A. M.

    2016-11-01

    In many types of human tumor cells and infectious agents, the demand for pyrimidine nitrogen bases increases during the development of the disease, thus increasing the role of the enzyme uridine phosphorylase in metabolic processes. The rational use of uridine phosphorylase and its ligands in pharmaceutical and biotechnology industries requires knowledge of the structural basis for the substrate specificity of the target enzyme. This paper summarizes the results of the systematic study of the three-dimensional structure of uridine phosphorylase from the pathogenic bacterium Vibrio cholerae in complexes with substrates of enzymatic reactions—uridine, phosphate anion, thymidine, uracil, and thymine. These data, supplemented with the results of molecular modeling, were used to consider in detail the structural basis for the substrate specificity of uridine phosphorylases. It was shown for the first time that the formation of a hydrogen-bond network between the 2'-hydroxy group of uridine and atoms of the active-site residues of uridine phosphorylase leads to conformational changes of the ribose moiety of uridine, resulting in an increase in the reactivity of uridine compared to thymidine. Since the binding of thymidine to residues of uridine phosphorylase causes a smaller local strain of the β-N1-glycosidic bond in this the substrate compared to the uridine molecule, the β-N1-glycosidic bond in thymidine is more stable and less reactive than that in uridine. It was shown for the first time that the phosphate anion, which is the second substrate bound at the active site, interacts simultaneously with the residues of the β5-strand and the β1-strand through hydrogen bonding, thus securing the gate loop in a conformation

  5. Functional characterization of Tet-AMPA [tetrazolyl-2-amino-3-(3-hydroxy-5-methyl- 4-isoxazolyl)propionic acid] analogues at ionotropic glutamate receptors GluR1-GluR4. The molecular basis for the functional selectivity profile of 2-Bn-Tet-AMPA

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Christesen, Thomas; Bølcho, Ulrik

    2007-01-01

    Four 2-substituted Tet-AMPA [Tet = tetrazolyl, AMPA = 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid] analogues were characterized functionally at the homomeric AMPA receptors GluR1i, GluR2Qi, GluR3i, and GluR4i in a Fluo-4/Ca2+ assay. Whereas 2-Et-Tet-AMPA, 2-Pr-Tet-AMPA, and 2-i...

  6. Photo-Crosslinking of Pendent Uracil Units Provides Supramolecular Hole Injection/Transport Conducting Polymers for Highly Efficient Light-Emitting Diodes

    Directory of Open Access Journals (Sweden)

    Hsi-Kang Shih

    2015-04-01

    Full Text Available A new process for modifying a polymeric material for use as a hole injection transport layer in organic light-emitting diodes has been studied, which is through 2π + 2π photodimerization of a DNA-mimetic π-conjugated poly(triphenylamine-carbazole presenting pendent uracil groups (PTC-U under 1 h of UV irradiation. Multilayer florescence OLED (Organic light-emitting diodes device with the PTC-U-1hr as a hole injection/transport layer (ITO (Indium tin oxide/HITL (hole-injection/transport layer (15 nm/N,N'-di(1-naphthyl- N,N'-diphenyl-(1,1'-biphenyl-4,4'-diamine (NPB (15 nm/Tris-(8-hydroxyquinoline aluminum (Alq3 (60 nm/LiF (1 nm/Al (100 nm is fabricated, a remarkable improvement in performance (Qmax (external quantum efficiency = 2.65%, Bmax (maximum brightness = 56,704 cd/m2, and LE (luminance efficiencymax = 8.9 cd/A relative to the control PTC-U (Qmax = 2.40%, Bmax = 40,490 cd/m2, and LEmax = 8.0 cd/A. Multilayer phosphorescence OLED device with the PTC-U-1hr as a hole injection/transport layer (ITO/HITL (15 nm/Ir(ppy3:PVK (40 nm/BCP (10nm/Alq3 (40 nm/LiF (1 nm/Al (100 nm is fabricated by successive spin-coating processes, a remarkable improvement in performance (Qmax = 9.68%, Bmax = 41,466 cd/m2, and LEmax = 36.6 cd/A relative to the control PTC-U (Qmax = 8.35%, Bmax = 34,978 cd/m2, and LEmax = 30.8 cd/A and the commercial product (poly(3,4-ethylenedioxythiophene:polystyrenesulfonate PEDOT:PSS (Qmax = 4.29%, Bmax = 15,678 cd/m2, and LEmax = 16.2 cd/A has been achieved.

  7. Uracil/ftorafur/leucovorin combined with irinotecan (TEGAFIRI) or oxaliplatin (TEGAFOX) as first-line treatment for metastatic colorectal cancer patients: results of randomised phase II study

    Science.gov (United States)

    Bajetta, E; Di Bartolomeo, M; Buzzoni, R; Mariani, L; Zilembo, N; Ferrario, E; Lo Vullo, S; Aitini, E; Isa, L; Barone, C; Jacobelli, S; Recaldin, E; Pinotti, G; Iop, A

    2007-01-01

    This randomised phase II study evaluates the safety and efficacy profile of uracil/tegafur/leucovorin combined with irinotecan (TEGAFIRI) or with oxaliplatin (TEGAFOX). One hundred and forty-three patients with measurable, non-resectable metastatic colorectal cancer were randomised in a multicentre study to receive TEGAFIRI (UFT 250 mg m−2 day days 1–14, LV 90 mg day days 1–14, irinotecan 240 mg m−2 day 1; q21) or TEGAFOX (UFT 250 mg m−2 day days 1–14, LV 90 mg day days 1–14, oxaliplatin 120 mg m−2 day 1; q21). Among 143 randomised patients, 141 were analysed (68 received TEGAFIRI and 73 TEGAFOX). The main characteristics of the two arms were well balanced. The most common grade 3–4 treatment-related adverse events were neutropenia (13% of cases with TEGAFIRI; 1% in the TEGAFOX group). Diarrhoea was prevalent in the TEGAFIRI arm (16%) vs TEGAFOX (4%). Six complete remission (CR) and 19 partial remission (PR) were recorded in the TEGAFIRI arm (odds ratio (OR): 41.7; 95% confidence limit (CL), 29.1–55.1%), and six CR and 22 PR were recorded in the TEGAFOX group, (OR: 38.9; 95% CL, 27.6–51.1). At a median time follow-up of 17 months (intequartile (IQ) range 12–23), a median survival probability of 20 and 19 months was obtained in the TEGAFIRI and TEGAFOX groups, respectively. Median time to progression was 8 months for both groups. TEGAFIRI and TEGAFOX are both effective and tolerable first-line therapies in MCRC patients. The employment of UFT/LV given in doublet combination is interesting and the presented data appear comparable to equivalent infusion regimens described in the literature. The safety profile of the two combinations also allows an evaluation with other biological agents such as monoclonal antibodies. PMID:17245343

  8. Toward feasible and comprehensive computational protocol for simulation of the spectroscopic properties of large molecular systems: the anharmonic infrared spectrum of uracil in the solid state by the reduced dimensionality/hybrid VPT2 approach.

    Science.gov (United States)

    Fornaro, Teresa; Carnimeo, Ivan; Biczysko, Malgorzata

    2015-05-28

    Feasible and comprehensive computational protocols for simulating the spectroscopic properties of large and complex molecular systems are very sought after. Indeed, due to the great variety of intra- and intermolecular interactions that may take place, the interpretation of experimental data becomes more and more difficult as the system under study increases in size or is placed in a complex environment, such as condensed phases. In this framework, we are actively developing a comprehensive and robust computational protocol aimed at quantitative reproduction of the spectra of nucleic acid base complexes, with increasing complexity toward condensed phases and monolayers of biomolecules on solid supports. We have resorted to fully anharmonic quantum mechanical computations within the generalized second-order vibrational perturbation theory (GVPT2) approach, combined with the cost-effective B3LYP-D3 method, in conjunction with basis sets of double-ζ plus polarization quality. Such an approach has been validated in a previous work ( Phys. Chem. Chem. Phys. 2014 , 16 , 10112 - 10128 ) for simulating the IR spectra of the monomers of nucleobases and some of their dimers. In the present contribution we have extended such computational protocol to simulate spectroscopic properties of a molecular solid, namely polycrystalline uracil. First we have selected a realistic molecular model for representing the spectroscopic properties of uracil in the solid state, the uracil heptamer, and then we have computed the relative anharmonic frequencies combining less demanding approaches such as the hybrid B3LYP-D3/DFTBA one, in which the harmonic frequencies are computed at a higher level of theory (B3LYP-D3/N07D) whereas the anharmonic shifts are evaluated at a lower level of theory (DFTBA), and the reduced dimensionality VPT2 (RD-VPT2) approach, where only selected vibrational modes are computed anharmonically along with the couplings with other modes. The good agreement between the

  9. Eight new crystal structures of 5-(hydroxymethyl)uracil, 5-carboxyuracil and 5-carboxy-2-thiouracil: insights into the hydrogen-bonded networks and the predominant conformations of the C5-bound residues.

    Science.gov (United States)

    Seiler, Vanessa Kristina; Hützler, Wilhelm Maximilian; Bolte, Michael

    2016-05-01

    In order to examine the preferred hydrogen-bonding pattern of various uracil derivatives, namely 5-(hydroxymethyl)uracil, 5-carboxyuracil and 5-carboxy-2-thiouracil, and for a conformational study, crystallization experiments yielded eight different structures: 5-(hydroxymethyl)uracil, C5H6N2O3, (I), 5-carboxyuracil-N,N-dimethylformamide (1/1), C5H4N2O4·C3H7NO, (II), 5-carboxyuracil-dimethyl sulfoxide (1/1), C5H4N2O4·C2H6OS, (III), 5-carboxyuracil-N,N-dimethylacetamide (1/1), C5H4N2O4·C4H9NO, (IV), 5-carboxy-2-thiouracil-N,N-dimethylformamide (1/1), C5H4N2O3S·C3H7NO, (V), 5-carboxy-2-thiouracil-dimethyl sulfoxide (1/1), C5H4N2O3S·C2H6OS, (VI), 5-carboxy-2-thiouracil-1,4-dioxane (2/3), 2C5H4N2O3S·3C6H12O3, (VII), and 5-carboxy-2-thiouracil, C10H8N4O6S2, (VIII). While the six solvated structures, i.e. (II)-(VII), contain intramolecular S(6) O-H...O hydrogen-bond motifs between the carboxy and carbonyl groups, the usually favoured R2(2)(8) pattern between two carboxy groups is formed in the solvent-free structure, i.e. (VIII). Further R2(2)(8) hydrogen-bond motifs involving either two N-H...O or two N-H...S hydrogen bonds were observed in three crystal structures, namely (I), (IV) and (VIII). In all eight structures, the residue at the ring 5-position shows a coplanar arrangement with respect to the pyrimidine ring which is in agreement with a search of the Cambridge Structural Database for six-membered cyclic compounds containing a carboxy group. The search confirmed that coplanarity between the carboxy group and the cyclic residue is strongly favoured.

  10. Synthesis, crystal structure, insecticidal activity and DFT study on the geometry and vibration of O-( E)-1-{1-[(6-chloropyridin-3-yl)methyl]-5-methyl-1 H-1,2,3-triazol-4-yl}ethyleneamino- O-ethyl- O-phenylphosphorothioate

    Science.gov (United States)

    Shi, De-Qing; Zhu, Xiao-Fei; Song, Yuan-Zhi

    2008-12-01

    The title compound, O-( E)-1-{1-[(6-chloropyridin-3-yl)methyl]-5-methyl-1 H-1,2,3-triazol-4-yl}ethyleneamino- O-ethyl- O-phenylphosphorothioate, has been synthesized via the condensation reaction of 1-{1-[(6-chloropyridin-3-yl)methyl]-5-methyl-1 H-1,2,3-triazol-4-yl}ethanone oxime and O-ethyl- O-phenylphosphorochloridothioate in the presence of NaOH powder in refluxing EtOH. Its structure was characterized by 1H NMR, FTIR, Raman, elemental analysis and X-ray single crystal diffraction. The results of preliminary bioassays indicated that the title compound displays good insecticidal activity. Density functional (DFT) calculations have been carried out for the title compound by using the Becke-Lee-Yang-Parr's three-parameter hybrid functional (B3LYP) method at 6-31G** and 6-31G* basis sets. The calculated results show that the predicted geometry can well reproduce the structural parameters. The vibrational wave numbers of the title compound were calculated at same level. Predicted vibrational frequencies have been assigned and compared with experimental IR and Raman spectra and they are supported each other.

  11. Hexa-μ2-acetato-1:2κ4O:O′;1:2κ2O:O;2:3κ4O:O′;2:3κ2O:O-bis(2-amino-7-chloro-5-methyl-1,8-naphthyridine-1κN1,3κN1-trizinc(II

    Directory of Open Access Journals (Sweden)

    Su-Mei Zhang

    2008-09-01

    Full Text Available The title complex, [Zn3(C2H3O26(C9H8ClN32], contains three ZnII atoms bridged by six acetate ligands. The central ZnII ion, located on an inversion centre, is surrounded by six O atoms from acetate ligands in a distorted octahedral geometry [Zn—O = 1.9588 (12–2.1237 (12 Å]. The terminal ZnII ions are coordinated by one N atom of 2-amino-7-chloro-5-methyl-1,8-naphthyridine and three O atoms of three acetate ligands in a distorted tetrahedral geometry. The separation between the central and terminal ZnII ions is 3.245 (3 Å.

  12. Balance of Attraction and Repulsion in Nucleic-Acid Base Stacking: CCSD(T)/Complete-Basis-Set-Limit Calculations on Uracil Dimer and a Comparison with the Force-Field Description

    Energy Technology Data Exchange (ETDEWEB)

    Morgado, Claudio A.; Jurecka, Petr; Svozil, Daniel; Hobza, Pavel; Sponer, Jiri

    2009-06-09

    We have carried out reference quantum-chemical calculations for about 100 geometries of the uracil dimer in stacked conformations. The calculations have been specifically aimed at geometries with unoptimized distances between the monomers including geometries with mutually tilted monomers. Such geometries are characterized by a delicate balance between local steric clashes and local unstacking and had until now not been investigated using reference quantummechanics (QM) methods. Nonparallel stacking geometries often occur in nucleic acids and are of decisive importance, for example, for local conformational variations in B-DNA. Errors in the shortrange repulsion region would have a major impact on potential energy scans which were often used in the past to investigate local geometry variations in DNA. An incorrect description of such geometries may also partially affect molecular dynamics (MD) simulations in applications when quantitative accuracy is required. The reference QM calculations have been carried out using the MP2 method extrapolated to the complete basis-set limit and corrected for higher-order electron-correlation contributions using CCSD(T) calculations with a medium-sized basis set. These reference calculations have been used as benchmark data to test the performance of the DFT-D, SCS(MI)-MP2, and DFTSAPT QM methods and of the AMBER molecular-mechanics (MM) force field. The QM methods show close to quantitative agreement with the reference data, albeit the DFT-D method tends to modestly exaggerate the repulsion of steric clashes. The force field in general also provides a good description of base stacking for the systems studied here. However, for geometries with close interatomic contacts and clashes, the repulsion effects are rather severely exaggerated. The discrepancy reported here should not affect the overall stability of MD simulations and qualitative applications of the force field. However, it may affect the description of subtle

  13. 1-(2′-烷硫基乙氧基)甲基尿嘧啶及其氧化物的合成%Synthesis of 1- (2′ -Alkylthioethoxyl ) methyl Uracil and Its Oxidation Products

    Institute of Scientific and Technical Information of China (English)

    刘学军; 陈茹玉

    2000-01-01

    As a continuation to our projects of searching for new anticancer and antiviral agents, the series of novel 1-(2′ -alkylthioethoxy)methyl uracils have been synthesized in overall yields of 70. 4 %-74. 9 % in three steps from uracil, and they have been smoothly oxidized into corresponding sulfoxides in yields of 88.5 %-94.4 % by NaIO4 in ethanol/water. Corresponding sulfones were obtained in yields of 86.2 %93.5% from sulfides and sulfoxides by means of 30% H2O2/DEAD (diethyl diazodicarboxylate) as oxidation reagent in methanol or THF. All the new compounds have been characterized by 1H NMR, IR spectrum and elemental analysis. The literature procedure of synthesizing the key intermediate (1,4bistrimethylsilyluracil) was improved by hexamethyldisiylazane (HMDS)/trimethyl chloride (TMSC1) as substituent of HMDS/(NH4)2SO4, and reaction time was shortened so much from 12 h to 3 h in new procedure. The experimental results indicated that the conversion of sulfides and sulfoxides to the corresponding sulfones was very slow and in low yields(42. 5% and 47.3%), when only 30% H2O2 was used as the oxidation reagent. After addition of DEAD into the reaction mixture, the reaction could be considerably accelerated, and conversion rates of the reaction were raised (86. 2%-93. 5%). The anticancer and antiviral activities of the compounds 4, 5, 6 are being testing.%采用30%H202/DEAD的试剂组合,用于将硫醚及亚砜的衍生物氧化成砜类物质的反应,合成了1-(2-烷硫基乙氧基)甲基尿嘧啶及其氧化物,产物结构经元素分析、1H NMR和IR进行表征,并研究了其抗癌活性.

  14. Association of right-sided tumors with high thymidine phosphorylase gene expression levels and the response to oral uracil and tegafur/leucovorin chemotherapy among patients with colorectal cancer.

    Science.gov (United States)

    Sadahiro, Sotaro; Suzuki, Toshiyuki; Tanaka, Akira; Okada, Kazutake; Nagase, Hideki; Uchida, Junji

    2012-08-01

    To identify useful predictive factors for the response to 5-fluorouracil (5-FU)/leucovorin (LV) and oral uracil and tegafur (UFT)/LV chemotherapy among patients with colorectal cancer, we investigated the association between the gene expression levels of pyrimidine and folate metabolism-related enzymes in colorectal cancer (CRC) tissues and the response to UFT/LV neoadjuvant chemotherapy. The subjects were 76 CRC patients who were scheduled to undergo surgery. UFT (300 mg/m(2)/day) and LV (75 mg/body/day) were administered for 2 weeks before surgery. Biopsy samples were endoscopically obtained before drug administration. The gene expression levels of 14 genes in the biopsy samples were quantitatively evaluated using a real-time polymerase chain reaction (RT-PCR) assay. Fifteen patients (19.7 %) with marked pathological regression were judged to be responders. Thymidine phosphorylase (TP) gene expression levels among the responders were significantly higher than those among the non-responders. Right-sided tumors with high TP gene expression levels were associated with a significantly higher response rate to UFT/LV chemotherapy than left-sided tumors. TP gene expression levels in primary CRC tissues and the primary tumor site may be useful predictors of the efficacy of oral UFT/LV chemotherapy.

  15. Improved survival for hepatocellular carcinoma with portal vein tumor thrombosis treated by intra-arterial chemotherapy combining etoposide, carboplatin, epirubicin and pharmacokinetic modulating chemotherapy by 5-FU and enteric-coated tegafur/uracil: A p

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the poor prognosis of HCC with PVTT, we evaluated the efficacy by a new combination chemotherapy for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT).METHODS: From 2002 to 2007, a total of 10 consecutive patients with Stage IVA HCC accompanied by PVTT were studied prospectively to examine the efficacy of treatment by intra-arterial infusion of a chemotherapeutic agents consisting of etoposide, carboplatin, epirubicin and pharmacokinetic modulating chemotherapy by 5-FU and enteric-coated tegafur/uracil.RESULTS: The mean course of chemotherapy was 14.4 (range, 9-21) mo. One patient showed complete response (CR) with disappearance of HCC and PVTT after treatment, and the two patients showed partialresponse (PR), response rate (CR + PR/All cases 30%).The median survival time after the therapy was 457.2 d. The one-year survival rate was 70%. Adverse reactions were tolerable.CONCLUSION: Although the prognosis of most patients with Stage IVA HCC by PVTT is poor, our combination chemotherapy may induces long-term survival and is an effective treatment and produced anti-tumor activity with tolerable adverse effects in patients for advanced Stage IVA HCC accompanied by PVTT.

  16. Simultaneous determination of 1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) uracil (FAU) and 1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) 5-methyluracil (FMAU) in human plasma by liquid chromatography/tandem mass spectrometry.

    Science.gov (United States)

    Wiegand, Richard; Wu, Jianmei; Shields, Anthony F; Lorusso, Patricia; Li, Jing

    2012-04-01

    A liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) assay was developed and validated for simultaneous determination of 1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) uracil (FAU) and its active metabolite 1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) 5-methyluracil (FMAU) in human plasma. FAU and FMAU were extracted from plasma samples using solid-phase extraction with Waters Sep-Pak® Vac C₁₈ cartridge. Chromatographic separation was achieved on a Waters Atlantis T3 C₁₈ column with a gradient mobile phase consisting of methanol and water with 0.45% formic acid (v/v) running at a flow rate of 0.2 ml/min. The analytes were monitored by triple quadrupole mass spectrometer under positive ionization mode. The lower limit of quantitation (LLOQ) was 10 and 2 ng/ml for FAU and FMAU in plasma, respectively. Calibration curves were linear over FAU and FMAU plasma concentration range of 10-2000 and 2-1000 ng/ml, respectively. The intra-day and inter-day accuracy and precision were within the generally accepted criteria for bioanalytical method (FAU and FMAU in cancer patients receiving 1-h intravenous infusion of FAU 50 mg/m².

  17. 3-Ethylsulfinyl-2-(4-iodophenyl-5-methyl-1-benzofuran

    Directory of Open Access Journals (Sweden)

    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].

  18. 5-Methyl-1,2-oxazole-3-carboxylic acid

    Directory of Open Access Journals (Sweden)

    Jin-Feng Li

    2011-10-01

    Full Text Available In the crystal structure of the title compound, C5H5NO3, all the non-H atoms are approximately coplanar: the carboxy O atoms deviating by 0.013 (2 and −0.075 (2 Å from the isoxazole ring plane. In the crystal, the molecules form inversion dimers linked by pairs of O—H...O hydrogen bonds and the dimers stack via π–π interactions [centroid–centroid distance = 3.234 (2 Å].

  19. 3-Benzyl-5-methyl-1,2-benzoxazole 2-oxide

    Directory of Open Access Journals (Sweden)

    G. Anuradha

    2012-10-01

    Full Text Available In the title compound, C15H13NO2, the isoxazole unit and the attached benzene ring are almost coplanar, making a dihedral angle of 1.42 (8°. The benzyl ring is inclined to the isoxazole ring by 74.19 (8° and is in a +sc conformation with respect to the benzisoxazole unit. In the crystal, C—H...O hydrogen bonds link the molecules, forming zigzag chains propagating along the b axis. There are also π–π interactions present involving the isoxazole and benzyl rings [centroid–centroid distance = 3.5209 (10 Å], and C—H...π interactions involving the benzene ring of the benzoisoxazole unit and the methylene bridging group.

  20. Ethyl 5-methyl-1H-pyrrole-2-carboxylate

    Directory of Open Access Journals (Sweden)

    Zhao-Po Zhang

    2011-07-01

    Full Text Available In the title molecule, C8H11NO2, the r.m.s. deviation of non-H atoms from their best plane is 0.031 Å. Molecules are connected via a pair of N—H...O hydrogen bonds into a centrosymmetric dimer.

  1. (E-4-[(5-Methyl-2-furylmethyleneamino]benzenesulfonic acid

    Directory of Open Access Journals (Sweden)

    Jianlan Suo

    2008-09-01

    Full Text Available The title compound, C12H11NO4S, is a Schiff base derived from the condensation reaction of equimolar quantities of sulfamide and furfural. The molecule has a trans configuration with respect to the imine C=N double bond. The N atom is involved in an intermolecular O—H—N hydrogen bond.

  2. N-(2-Chloro-5-methyl-phen-yl)succinamic acid.

    Science.gov (United States)

    Gowda, B Thimme; Foro, Sabine; Chaithanya, U

    2012-01-01

    In the title compound, C(11)H(12)ClNO(3), the conformation of the N-H bond in the amide segment is syn with respect to the ortho-Cl atom. The amide and carboxyl C=O groups are syn to each other. Furthermore, the C=O and O-H bonds of the carboxyl group are in syn positions with respect to each other. The dihedral angle between the benzene ring and the amide group is 47.8 (2)°. In the crystal, mol-ecules are connected by pairs of O-H⋯O hydrogen bonds, forming inversion dimers. The dimers are further linked by N-H⋯O hydrogen bonds into double chains along the b-axis direction.

  3. Electrophysiological study, biodistribution in mice, and preliminary PET evaluation in a rhesus monkey of 1-amino-3-[{sup 18}F]fluoromethyl-5-methyl-adamantane ({sup 18}F-MEM): a potential radioligand for mapping the NMDA-receptor complex

    Energy Technology Data Exchange (ETDEWEB)

    Samnick, Samuel; Ametamey, Simon; Leenders, Klaus L.; Vontobel, Peter; Quack, Guenter; Parsons, Chris G.; Neu, Henrik; Schubiger, Pius A

    1998-05-01

    The effect of the fluorinated memantine derivative and NMDA receptor antagonist, 1-amino-3-fluoromethyl-5-methyl-adamantane ({sup 19}F-MEM), at the NMDA receptor ion channel was studied by patch clamp recording. The results showed that {sup 19}F-MEM is a moderate NMDA receptor channel blocker. A procedure for the routine preparation of the {sup 18}F-labelled analog {sup 18}F-MEM has been developed using a two-step reaction sequence. This involves the no-carrier-added nucleophilic radiofluorination of 1-[N-(tert-butyloxy)carbamoyl]-3-(toluenesulfonyloxy)methyl-5- methyl-adamantane and the subsequent cleavage of the BOC-protecting group using aqueous HCl. The {sup 18}F-MEM was obtained in 22{+-}7% radiochemical yield (decay-corrected to EOB) in a total synthesis time including HPLC purification of 90 min. A biodistribution study after IV injection of {sup 18}F-MEM in mice showed a fast clearance of radioactivity from blood and relatively high initial uptake in the kidney and in the lung, which gradually decreased with time. The brain uptake was high (up to 3.6% ID/g, 60 min postinjection) with increasing brain-blood ratios: 2.40, 5.10, 6.33, and 9.27 at 5, 30, 60, and 120 min, respectively. The regional accumulation of the radioactivity in the mouse brain was consistent with the known distribution of the PCP recognition site. Preliminary PET evaluation of the radiotracer in a rhesus monkey demonstrated good uptake and prolonged retention in the brain, with a plateau from 35 min onwards p.i. in the NMDA receptor-rich regions (frontal cortex, striata, and temporal cortex). Delineation of the hippocampus, a region known to contain a high density of NMDA receptors, was not possible owing to the resolution of the PET tomograph. The regional brain uptake of {sup 18}F-MEM was changed by memantine and by a pharmacological dose of (+)-MK-801, indicating competition for the same binding sites. In a preliminary experiment, haloperidol, a dopamine D2 and sigma receptor

  4. 7-Chloro-5-(furan-3-yl)-3-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-Dioxide as Positive Allosteric Modulator of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor. The End of the Unsaturated-Inactive Paradigm?

    Science.gov (United States)

    Citti, Cinzia; Battisti, Umberto M; Cannazza, Giuseppe; Jozwiak, Krzysztof; Stasiak, Natalia; Puja, Giulia; Ravazzini, Federica; Ciccarella, Giuseppe; Braghiroli, Daniela; Parenti, Carlo; Troisi, Luigino; Zoli, Michele

    2016-02-17

    5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-PAMs) have received particular attention in the past decade for their nootropic activity and lack of the excitotoxic side effects of direct agonists. Recently, our research group has published the synthesis and biological activity of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (1), one of the most active benzothiadiazine-derived AMPA-PAMs in vitro to date. However, 1 exists as two stereolabile enantiomers, which rapidly racemize in physiological conditions, and only one isomer is responsible for the pharmacological activity. In the present work, experiments carried out with rat liver microsomes show that 1 is converted by hepatic cytochrome P450 to the corresponding unsaturated derivative 2 and to the corresponding pharmacologically inactive benzenesulfonamide 3. Surprisingly, patch-clamp experiments reveal that 2 displays an activity comparable to that of the parent compound. Molecular modeling studies were performed to rationalize these results. Furthermore, mice cerebral microdialysis studies suggest that 2 is able to cross the blood-brain barrier and increases acetylcholine and serotonin levels in the hippocampus. The experimental data disclose that the achiral hepatic metabolite 2 possesses the same pharmacological activity of its parent compound 1 but with an enhanced chemical and stereochemical stability, as well as an improved pharmacokinetic profile compared with 1.

  5. Initial human studies with single-photon emission tomography using iodine-123 labelled 3-(5-cyclopropyl-1,2,4-oxadiazo-3-yl)-7-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine (NNC 13-8241)

    Energy Technology Data Exchange (ETDEWEB)

    Kuikka, J.T. [Dept. of Clinical Physiology, Kuopio Univ. Hospital (Finland); Hiltunen, J. [MAP Medical Technologies Oy, Tikkakoski (Finland); Foged, C. [NOVO Nordisk A/S, Maalov (Denmark); Bergstroem, K.A. [Dept. of Clinical Physiology, Kuopio Univ. Hospital (Finland)]|[Karolinska Inst., Dept. of Clinical Neuroscience, Psychiatry Section, Stockholm (Sweden); Halldin, C. [Karolinska Inst., Dept. of Clinical Neuroscience, Psychiatry Section, Stockholm (Sweden); Aakerman, K. [Dept. of Clinical Physiology, Kuopio Univ. Hospital (Finland); Tiihonen, J. [Niuvaniemi Hospital, Kuopio (Finland); Farde, L. [Karolinska Inst., Dept. of Clinical Neuroscience, Psychiatry Section, Stockholm (Sweden)

    1996-07-01

    The iodine-123 labelled ligand 3-(5-cyclopropyl-1,2,4-oxadiazo-3-yl)-7-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a][1,4]-benzodiazepine ([{sup 123}I]NNC 13-8241) was evaluated as a probe for in vivo imaging of benzodiazepine receptor sites in the human brain. Four healthy volunteers were imaged with a high-resolution single-photon emission tomography (SPET) scanner. The metabolism of [{sup 123}I]NNC 13-8241 in plasma was slow. The total brain uptake was about 1.5-fold higher than that of [{sup 123}I]iomazenil. The specific binding in the cortical areas was high and less intense in the thalamus. The most intense uptake was seen in the occipital cortex. The peak cortical uptake of [{sup 123}I]NNC 13-8241 was observed 6-10 h after the injection of tracer. The radiation burden to the patient was moderate, being 2.5 x 10{sup -2} mSv/MBq (effective dose equivalent). A slow metabolism together with favourable kinetics indicates that [{sup 123}I]NNC 13-8241 is a specific and promising SPET ligand for imaging benzodiazepine receptor sites in the living human brain. (orig.)

  6. Synthesis and Crystal Structure of a Co(Ⅱ)Complex with Taurine-5-methyl-2-hydroxyisophthalaldehyde Schiff Bases[Co(C13H16N2O7S2)(H2O)3]2·H2O

    Institute of Scientific and Technical Information of China (English)

    QIN Xiu-Ying; JIANG Yi-Min; ZHANG Shu-Hua; MO Qian-Qun

    2008-01-01

    The title complex[CoL(H2O)3]2·H2O(C26H46N4O21S4Co2),where L=taurine-5-methyl-2-hydroxyisophthalaldehydes,has been synthesized and characterized by IR and X-ray diffraction analysis.The crystal of the complex belongs to the triclinic system,space group P(l),with a=11.197(4),b=13.309(5),c=14.486(5)(A),a=78.827(13),β=70.547(11),γ=81.058(13)°,Mr=996.77,S=1.08,V=1987.2(13)(A)3,Z=2,Dc=1.666 g/cm3,F(000)=1032,μ=1.131mam-1,R=0.0633 and wR=0.1293.According to the structural analysis,the Co(Ⅱ)ion adopts a slightly distorted six-coordinated octahedral geometry.One N atom of the Schiff base of each molecule was hydrogenated to form hydrogen bond with O atom.Two coterminous molecules packed in one crystal water molecule are linked by intermolecular hydrogen bonds,thus generating an infinite chain constructed by hydrogen bonds.

  7. Synthesis, biological evaluation, and automated docking of constrained analogues of the opioid peptide H-Dmt-D-Ala-Phe-Gly-NH₂ using the 4- or 5-methyl substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold.

    Science.gov (United States)

    De Wachter, Rien; de Graaf, Chris; Keresztes, Atilla; Vandormael, Bart; Ballet, Steven; Tóth, Géza; Rognan, Didier; Tourwé, Dirk

    2011-10-13

    The Phe(3) residue of the N-terminal tetrapeptide of dermorphin (H-Dmt-d-Ala-Phe-Gly-NH(2)) was conformationally constrained using 4- or 5-methyl-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) stereoisomeric scaffolds. Several of the synthesized peptides were determined to be high affinity agonists for the μ opioid receptor (OPRM) with selectivity over the δ opioid receptor (OPRD). Interesting effects of the Aba configuration on ligand binding affinity were observed. H-Dmt-d-Ala-erythro-(4S,5S)-5-Me-Aba-Gly-NH(2)9 and H-Dmt-threo-(4R,5S)-5-Me-Aba-Gly-NH(2)12 exhibited subnanomolar affinity for OPRM, while they possess an opposite absolute configuration at position 4 of the Aba ring. However, in the 4-methyl substituted analogues, H-Dmt-d-Ala-(4R)-Me-Aba-Gly-NH(2)14 was significantly more potent than the (4S)-derivative 13. These unexpected results were rationalized using the binding poses predicted by molecular docking simulations. Interestingly, H-Dmt-d-Ala-(4R)-Me-Aba-Gly-NH(2)14 is proposed to bind in a different mode compared with the other analogues. Moreover, in contrast to Ac-4-Me-Aba-NH-Me, which adopts a β-turn in solution and in the crystal structure, the binding mode of this analogue suggests an alternative receptor-bound conformation.

  8. Synthesis, DFT calculations, electronic structure, electronic absorption spectra, natural bond orbital (NBO) and nonlinear optical (NLO) analysis of the novel 5-methyl-8H-benzo[h]chromeno[2,3-b][1,6] naphthyridine-6(5H),8-dione (MBCND)

    Science.gov (United States)

    Halim, Shimaa Abdel; Ibrahim, Magdy A.

    2017-02-01

    New derivative of heteroannulated chromone identified as 5-methyl-8H-benzo[h]chromeno[2,3-b][1,6]naphthyridine-6(5H),8-dione (5, MBCND) was easily and efficiently synthesized from DBU catalyzed condensation reaction of 2-aminochromone-3-carboxaldehyde (1) with 4-hydroxy-1-methylquinolin-2(1H)-one (2). The same product 5 was isolated from condensation reaction of aldeyde 1 with 3-(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxopropanoic acid (3) or ethyl 4-(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-2,4-dioxobutanoate (4). Structure of compound (5, MBCND) was deduced based on their elemental analyses and spectral data (IR, 1H NMR and mass spectra). Density Functional Theory (DFT) calculations at the B3LYP/6-311G (d,p) level of theory have been carried out to investigate the equilibrium geometry of the novel compound (5, MBCND). Moreover, total energy, energy of HOMO and LUMO and Mullikan atomic charges were calculated. In addition, the dipole moment, theoretical study of the electronic structure, nonlinear optical properties (NLO), and natural bonding orbital (NBO) analysis and orientation have been performed and discussed. Also the electronic absorption spectra were measured in polar (methanol) as well as non polar (dioxane) solvents and the assignment of the observed bands has been discussed by TD-DFT calculations. The correspondences between calculated and experimental transitions energies are satisfactory.

  9. Influence of Transition Metal Cationization versus Sodium Cationization and Protonation on the Gas-Phase Tautomeric Conformations and Stability of Uracil: Application to [Ura+Cu]+ and [Ura+Ag]+

    Science.gov (United States)

    Akinyemi, T. E.; Wu, R. R.; Nei, Y.-W.; Cunningham, N. A.; Roy, H. A.; Steill, J. D.; Berden, G.; Oomens, J.; Rodgers, M. T.

    2017-09-01

    The gas-phase conformations of transition metal cation-uracil complexes, [Ura+Cu]+ and [Ura+Ag]+, were examined via infrared multiple photon dissociation (IRMPD) action spectroscopy and theoretical calculations. IRMPD action spectra were measured over the IR fingerprint and hydrogen-stretching regions. Structures and linear IR spectra of the stable tautomeric conformations of these complexes were initially determined at the B3LYP/6-31G(d) level. The four most stable structures computed were also examined at the B3LYP/def2-TZVPPD level to improve the accuracy of the predicted IR spectra. Two very favorable modes of binding are found for [Ura+Cu]+ and [Ura+Ag]+ that involve O2N3 bidentate binding to the 2-keto-4-hydroxy minor tautomer and O4 monodentate binding to the canonical 2,4-diketo tautomer of Ura. Comparisons between the measured IRMPD and calculated IR spectra enable elucidation of the conformers present in the experiments. These comparisons indicate that both favorable binding modes are represented in the experimental tautomeric conformations of [Ura+Cu]+ and [Ura+Ag]+. B3LYP suggests that Cu+ exhibits a slight preference for O4 binding, whereas Ag+ exhibits a slight preference for O2N3 binding. In contrast, MP2 suggests that both Cu+ and Ag+ exhibit a more significant preference for O2N3 binding. The relative band intensities suggest that O4 binding conformers comprise a larger portion of the population for [Ura+Ag]+ than [Ura+Cu]+. The dissociation behavior and relative stabilities of the [Ura+M]+ complexes, M+ = Cu+, Ag+, H+, and Na+) are examined via energy-resolved collision-induced dissociation experiments. The IRMPD spectra, dissociation behaviors, and binding preferences of Cu+ and Ag+ are compared with previous and present results for those of H+ and Na+. [Figure not available: see fulltext.

  10. Copper complex of 5-methyl-amino salicylic acid salicylaldehyde Schiff base:synthesis, characterization and antitumor activity in vitro%5-甲基水杨醛缩对氨基水杨酸希夫碱铜配合物合成表征与体外抗肿瘤活性研究

    Institute of Scientific and Technical Information of China (English)

    郭永胜; 陈红林; 刘文; 孙体健

    2016-01-01

    Objective To synthesize the copper complex of 5-methyl-amino salicylic acid Schiff base and de-termine its anti-tumor effect in vitro. Methods The conventional heating under reflux method was used for synthesis of the target compound. Ultraviolet absorption, elemental analysis and infrared spectroscopy were employed to charac-terize the synthesized product. MTT assay was used to investigate the inhibitory effect of the copper complex against proliferation of human cervical cancer SiHa and HeLa cell lines. AO/EB double staining fluorescence microscopy was used to study the change in SiHa cell morphology as induced by the copper complex. Results The molecular formula of the target compound was found to be [C30H24N2O8Na2Cu]·2H2O. The copper complex exhibited varying degrees of in-hibitory effects on SiHa and HeLa cell lines in a significant dose-response manner. The anti-tumor effect was more ac-tive against SiHa than HeLa cells. The compound was found to induce obvious changes in tumor cell morphology, apoptosis or necrosis of the tumor cell lines. Conclusion The copper complex of 5-methyl-aminosalicylic acid Schiff base may inhibit the proliferation of HeLa and SiHa cell lines of cervical cancer, and thereby shows satisfactory anti-tumor activity in vitro.%目的:合成5-甲基水杨醛缩对氨基水杨酸希夫碱铜配合物药物并研究其体外抗肿瘤作用。方法采用常规加热回流法合成目标化合物,利用紫外吸收、元素分析和红外光谱等方法对其进行表征研究。采用四甲基偶氮唑盐(MTT)法考察药物对人宫颈癌细胞SiHa和HeLa增殖的抑制作用,并采用吖啶橙/溴乙锭(AO/EB)双染色荧光显微镜观察药物对SiHa细胞形态的变化。结果目标化合物的组成为[C30H24N2O8Na2Cu ]·2H2O;对SiHa和HeLa细胞都有不同程度的抑制作用,呈现良好的剂量-效应关系,对SiHa的活性优于HeLa;并且可使肿瘤细胞的形态发生显著变化,引起细胞株

  11. 5-(1-苯基-5-甲基-1,2,3-三唑-4-基)-4-芳基 -1,2,4-三唑-3-硫基乙酸的合成和抗菌活性%Synthesis and Antifungal Activities of 4-Aryl-5- (1-phenyl-5-methyl-1,2,3-triazol-4-yl) -1,2,4-triazol-3-thioacetic Acids

    Institute of Scientific and Technical Information of China (English)

    褚长虎; 张艳; 惠新平; 张自义; 李之春; 廖仁安

    2001-01-01

    A series of new 4-Aryl-5-(5-methyl-1-phenyl-1,2,3-triazol-4-yl)-1,2,4-triazol-3-thioacetic acids 2a-k have been synthesized by the condensation of 4-Aryl-5-(5-methyl-1-phenyl-1,2,3-triazol-3-yl)-1,2,4-triazol-3-thiones with chloroacetic acid in the presence of potassium hydroxide methanol-water solution. Supports for the structure of the synthesized compounds have been provided by their elemental analyses and spectra data. The preliminary biological test showed that the compounds possessed some antifungal activities.%合成一系列新的5-(1-苯基-5-甲基-1,2,3-三唑-4-基)-4-芳基-1,2,4-三唑-3-硫基乙酸,所有化合物均经元素分析和波谱数据予以鉴定.对代表性化合物作了抗菌活性测试,结果表明它们都表现出不同程度的抗菌活性.

  12. 5-methyl-1H-benzotriazole as potential corrosion inhibitor for electrochemical-mechanical planarization of copper%5-甲基苯并三氮唑作为电腐蚀抑制剂在铜电化学机械平坦化中的应用

    Institute of Scientific and Technical Information of China (English)

    边燕飞; 翟文杰; 朱宝全

    2013-01-01

    根据电化学分析,5-甲基苯并三氮唑(m-BTA)的腐蚀抑制能力要高于苯并三唑(BTA)的。当羟基乙叉二膦酸(HEDP)电解液中同时含有m-BTA及氯离子时,其抑制解离能力比只含有m-BTA的更好,即使施加更高的阳极氧化电位依然能保持良好的抑制能力。由电化学阻抗谱法、纳米划痕实验以及能谱分析结果得知,m-BTA抑制能力的提升是因为整体钝化膜厚度的增加而引起的。由X射线光电子能谱分析得知,氯离子与m-BTA钝化层形成[Cu(I)Cl(m-BTA)]n高分子化合物,使得整体钝化层厚度增加。因此,在含有m-BTA的HEDP电解液中添加氯离子有助于m-BTA钝化层抑制能力的增强,进而更有效的电位操作区间得到扩展。%According to the electrochemical analysis, the corrosion inhibition efficiency of 5-methyl-1H-benzotriazole (m-BTA) is higher than that of benzotrizaole (BTA). The inhibition capability of the m-BTA passive film formed in hydroxyethylidenediphosphonic acid (HEDP) electrolyte containing both m-BTA and chloride ions is superior to that formed in m-BTA-alone electrolyte, even at a high anodic potential. The results of electrical impedance spectroscopy, nano-scratch experiments and energy dispersive analysis of X-ray (EDAX) indicate that the enhancement of m-BTA inhibition capability may be due to the increasing thickness of passive film. Furthermore, X-ray photoelectron spectrometry (XPS) analysis indicates that the increase in passive film thickness can be attributed to the incorporation of Cl− into the m-BTA passive film and the formation of [Cu(I)Cl(m-BTA)]n polymer film on Cu surface. Therefore, the introduction of Cl− into m-BTA-containing HEDP electrolyte is effective to enhance the passivation capability of m-BTA passive film, thus extending the operating potential window.

  13. 竞争性α-氨基-3-羟基-5-甲基-4-异唑恶唑丙酸受体拮抗剂研究进展%Competitiveα-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid receptor antagonists:research advances

    Institute of Scientific and Technical Information of China (English)

    肖典; 王凌霄; 周辛波; 李松

    2014-01-01

    α-氨基-3-羟基-5-甲基-4-异唑恶唑丙酸(AMPA)受体是游离型谷氨酸受体,广泛分布于中枢神经系统,介导快速兴奋性突触传递。越来越多的证据表明,其在突触可塑性及中枢敏化中发挥重要作用,并且与神经系统疾病关系密切。过度刺激AMPA受体产生兴奋性毒性会导致神经元损伤,引发癫痫、肌萎缩侧索硬化和帕金森病等一系列神经系统疾病的发生。竞争性AMPA受体拮抗剂能够有效下调AMPA受体活性,对预防和治疗神经系统疾病意义重大。本文对竞争性AMPA受体拮抗剂的研究进展进行综述。%α-Amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) receptor, a subtype of ionotropic glutamate receptors widely distributed in the central nervous system, mediates the fast excitatory neurotransmission. Meanwhile more and more evidence indicates that AMPA receptor plays an important role in synaptic plasticity as well as central sensitization, and it also has close relationships with nervous system diseases. Over stimulation of AMPA receptor would produce excitotoxicity, leading to neuronal damage and finally resulting in a multitude of nervous system diseases, such as epilepsy, amyotrophic lateral scelerosis,Parkinson′s dis-ease. Competitive AMPA receptor antagonists that downregulate AMPA receptor′s function are of great importance in the prevention and treatment of nervous system diseases. This article reviews the research advances of competitive AMPA receptor antagonists.

  14. 5-甲基-2-巯基-1,3,4-噻二唑衍生物的合成及摩擦学性能研究%THE SYNTHESIS AND TRIBOLOGICAL PROPERTIES OF 5-METHYL-2-MECAPTO-1,3,4-THIADIAZOLE DERIVATIVES

    Institute of Scientific and Technical Information of China (English)

    钱建华; 朱江丽; 郑艳秋

    2011-01-01

    A novel thiadiazole derivative(TM) was synthesized using 5-methyl-2-mecapto-l,3,4-thiadiazole and salicylic acid as main raw materials,and it was characterized by FT-IR.elementary analysis, LC and MS. The thermal stability of TM was evaluated by TGA.and its wear and friction behavior was investigated by a four-ball testing machine using rapeseed oil as base oil. Results show that the synthesized TM possesses good thermal stability with a thermal decomposition temperature of 225. 6℃. Due to its good anti-wear and friction reducing properties, the obtained TM could be used as lube additive, it exhibits an optimum anti-wear and friction reducing performance at an amount of 0. 6%.%以5-甲基-2-巯基-1,3,4-噻二唑(MMTD)和水杨酸为主要原料,合成一种新的噻二唑衍生物——水杨酸硫代-(5-甲基-1,3,4-噻二唑)酯(TM).利用红外光谱、元素分析、液相色谱、质谱等分析手段对产物进行结构表征,采用热重分析评价产物的热稳定性,利用四球摩擦磨损试验机考察TM在菜籽油中的抗磨减摩性能.结果表明:合成产品TM的热分解温度为225.6℃,具有较好的热稳定性;合成产品TM具有良好的抗磨减摩性能,可作为油品的抗磨减摩添加剂,当添加量(ω)为0.6%时,其抗磨减摩效果最佳.

  15. 双(3-对甲苯基-2-硫代咪唑-1-基)-(3-甲基-5-苯基吡唑-1-基) 硼氢酸根的镉及钴配合物的合成与结构表征%Syntheses and Crystal Structures of Cadmium(Ⅱ) and Cobalt(Ⅱ) Complexes with Hydro[bis(3-p-tolyl-2-thioimidazol- 1-yl)-(3-phenyl-5-methyl-pyrazol-1-yl)] Borate

    Institute of Scientific and Technical Information of China (English)

    舒谋海; 屠春来; 崔靖; 孙杰

    2006-01-01

    Two new complexes CdL2 (1) and CoL2 (2) were synthesized by reactions of L {L =hydro[bis(3-p-tolyl-2-thioimidazol-1-yl)-(3-phenyl-5-methyl-pyrazol-1-yl)]borate} with cadmium(Ⅱ) and cobalt(Ⅱ) acetate respectively, and structurally characterized. The title complexes feature distorted trigonal dipyramidal geometries with a S4H donor set defined by the sulphur and hydrogen atoms of two tripodal sulfur-rich ligands. CCDC: 235514, 1; 244021, 2.

  16. Communication: Electronic UV-Vis transient spectra of the ∙OH reaction products of uracil, thymine, cytosine, and 5,6-dihydrouracil by using the complete active space self-consistent field second-order perturbation (CASPT2//CASSCF) theory.

    Science.gov (United States)

    Francés-Monerris, Antonio; Merchán, Manuela; Roca-Sanjuán, Daniel

    2013-08-21

    Addition of ∙OH radicals to pyrimidine nucleobases is a common reaction in DNA/RNA damage by reactive oxygen species. Among several experimental techniques, transient absorption spectroscopy has been during the last decades used to characterize such compounds. Discrepancies have however appeared in the assignment of the adduct or adducts responsible for the reported transient absorption UV-Vis spectra. In order to get an accurate assignment of the transient spectra and a unified description of the absorption properties of the ∙OH reaction products of pyrimidines, a systematic complete active space self-consistent field second-order perturbation (CASPT2//CASSCF) theory study has been carried out on the uracil, thymine, and cytosine ∙OH addition adducts, as well as on the 5,6-dihydrouracil hydrogen abstraction products. With the obtained findings, the C5OH contributions to the lowest-energy band can be finally discarded. Instead, a bright (2)(π2) state of the C6OH adducts is determined to be the main responsible in all compounds for the absorption band in the Vis range.

  17. Simultaneous determination of 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl) uracil (FAU) and 1-(2′-deoxy-2′-fluoro- β-D-arabinofuranosyl 5-methyluracil (FMAU) in human plasma by liquid chromatography/tandem mass spectrometry

    Science.gov (United States)

    Wiegand, Richard; Wu, Jianmei; Shields, Anthony F.; LoRusso, Patricia; Li, Jing

    2013-01-01

    A liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) assay was developed and validated for simultaneously determination of 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl) uracil (FAU) and its active metabolite 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl 5-methyluracil (FMAU) in human plasma. FAU and FMAU were extracted from plasma samples using solid-phase extraction with Waters Sep-Pak® Vac C18 cartridge. Chromatographic separation was achieved on a Waters Atlantis T3 C18 column with a gradient mobile phase consisting of methanol and water with 0.45% formic acid (v/v) running at a flow rate of 0.2 ml/min. The analytes were monitored by triple quadrupole mass spectrometer under positive ionization mode. The lower limit of quantitation (LLOQ) was 10 and 2 ng/ml for FAU and FMAU in plasma, respectively. Calibration curves were linear over FAU and FMAU plasma concentration range of 10–2000 and 2 – 1000 ng/ml, respectively. The intra-day and inter-day accuracy and precision were within the generally accepted criteria for bioanalytical method (FAU and FMAU in cancer patients receiving 1-h intravenous infusion of FAU 50 mg/m2. PMID:22410089

  18. 2-(5-Methyl-3-methylsulfinyl-1-benzofuran-2-ylacetic acid

    Directory of Open Access Journals (Sweden)

    Hong Dae Choi

    2009-09-01

    Full Text Available In the title compound, C12H12O4S, the O atom and the methyl group of the methylsulfinyl substituent are located on opposite sides of the plane of the benzofuran fragment. In the crystal structure, intermolecular C—H...O and O—H...O hydrogen-bonding interactions are found. The structure also exhibits aromatic π–π interactions between the furan and benzene rings [centroid–centroid distance = 3.841 (5 Å].

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Antispasmodic action of 5-methyl benzoxazoline-2-one: A preliminary study

    Digital Repository Service at National Institute of Oceanography (India)

    DeSouza, R.D.; Bhandare, P.N.; Fernandes, N.; Wahidullah, S.; DeSouza, L.

    In the present study, compound (1) depressed both phases of the dose-response curve. The marked effect on 5-HT response cannot be attributed solely to an antimuscarinic action of the compound which was much less (66%) as compared to (88...

  1. 1-Anilino-5-methyl-1H-1,2,3-triazole-4-carbaldehyde

    Directory of Open Access Journals (Sweden)

    Anna C. Cunha

    2016-01-01

    Full Text Available The title compound, C10H10N4O, is twisted about the Nring—Namine bond with the dihedral angle between the 1,2,3-triazolyl and N-bound phenyl rings being 79.14 (9°. The C-bound aldehyde group is coplanar with the triazolyl ring, with the N—C—C—O torsion angle being 3.5 (3°. While coplanar, the aldehyde O atom is orientated in the opposite direction to the triazolyl-bound methyl group. The most prominent feature of the molecular packing is the formation of zigzag chains (glide symmetry along the b axis and mediated by amine-N—H...N(triazolyl hydrogen bonds. The chains are connected into supramolecular layers by phenyl- and methyl-C—H...O(aldehyde interactions, with phenyl groups projecting to either side. Layers stack along the c axis with no directional interactions between them.

  2. Ammonium hydrogen (RS-[(5-methyl-2-oxo-1,3-oxazolidin-3-ylmethyl]phosphonate

    Directory of Open Access Journals (Sweden)

    Petar Todorov

    2010-01-01

    Full Text Available In the title compound, NH4+·C5H9NO5P−, the five-membered methyloxazolidin-2-one unit is disordered over two positions, the major component having a site occupancy of 0.832 (9. A three-dimensional network of O—H...O and N—H...O hydrogen bonds stabilizes the crystal structure.

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

    Science.gov (United States)

    Godlewska, Sylwia; Baranowska, Katarzyna; Socha, Joanna; Dołęga, Anna

    2011-12-01

    The Cu(II) ion in the title compound, [CuBr(C(6)H(10)N(2))(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 Cu(II) and Br(-) atoms lie on a crystallographic fourfold axis. In the crystal, the [CuBr(C(6)H(10)N(2))(4)](+) complex cations are linked to the uncoordinated Br(-) anions (site symmetry [Formula: see text]) by N-H⋯Br hydrogen bonds, generating a three-dimensional network. The ethyl group of the imidazole ligand was modelled as disordered over two orientations with occupancies of 0.620 (8) and 0.380 (8).

  4. N-{2-[2-(5-Methyl-1H-pyrazol-3-ylacetamido]phenyl}benzamide monohydrate

    Directory of Open Access Journals (Sweden)

    Karim Chkirate

    2017-02-01

    Full Text Available The asymmetric unit of the title compound, C19H18N4O2·H2O, comprises the U-shaped pyrazole derivative and a solvent water molecule. The molecular conformation is partly determined by an intramolecular N—H...O hydrogen bond. The crystal packing is directed by an extensive network of O—H...O, N—H...O, N—H...N and C—H...O hydrogen bonds together with C—H...π(ring contacts that generate a three-dimensional network.

  5. Detection of oxidation products of 5-methyl-2'-deoxycytidine in Arabidopsis DNA.

    Directory of Open Access Journals (Sweden)

    Shuo Liu

    Full Text Available Epigenetic regulations play important roles in plant development and adaptation to environmental stress. Recent studies from mammalian systems have demonstrated the involvement of ten-eleven translocation (Tet family of dioxygenases in the generation of a series of oxidized derivatives of 5-methylcytosine (5-mC in mammalian DNA. In addition, these oxidized 5-mC nucleobases have important roles in epigenetic remodeling and aberrant levels of 5-hydroxymethyl-2'-deoxycytidine (5-HmdC were found to be associated with different types of human cancers. However, there is a lack of evidence supporting the presence of these modified bases in plant DNA. Here we reported the use of a reversed-phase HPLC coupled with tandem mass spectrometry method and stable isotope-labeled standards for assessing the levels of the oxidized 5-mC nucleosides along with two other oxidatively induced DNA modifications in genomic DNA of Arabidopsis. These included 5-HmdC, 5-formyl-2'-deoxycytidine (5-FodC, 5-carboxyl-2'-deoxycytidine (5-CadC, 5-hydroxymethyl-2'-deoxyuridine (5-HmdU, and the (5'S diastereomer of 8,5'-cyclo-2'-deoxyguanosine (S-cdG. We found that, in Arabidopsis DNA, the levels of 5-HmdC, 5-FodC, and 5-CadC are approximately 0.8 modifications per 10(6 nucleosides, with the frequency of 5-HmdC (per 5-mdC being comparable to that of 5-HmdU (per thymidine. The relatively low levels of the 5-mdC oxidation products suggest that they arise likely from reactive oxygen species present in cells, which is in line with the lack of homologous Tet-family dioxygenase enzymes in Arabidopsis.

  6. Methotrexate-induced misincorporation of uracil into DNA

    OpenAIRE

    Goulian, M; Bleile, B.; Tseng, B. Y.

    1980-01-01

    A line of human lymphoid cells was tested for the presence of dUMP in DNA with or without treatment with the dihydrofolate reductase inhibitor, methotrexate. Cells treated with methotrexate and labeled with [3H]dUrd contained dUMP in DNA in readily detectable amounts (≈0.8 pmol of dUMP per μmol of total DNA nucleotide), and this was increased ≈3-fold if the cells were also treated with Ura at the same time. No dUMP (

  7. Crystal structure of (2-{[3,5-bis(1,1-dimethylethyl-4-hydroxyphenyl](5-methyl-2H-pyrrol-2-ylidenemethyl}-5-methyl-1H-pyrrolido-κ2N,N′difluoridoboron

    Directory of Open Access Journals (Sweden)

    Yukio Morimoto

    2015-09-01

    Full Text Available The title compound, C25H31BF2N2O, is a potential boron tracedrug in boron neutron capture therapy (BNCT, in which the B atom adopts a distorted BN2F2 tetrahedral geometry: it is soluble in dimethyl sulfoxide, dimethylformamide and methanol. The pyrrolylidenemethylpyrrole triple fused ring system is almost planar (r.m.s. deviation = 0.031 Å and subtends a dihedral angle of 47.09 (5° with the plane of the pendant phenol ring. The phenol –OH group is blocked from forming hydrogen bonds by the adjacent bulky tert-butyl groups. In the crystal, inversion dimers linked by pairs of very weak C—H...F interactions generate R22(22 loops.

  8. (5S,6R-5-Methyl-6-phenyl-4-propyl-1,3,4-oxadiazinane-2-thione

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    Joshua L. Kocher

    2009-06-01

    Full Text Available The title molecule, C13H18N2OS, is an oxadiazinanthione derived from (1R,2S-norephedrine. There are two molecules in the asymmetric. Both adopt roughly half-chair conformations; however, the 5-position carbon orients out of opposite faces of the oxadiazinanthiones plane in the two molecules. In the crystal structure, they are oriented as a dimer linked by a pair of N—H...S hydrogen bonds. The absolute configuration has been established from anomalous dispersion and confirms the known stereochemistry based on the synthetic procedure.

  9. 10-Ethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl-10H-phenothiazine

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    Li-Cheng Sun

    2012-03-01

    Full Text Available In the title compound, C17H15N3OS, the phenothiazine ring system is slightly bent, with a dihedral angle of 13.68 (7° between the benzene rings. The dihedral angle between the oxadiazole ring and the adjacent benzene ring is 7.72 (7°. In the crystal, a π–π interaction with a centroid–centroid distance of 3.752 (2 Å is observed between the benzene rings of neighbouring molecules.

  10. N-[2-(4-Bromophenyl-5-methyl-4-oxo-1,3-thiazolidin-3-yl]pyridine-3-carboxamide

    Directory of Open Access Journals (Sweden)

    Mehmet Akkurt

    2011-04-01

    Full Text Available In the title compound, C16H14BrN3O2S, the atoms of the 1,3-thiazolidine group, except for the N and the C atoms attached to the bromobenzene ring, are disordered over two sets of sites with occupancies of 0.605 (13 and 0.395 (13. The benzene and pyridine rings make a dihedral angle of 86.2 (2°. In the crystal, molecules are linked by intermolecular N—H...N and C—H...O hydrogen bonds, forming a three-dimensional network. Furthermore, there is a π–π stacking interaction [centroid–centroid distance = 3.758 (2 Å] between the pyridine and benzene rings.

  11. Methyl 5-methyl-1-(1H-pyrazol-3-yl-1H-1,2,3-triazole-4-carboxylate

    Directory of Open Access Journals (Sweden)

    Xiao-Guang Bai

    2014-07-01

    Full Text Available The asymmetric unit of the title compound, C8H9N5O2, contains two independent molecules (A and B in which the dihedral angles between the triazole and pyrazole rings are 4.80 (14 and 8.45 (16°. In the crystal, molecules are linked by N—H...N hydrogen bonds into supramolecular independent A and B chains propagating along the b-axis direction. The crystal structure also features π–π stacking between the aromatic rings of adjacent chains, the centroid–centroid separations being 3.8001 (15, 3.8078 (17, 3.8190 (14 and 3.8421 (15 Å.

  12. Synthesis and Some Reactions of 1-aryl-4-acetyl-5-methyl-1,2,3-triazole Derivatives with Anticonvulsant Activity.

    Science.gov (United States)

    Nassar, Ekhlass M; Abdelrazek, Fathy M; Ayyad, Rezk R; El-Farargy, Ahmed F

    2016-01-01

    The triazoles 3a-d underwent condensation reactions with 4-(piperidin-1-yl)-benzaldehyde to afford the chalcones 5a-d. Chalcone derivatives 5a-d were reacted with 2,3-diaminomaleonitrile, thiourea and hydrazine hydrate to afford the novel diazepine-dicarbonitrile derivatives 7a-d, the pyrimidine-2-thiol derivatives 9a-d and hydrazino-pyrimidines 10a-d respectively. Structures of the prepared compounds were elucidated by physical and spectral data like FT-IR, (1)H NMR, (13)C NMR, and mass spectroscopy. Some of the synthesized compounds were screened for their anticonvulsant activity and SAR.

  13. Crystal structure of 2,2-dimethyl-N-(5-methyl-pyridin-2-yl)propanamide.

    Science.gov (United States)

    El-Hiti, Gamal A; Smith, Keith; Hegazy, Amany S; Alanazi, Saud A; Kariuki, Benson M

    2015-06-01

    There are two mol-ecules in the asymmetric unit of the title compound, C11H16N2O. The pyridine rings and amide groups overlap almost perfectly (r.m.s. overlay fit = 0.053 Å), but the tertiary butyl groups have different orientations: in one mol-ecule, one of the methyl C atoms is syn to the amide O atom [O-C-C-C = -0.8 (3)°] and in the other the equivalent torsion angle is 31.0 (2)°. In the crystal, the two independent mol-ecules are linked by a pair of N-H⋯N hydrogen bonds in the form of an R 2 (2)(8) loop to form a dimer. A C-H⋯O inter-action connects the dimers into [100] chains.

  14. [1-(2,5-Dichloroanilino-5-methyl-1H-1,2,3-triazol-4-yl]methanol

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    Anna C. Cunha

    2016-01-01

    Full Text Available In the title compound, C10H10Cl2N4O, the hydroxy group and benzene ring are disposed to opposite sides of the central 1,2,3-triazolyl ring. The dihedral angle between the five- and six-membered rings is 87.51 (12°, and the C—O bond of the hydroxy group lies almost normal to the plane of the 5-membered ring [N—C—C—O = −93.2 (2°]. An intramolecular amino-N—H...Cl hydrogen bond is noted. In the extended structure, supramolecular layers in the ab plane are formed via hydroxy-O—H...N(ring and amine-N—H...O(hydroxy hydrogen bonds. The layers are connected along the c axis by π–π contacts between benzene rings [inter-centroid distance = 3.7789 (13 Å] and by C—Cl...π interactions.

  15. Synthesis and spectroscopy studies of the inclusion complex of 3-amino-5-methyl pyrazole with beta-cyclodextrin

    Science.gov (United States)

    Louiz, S.; Labiadh, H.; Abderrahim, R.

    2015-01-01

    Amino pyrazole belongs to anti-inflammatory class, and is characterized by a low solubility in water. (In order to increase its solubility in water, inclusion complex of amino pyrazole with β-CD was obtained.) The inclusion complex obtained between AMP and β-cyclodextrin, was characterized by FT-IR, 1H NMR, 1H-1H NOESY, 13C NMR, DEPT, XHCOR, spectra, through TG analysis, DTA, DSC and Scanning Electron Microscopy (SEM). The stoichiometry of inclusion complex is 1:1 (guest-host) and K stability is 1.1 × 104 M-1.

  16. Synthesis and crystal structure studies of ethyl 5-methyl-1, 3-diphenyl-1H-pyrazole-4-carboxylate

    Science.gov (United States)

    Chandra, Srikantamurthy, N.; Babu, E. A. Jithesh; Umesha, K. B.; Mahendra, M.

    2014-04-01

    The title compound, C19H18N2O2, was investigated by single crystal X-ray diffraction method. It crystallizes in monoclinic class under the space group P21/c with cell parameters a= 8.4593(4) Å, b=15.6284(6) Å, c=12.4579(5) Å, α=90°, β=98.241(3)°, γ=90° and Z=2. The ethoxycarbonyl group is slightly twisted from the pyrazole ring, and adopts syn-periplanar conformation. The crystal structure is stabilized by intermolecular C-H….O hydrogen bonds, which help in stabilizing the crystal structure.

  17. Synthesis and crystal structure studies of ethyl 5-methyl-1, 3-diphenyl-1H-pyrazole-4-carboxylate

    Energy Technology Data Exchange (ETDEWEB)

    Chandra,; Babu, E. A. Jithesh; Mahendra, M., E-mail: mahendra@physics.uni-mysore.ac.in [Department of Studies in Physics, Manasagangotri, University of Mysore, Mysore-570006 (India); Srikantamurthy, N.; Umesha, K. B. [Department of Chemistry, Yuvaraja' s College, University of Mysore, Mysore-570005 (India)

    2014-04-24

    The title compound, C{sub 19}H{sub 18}N{sub 2}O{sub 2}, was investigated by single crystal X-ray diffraction method. It crystallizes in monoclinic class under the space group P2{sub 1}/c with cell parameters a= 8.4593(4) Å, b=15.6284(6) Å, c=12.4579(5) Å, α=90°, β=98.241(3)°, γ=90° and Z=2. The ethoxycarbonyl group is slightly twisted from the pyrazole ring, and adopts syn-periplanar conformation. The crystal structure is stabilized by intermolecular C-H….O hydrogen bonds, which help in stabilizing the crystal structure.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. N-[2-(4-Chlorophenyl-5-methyl-4-oxo-1,3-thiazolidin-3-yl]pyridine-3-carboxamide

    Directory of Open Access Journals (Sweden)

    Mehmet Akkurt

    2011-04-01

    Full Text Available The title compound, C16H14ClN3O2S, crystallizes with two molecules in the asymmetric unit. In the 1,3-thiazolidine rings, the carbonyl O atoms, the S atoms, the methyl groups and the ring carbon attached to the methyl groups are disordered with occupancy ratios of 0.509 (7:0.491 (7 in one molecule and 0.464 (14:0.536 (14 in the other. The crystal structure is stabilized by intermolecular N—H...N, C—H...O hydrogen bonds and C—H...Cl interactions. In addition, there is a π–π stacking interaction [centroid–centroid distance = 3.794 (3 Å] between the benzene and pyridine rings.

  20. Contrasting reactions of hydrated electron and formate radical with 2-thio analogues of cytosine and uracil.

    Science.gov (United States)

    Prasanthkumar, Kavanal P; Alvarez-Idaboy, Juan R; Kumar, Pavitra V; Singh, Beena G; Priyadarsini, K Indira

    2016-10-19

    2-Thiocytosine (TC) and 2-thiouracil (TU) were subjected to hydrated electron (eaq(-)), formate radical (CO2˙(-)) and 2-hydroxypropan-2-yl radical ((CH3)2˙COH) reactions in aqueous medium. Transients were characterized by absorption spectroscopy and the experimental findings were rationalized by DFT calculations at LC-ωPBE and M06-2X levels using a 6-311+G(d,p) basis set and SMD solvation. In eaq(-) reactions, a ring N-atom protonated radical of TC and an exocyclic O-atom protonated radical of TU were observed via addition of eaq(-) and subsequent protonation by solvent molecules. However, two competing but simultaneous mechanisms are operative in CO2˙(-) reactions with TC and TU. The first one corresponds to formations of N(O)-atom protonated radicals (similar to eaq(-) reactions); the second mechanism led to 2 center-3 electron, sulfur-sulfur bonded neutral dimer radicals, TCdim˙ and TUdim˙. DFT calculations demonstrated that H-abstraction by CO2˙(-) from TC(TU) results in S-centered radical which upon combination with TC(TU) provide the dimer radical. In some cases, DFT energy profiles were further validated by CBS-QB3//M06-2X calculations. This is the first time report for a contradictory behavior in the mechanisms of eaq(-) and CO2˙(-) reactions with any pyrimidines or their thio analogues.

  1. Archaeoglobus Fulgidus DNA Polymerase D: A Zinc-Binding Protein Inhibited by Hypoxanthine and Uracil

    OpenAIRE

    Abellón-Ruiz, Javier; Waldron, Kevin J.; Connolly, Bernard A.

    2016-01-01

    Archaeal family-D DNA polymerases (Pol-D) comprise a small (DP1) proofreading subunit and a large (DP2) polymerase subunit. Pol-D is one of the least studied polymerase families, and this publication investigates the enzyme from Archaeoglobus fulgidus (Afu Pol-D). The C-terminal region of DP2 contains two conserved cysteine clusters, and their roles are investigated using site-directed mutagenesis. The cluster nearest the C terminus is essential for polymerase activity, and the cysteines are ...

  2. Non-canonical uracil processing in DNA gives rise to double-strand breaks and deletions

    DEFF Research Database (Denmark)

    Bregenhorn, Stephanie; Kallenberger, Lia; Artola-Borán, Mariela

    2016-01-01

    During class switch recombination (CSR), antigen-stimulated B-cells rearrange their immunoglobulin constant heavy chain (CH) loci to generate antibodies with different effector functions. CSR is initiated by activation-induced deaminase (AID), which converts cytosines in switch (S) regions, repet...

  3. Dual Targeting of Tumor Angiogenesis and Chemotherapy by Endostatin-Cytosine Deaminase-Uracil Phosphoribosyl Transferase

    OpenAIRE

    Chen, Chun-Te; Yamaguchi, Hirohito; Lee, Hong-Jen; Du, Yi; Lee, Heng-Huan; Xia, Weiya; Yu, Wen-Hsuan; Hsu, Jennifer L.; Yen, Chia-Jui; Sun, Hui-Lung; Wang, Yan; Yeh, Edward T H; Hortobagyi, Gabriel N.; Hung, Mien-Chie

    2011-01-01

    Several antiangiogenic drugs targeting VEGF/VEGFR approved by the FDA for many cancer types including colorectal and lung cancer can effectively reduce tumor growth. However, targeting the VEGF signaling pathway will likely influence the normal function of endothelial cells in maintaining homeostasis and cause unwanted adverse effects. Indeed, emerging experimental evidence suggests that VEGF-targeting therapy induced less tumor cell–specific cytotoxicity, allowing residual cells to become mo...

  4. Non-canonical uracil processing in DNA gives rise to double-strand breaks and deletions

    DEFF Research Database (Denmark)

    Bregenhorn, Stephanie; Kallenberger, Lia; Artola-Borán, Mariela;

    2016-01-01

    During class switch recombination (CSR), antigen-stimulated B-cells rearrange their immunoglobulin constant heavy chain (CH) loci to generate antibodies with different effector functions. CSR is initiated by activation-induced deaminase (AID), which converts cytosines in switch (S) regions, repet...... choice in DSB repair. Given its amenability to manipulation, our system represents a powerful tool for the molecular dissection of CSR....

  5. UCE: A uracil excision (USERTM)-based toolbox for transformation of cereals

    DEFF Research Database (Denmark)

    Hebelstrup, Kim H; Christiansen, Michael W; Carciofi, Massimiliano;

    2010-01-01

    Background Cloning of gene casettes and other DNA sequences into the conventional vectors for biolistic or Agrobacterium-mediated transformation is hampered by a limited amount of unique restriction sites and by the difficulties often encountered when ligating small single strand DNA overhangs...... (USER cereal), ready for use in cloning of complex constructs into the T-DNA. A series of the vectors were tested and shown to perform successfully in Agrobacterium-mediated transformation of barley (Hordeum vulgare L.) as well as in biolistic transformation of endosperm cells conferring transient...

  6. Aqua[bis(2-ethyl-5-methyl-1H-imidazol-4-yl-κN3methane]oxalatocopper(II dihydrate

    Directory of Open Access Journals (Sweden)

    Yang-Hui Luo

    2011-02-01

    Full Text Available In the title compound, [Cu(C2O4(C13H20N4(H2O]·2H2O, the CuII atom exhibits a distorted square-pyramidal geometry with the two N atoms of the imidazole ligand and the two O atoms of the oxalate ligand forming the basal plane, while the O atom of the coordinated water molecule is in an apical position. The CuII atom is shifted 0.232 (2 Å out of the basal plane toward the water molecule. The asymmetric unit is completed by two solvent water molecules. These water molecules participate in the formation of an intricate three-dimensionnal network of hydrogen bonds involving the coordinated water molecule and the NH groups.

  7. 3-(4-{3,3,4,4,5,5-Hexafluoro-2-[5-(3-methoxyphenyl-2-methyl-3-thienyl]cyclopent-1-enyl}-5-methyl-2-thienylbenzonitrile

    Directory of Open Access Journals (Sweden)

    An-yin Chen

    2009-10-01

    Full Text Available The title compound, C29H19F6NOS2, is a new unsymmetrical photochromic diarylethene derivative with different meta-phenyl substituents. The distance between the two reactive (i.e. can be irradiated to form a new chemical bond C atoms is 3.501 (4 Å; the dihedral angles between the mean plane of the main central cyclopentene ring and the thiophene rings are 47.7 (5 and 45.1 (2°, and those between the thiophene rings and the adjacent benzene rings are 29.4 (2 and 28.4 (3°. The three C atoms and the F atoms of hexafuorocyclopentene ring are disordered over two positions, with site-occupancy factors of 0.751 (4 and 0.249 (4.

  8. CCDC 945080: Experimental Crystal Structure Determination : 5,5'-((Dimethylstannanediyl)dibiphenyl-2',2-diyl)bis(5-methyl-5H-dibenzo[b,d]stannole)

    KAUST Repository

    Zeng, Zebing

    2013-01-01

    An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

  9. Synthesis of 2'-deoxy-2'-[.sup.18F]fluoro-5-methyl-1-B-D-arabinofuranosyluracil (.sup.18F-FMAU)

    Energy Technology Data Exchange (ETDEWEB)

    Li, Zibo; Cai, Hancheng; Conti, Peter S

    2014-12-16

    The present invention relates to methods of synthesizing .sup.18F-FMAU. In particular, .sup.18F-FMAU is synthesized using one-pot reaction conditions in the presence of Friedel-Crafts catalysts. The one-pot reaction conditions are incorporated into a fully automated cGMP-compliant radiosynthesis module, which results in a reduction in synthesis time and simplifies reaction conditions. The one-pot reaction conditions are also suitable for the production of 5-substituted thymidine or cytidine analogs. The products from the one-pot reaction (e.g. the labeled thymidine or cytidine analogs) can be used as probes for imaging tumor proliferative activity. More specifically, these [.sup.18F]-labeled thymidine or cytidine analogs can be used as a PET tracer for certain medical conditions, including, but not limited to, cancer disease, autoimmunity inflammation, and bone marrow transplant.

  10. 5-methyl-cytosine and 5-hydroxy-methyl-cytosine in the genome of Biomphalaria glabrata, a snail intermediate host of Schistosoma mansoni.

    Science.gov (United States)

    Fneich, Sara; Dheilly, Nolwenn; Adema, Coen; Rognon, Anne; Reichelt, Michael; Bulla, Jan; Grunau, Christoph; Cosseau, Céline

    2013-06-06

    Biomphalaria glabrata is the mollusc intermediate host for Schistosoma mansoni, a digenean flatworm parasite that causes human intestinal schistosomiasis. An estimated 200 million people in 74 countries suffer from schistosomiasis, in terms of morbidity this is the most severe tropical disease after malaria. Epigenetic information informs on the status of gene activity that is heritable, for which changes are reversible and that is not based on the DNA sequence. Epigenetic mechanisms generate variability that provides a source for potentially heritable phenotypic variation and therefore could be involved in the adaptation to environmental constraint. Phenotypic variations are particularly important in host-parasite interactions in which both selective pressure and rate of evolution are high. In this context, epigenetic changes are expected to be major drivers of phenotypic plasticity and co-adaptation between host and parasite. Consequently, with characterization of the genomes of invertebrates that are parasite vectors or intermediate hosts, it is also essential to understand how the epigenetic machinery functions to better decipher the interplay between host and parasite. The CpGo/e ratios were used as a proxy to investigate the occurrence of CpG methylation in B. glabrata coding regions. The presence of DNA methylation in B. glabrata was also confirmed by several experimental approaches: restriction enzymatic digestion with isoschizomers, bisulfite conversion based techniques and LC-MS/MS analysis. In this work, we report that DNA methylation, which is one of the carriers of epigenetic information, occurs in B. glabrata; approximately 2% of cytosine nucleotides are methylated. We describe the methylation machinery of B. glabrata. Methylation occurs predominantly at CpG sites, present at high ratios in coding regions of genes associated with housekeeping functions. We also demonstrate by bisulfite treatment that methylation occurs in multiple copies of Nimbus, a transposable element. This study details DNA methylation for the first time, one of the carriers of epigenetic information in B. glabrata. The general characteristics of DNA methylation that we observed in the B. glabrata genome conform to what epigenetic studies have reported from other invertebrate species.

  11. N-[4-Acetyl-5-methyl-5-(2-p-tolyl-prop-yl)-4,5-dihydro-1,3,4-thia-diazol-2-yl]acetamide.

    Science.gov (United States)

    Tebaa, Mohamed; Mazoir, Noureddine; Maya, Celia M; Nouzha, Bouhmaida; Benharref, Ahmed; Berraho, Moha

    2009-01-10

    The title heterocyclic compound, C(17)H(23)N(3)O(2)S, was synthesized from 4-(4-methyl-cyclo-hex-3-en-yl)pent-3-en-2-one, which was isolated from Cedrus atlantica essential oil. The thia-diazole ring adopts a flattened envelope conformation, with the flap sp(3)-hybridized C atom lying 0.259 (1) Å out of the plane of the other four atoms. The screw-related mol-ecules are linked into chains along the b axis by inter-molecular N-H⋯O hydrogen bonds.

  12. N-[4-Acetyl-5-methyl-5-(2-p-tolylpropyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]acetamide

    Directory of Open Access Journals (Sweden)

    Moha Berraho

    2009-02-01

    Full Text Available The title heterocyclic compound, C17H23N3O2S, was synthesized from 4-(4-methylcyclohex-3-enylpent-3-en-2-one, which was isolated from Cedrus atlantica essential oil. The thiadiazole ring adopts a flattened envelope conformation, with the flap sp3-hybridized C atom lying 0.259 (1 Å out of the plane of the other four atoms. The screw-related molecules are linked into chains along the b axis by intermolecular N—H...O hydrogen bonds.

  13. (±-N-[4-Acetyl-5-methyl-5-(4-methylcyclohex-3-enyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]acetamide

    Directory of Open Access Journals (Sweden)

    Ahmed Benharref

    2008-03-01

    Full Text Available The new title thiadiazole compound, C14H21N3O2S, was semi-synthesized starting from 1-(4-methylcyclohex-3-enylethanone, a natural product isolated from Cedrus atlantica essential oil. The stereochemistry has been confirmed by single-crystal X-ray diffraction. The thiadiazoline ring is roughly planar, although it may be regarded as having a half-chair conformation. The cyclohexenyl ring has a half-chair conformation. The most interesting feature is the formation of a pseudo-ring formed by four molecules associated through N—H...O hydrogen bonds around a fourfold inversion axis, forming an R44(28 motif.

  14. 2-((Z)-{3-[(Z)-(2-Hy-droxy-5-methyl-benzyl-idene)amino]-2,2-dimethyl-prop-yl}imino-meth-yl)-4-methyl-phenol.

    Science.gov (United States)

    Kia, Reza; Kargar, Hadi; Mirkhani, Valiollah; Ganji, Fatemeh; Tahir, Muhammad Nawaz

    2010-12-15

    In the title compound, C(21)H(26)N(2)O(2), the dihedral angle between the two benzene rings is 73.47 (16)°. Strong intra-molecular O-H⋯N hydrogen bonds generate S(6) ring motifs. The substituted benzene rings are twisted around the central quaternary C atom in opposite directions, making a vault geometry.

  15. Effect of C5-methylation of cytosine on the photoreactivity of DNA: a joint experimental and computational study of TCG trinucleotides.

    Science.gov (United States)

    Esposito, Luciana; Banyasz, Akos; Douki, Thierry; Perron, Marion; Markovitsi, Dimitra; Improta, Roberto

    2014-08-06

    DNA methylation, occurring at the 5 position of cytosine, is a natural process associated with mutational hotspots in skin tumors. By combining experimental techniques (optical spectroscopy, HPLC coupled to mass spectrometry) with theoretical methods (molecular dynamics, DFT/TD-DFT calculations in solution), we study trinucleotides with key sequences (TCG/T5mCG) in the UV-induced DNA damage. We show how the extra methyl, affecting the conformational equilibria and, hence, the electronic excited states, increases the quantum yield for the formation of cyclobutane dimers while reducing that of (6-4) adducts.

  16. Bromidotetra­kis­(1H-2-ethyl-5-methyl­imidazole-κN 3)copper(II) bromide

    Science.gov (United States)

    Godlewska, Sylwia; Baranowska, Katarzyna; Socha, Joanna; Dołęga, 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 ) by N—H⋯Br hydrogen bonds, generating a three-dimensional network. The ethyl group of the imidazole ligand was modelled as disordered over two orientations with occupancies of 0.620 (8) and 0.380 (8). PMID:22199662

  17. Synthesis and Anti-Yeast Evaluation of Novel 2-Alkylthio-4-chloro-5-methyl-N-[imino-(1-oxo-(1H-phthalazin-2-ylmethyl]benzenesulfonamide Derivatives

    Directory of Open Access Journals (Sweden)

    Jarosław Sławiński

    2014-09-01

    Full Text Available Pathogenic fungi are one of the main causes of hospital-related infections. Since conventional antifungals have become less effective because of the increasing fungal resistance to the standard drugs, the need for new agents is becoming urgent. Herein we report a synthesis of a series of novel N-[imino-(1-oxo-(1H-phthalazin-2-ylmethyl]-benzenesulfonamide derivatives with in vitro activity against yeast-like fungi isolated from the oral cavity and respiratory tract of patients with candidiasis. These compounds were synthesized by the one-step or two-step reactions of 1-(2-alkylthiobenzensulfonyl-2-aminoguanidines with the appropriate ortho-carbonyl benzoic acids. The biological study revealed that new derivatives have shown significant growth-inhibitory activity, superior or comparable, than those of the reference drug fluconazole. The most promising activities were observed against Candida albicans, with inhibition at least 1–3 (12.5%–37.5% of the eight tested strains at the low MIC level of ≤6.2–25 µg/mL.

  18. Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159

    DEFF Research Database (Denmark)

    Juknaite, Lina; Sugamata, Yutaro; Tokiwa, Kazuya

    2013-01-01

    IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogs that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neur...

  19. Crystal structure of 5-{3-[2,6-dimethyl-4-(5-methyl-1,2,4-oxadiazol-3-ylphenoxy]propyl}-N-(11-hydroxyundecylisoxazole-3-carboxamide hemihydrate

    Directory of Open Access Journals (Sweden)

    K. Salorinne

    2015-05-01

    Full Text Available The title compound, C29H42N4O5·0.5H2O, comprises four structural units. A flexible propyloxy unit in a gauche conformation, with a –C(H2—C(H2—C(H2—O– torsion angle of −64.32 (18°, connects an isoxazole ring and an approximately planar phenyloxadiazole ring system [with a maxixmum devation of 0.061 (2 Å], which are oriented almost parallel to one another with a dihedral angle of 10.75 (7°. Furthermore, a C11-alkyl chain with a terminal hydroxy group links to the 3-position of the isoxazole ring via an amide bond. In the crystal, a half-occupancy solvent water molecule connects to a neighbouring molecule via an intermolecular O—H...O(water hydrogen bond to the C11-alkyl chain hydroxy group.

  20. Piracetam Defines a New Binding Site for Allosteric Modulators of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors§

    Science.gov (United States)

    Ahmed, Ahmed H.; Oswald, Robert E.

    2010-01-01

    Glutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system and are important potential drug targets for cognitive enhancement and the treatment of schizophrenia. Allosteric modulators of AMPA receptors promote dimerization by binding to a dimer interface and reducing desensitization and deactivation. The pyrrolidine allosteric modulators, piracetam and aniracetam, were among the first of this class of drugs to be discovered. We have determined the structure of the ligand binding domain of the AMPA receptor subtypes GluA2 and GluA3 with piracetam and a corresponding structure of GluA3 with aniracetam. Both drugs bind to both GluA2 and GluA3 in a very similar manner, suggesting little subunit specificity. However, the binding sites for piracetam and aniracetam differ considerably. Aniracetam binds to a symmetrical site at the center of the dimer interface. Piracetam binds to multiple sites along the dimer interface with low occupation, one of which is a unique binding site for potential allosteric modulators. This new site may be of importance in the design of new allosteric regulators. PMID:20163115

  1. Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors.

    Science.gov (United States)

    Ahmed, Ahmed H; Oswald, Robert E

    2010-03-11

    Glutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system and are important potential drug targets for cognitive enhancement and the treatment of schizophrenia. Allosteric modulators of AMPA receptors promote dimerization by binding to a dimer interface and reducing desensitization and deactivation. The pyrrolidine allosteric modulators, piracetam and aniracetam, were among the first of this class of drugs to be discovered. We have determined the structure of the ligand binding domain of the AMPA receptor subtypes GluA2 and GluA3 with piracetam and a corresponding structure of GluA3 with aniracetam. Both drugs bind to GluA2 and GluA3 in a very similar manner, suggesting little subunit specificity. However, the binding sites for piracetam and aniracetam differ considerably. Aniracetam binds to a symmetrical site at the center of the dimer interface. Piracetam binds to multiple sites along the dimer interface with low occupation, one of which is a unique binding site for potential allosteric modulators. This new site may be of importance in the design of new allosteric regulators.

  2. Dichlorido{2-[(5-methyl-1H-pyrazol-3-yl-κN2methyl]-1H-1,3-benzimidazole-κN3}zinc

    Directory of Open Access Journals (Sweden)

    Karim Chkirate

    2017-01-01

    Full Text Available The asymmetric unit of the title complex, [ZnCl2(C12H12N4], contains two independent molecules having similar conformations. The coordination about the ZnII atom is distorted tetrahedral, with the geometrical constraints of the chelating ligand responsible for the observed distortion. Each of the independent molecules forms chains in the crystal through pairs of N—H...Cl hydrogen bonds, using the pyrazole and benzimidazole N—H groups as donors. The first molecule forms chains running parallel to the b axis, while the other molecule affords the same kind of one-dimensional supramolecular structure parallel to the a axis. The structure was refined as a two-component twin with BASF = 0.0437 (4.

  3. Ethyl (2E-3-dimethylamino-2-(5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7-ylprop-2-enoate

    Directory of Open Access Journals (Sweden)

    Sanae Lahmidi

    2016-12-01

    Full Text Available In the title molecule, C13H17N5O2, the triazolopyrimidine ring system and the (dimethyaminoacrylate unit are nearly perpendicular to each other, subtending a dihedral angle of 78.55 (6°. In the crystal, molecules are linked into a C(6 chain along the b-axis direction via C—H...O hydrogen bonds.

  4. Experimental and theoretical studies on the coordination chemistry of the N1-hexyl substituted pyrimidines (uracil, 5-fluorouracil and cytosine).

    Science.gov (United States)

    Barceló-Oliver, Miquel; Baquero, Beatriz Adriana; Bauzá, Antonio; García-Raso, Angel; Vich, Roberto; Mata, Ignasi; Molins, Elies; Terrón, Angel; Frontera, Antonio

    2013-06-01

    N(1)-Hexyl substituted pyrimidines were shown to present solubility properties closer to the real bases than the commonly used methyl and ethyl derivatives, yielding bi-layered structures in the solid state. The study of their coordination capabilities, mainly with Ag(I) and Hg(II), is presented in order to prove their reactivity. A series of coordination complexes, namely, [Hg(N(1)-hexyl-5-fluorouracilate)2]4·6H2O (1), (Ag(+))·[Ag(N(1)-hexyl-5-fluorouracilate)2](-) (2), [Ag(NO3)(N(1)-hexyluracil-κO(4))4] (3), [ZnBr2(N(1)-hexylcytosine)2] (4), [CdBr2(N(1)-hexylcytosine)2] (5), [HgBr2(N(1)-hexylcytosine)2] (6) and [CoBr2(N(1)-hexylcytosine)2] (7), have been synthesized in good yields and X-ray characterized. The presence of the hexyl chains and the fluorine atoms causes the formation of interesting 3D architectures in the solid state. Their structures have been further characterized by infrared spectra (IR) and elemental analyses. In addition, DFT-D3 calculations are used to study interesting noncovalent interactions observed in the solid state, like fluorine-fluorine, fluorine-π and hydrophobic interactions.

  5. Unlocked nucleic acids with a pyrene-modified uracil: Synthesis, hybridization studies, fluorescent properties and i-motif stability

    DEFF Research Database (Denmark)

    Perlíková, P.; Karlsen, K.K.; Pedersen, E.B.

    2014-01-01

    .2, both under molecular crowding and noncrowding conditions. The presence of the pyrene-modified UNA monomers in DNA strands led to decreases in the thermal stabilities of DNA/DNA and DNA/RNA duplexes, but these duplexes' thermal stabilities were better than those of duplexes containing unmodified UNA...... intensities upon hybridization to DNA or RNA. Efficient quenching of fluorescence of pyrene-modified UNA monomers was observed after formation of i-motif structures at pH 5.2. The stabilizing/destabilizing effect of pyrene-modified nucleic acids might be useful for designing antisense oligonucleotides...... and hybridization probes....

  6. UV-MALDI mass spectrometric quantitation of uracil based pesticides in fruit soft drinks along with matrix effects evaluation.

    Science.gov (United States)

    Ivanova, Bojidarka; Spiteller, Michael

    2014-02-01

    This study focused on the development of the accurate and precise quantitative method for the determination of pesticides bromacil (1), terbacil (2), lenacil (3), butafenacil (4) and flupropacil (5) in fruit based soft drinks. Three different types of drinks are bought from market; huddled orange fruit drink (100%) (I), red-oranges (II) and multivitamin drink containing strawberry, orange, banana and maracuja (III). Samples were analyzed "with" and "without" pulp utilizing LC-ESI (or APCI) MS/MS, HPLC-ESI-(or APCI)-MS/MS and UV-MALDI-Orbitrap-MS methods. The effect of high complexity of the food matrix on the analysis was discussed. Study focuses on the advantages of the UV-MALDI-Orbitrap-MS method compared to the traditionally involved GC alone or hybrid methods such as GC-MS and LC-MS/MS for quantification of pesticides in water and soft drinks. The developed method included the techniques performed for validation, calibration and standardization. The target pesticides are widely used for the treatment of citrus fruits and pineapples, but for soft drink products, there are still no clear regulations on pesticide residues limits. The matrix effects in the analysis of fruit drinks required implementation of the exact standard reference material corresponds to the variety of food matrices. This paper contributed to the broad analytical implementation of the UV-MALDI-Orbitrap-MS method in the quality control and assessment programs for monitoring of pesticide contamination in fruit based sodas.

  7. Synthesis,Crystal Structure and Biological Activities of O,O-Dialkyl α-[1-(2-Chlorothiazol-5-ylmethyl)-5-methyl1H-1,2,3-triazol-4-ylcarbonyloxy]alkylphosphonates

    Institute of Scientific and Technical Information of China (English)

    CHEN Xiao-Bao; SHI De-Qing; ZHU Xiao-Fei

    2007-01-01

    In order to search for novel agrochemicals with high activity and low toxicity,a series of phosphonate derivatives containing 1,2,3-triazole and thiazole rings were designed and synthesized using 2-chloro-5-(chloromethyl)thiazole as the starting material.Their structures were confirmed by IR,1H NMR,31P NMR,EI-MS or ESI-MS and elemental analyses.The crystal structure of 7a was determined by single crystal X-ray diffraction.Prelimihary bioassays indicated that most of the target compounds did not display insecticidal activities,but a fraction of them possessed herbicidal and fungicidal activities to some extent.

  8. Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a Clinical p38[alpha] MAP Kinase Inhibitor for the Treatment of Inflammatory Diseases

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Chunjian; Lin, James; Wrobleski, Stephen T.; Lin, Shuqun; Hynes, Jr., John; Wu, Hong; Dyckman, Alaric J.; Li, Tianle; Wityak, John; Gillooly, Kathleen M.; Pitt, Sidney; Shen, Ding Ren; Zhang, Rosemary F.; McIntyre, Kim W.; Salter-Cid, Luisa; Shuster, David J.; Zhang, Hongjian; Marathe, Punit H.; Doweyko, Arthur M.; Sack, John S.; Kiefer, Susan E.; Kish, Kevin F.; Newitt, John A.; McKinnon, Murray; Dodd, John H.; Barrish, Joel C.; Schieven, Gary L.; Leftheris, Katerina (BMS)

    2013-11-20

    The discovery and characterization of 7k (BMS-582949), a highly selective p38{alpha} MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38{alpha} inhibitor. Unlike alkyl and other cycloalkyls, the sp{sup 2} character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38{alpha} enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38{alpha} was confirmed by X-ray crystallographic analysis.

  9. Synthesis and 1H and 13C NMR spectral study of some r(2),c(4)-bis(isopropylcarbonyl)-c(5)-hydroxy-t(5)-methyl-t(3)-substituted phenyl, cyclohexanones and their oximes

    Science.gov (United States)

    Balachander, R.; Sameera, S. A.; Mohan, R. T. Sabapathy

    2016-07-01

    All the synthesized compounds have been characterized by 1H, 13C, 2D NMR and mass spectral studies. The spectral data suggest that compounds 2, 3, 5 and 6 exist in chair conformation with axial orientation of the hydroxyl group and equatorial orientations of all the other substituent. Long-range coupling is observed between OH proton to H-6a proton should be in a W arrangement. Compounds 1 and 4 diamagnetic anisotropic effect of the furyl group is not pronounced and absence of long-rang coupling between OH proton to H-6a proton. The oximation effects were discussed to all synthesized compounds using 1H and 13C chemical shifts.

  10. Persistent inflammation-induced up-regulation of brain-derived neurotrophic factor (BDNF) promotes synaptic delivery of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 subunits in descending pain modulatory circuits.

    Science.gov (United States)

    Tao, Wenjuan; Chen, Quan; Zhou, Wenjie; Wang, Yunping; Wang, Lu; Zhang, Zhi

    2014-08-08

    The enhanced AMPA receptor phosphorylation at GluA1 serine 831 sites in the central pain-modulating system plays a pivotal role in descending pain facilitation after inflammation, but the underlying mechanisms remain unclear. We show here that, in the rat brain stem, in the nucleus raphe magnus, which is a critical relay in the descending pain-modulating system of the brain, persistent inflammatory pain induced by complete Freund adjuvant (CFA) can enhance AMPA receptor-mediated excitatory postsynaptic currents and the GluA2-lacking AMPA receptor-mediated rectification index. Western blot analysis showed an increase in GluA1 phosphorylation at Ser-831 but not at Ser-845. This was accompanied by an increase in distribution of the synaptic GluA1 subunit. In parallel, the level of histone H3 acetylation at bdnf gene promoter regions was reduced significantly 3 days after CFA injection, as indicated by ChIP assays. This was correlated with an increase in BDNF mRNA levels and BDNF protein levels. Sequestering endogenous extracellular BDNF with TrkB-IgG in the nucleus raphe magnus decreased AMPA receptor-mediated synaptic transmission and GluA1 phosphorylation at Ser-831 3 days after CFA injection. Under the same conditions, blockade of TrkB receptor functions, phospholipase C, or PKC impaired GluA1 phosphorylation at Ser-831 and decreased excitatory postsynaptic currents mediated by GluA2-lacking AMPA receptors. Taken together, these results suggest that epigenetic up-regulation of BDNF by peripheral inflammation induces GluR1 phosphorylation at Ser-831 sites through activation of the phospholipase C-PKC signaling cascade, leading to the trafficking of GluA1 to pain-modulating neuronal synapses.

  11. [2-({Benzyl[2-(benzyl{5-methyl-2-oxido-3-[(pyridin-2-ylmethyliminomethyl]benzyl}aminoethyl]azaniumyl}methyl-4-methyl-6-[(pyridin-2-ylmethyliminomethyl]phenolato]nickel(II perchlorate methanol disolvate

    Directory of Open Access Journals (Sweden)

    Ming Liu

    2012-06-01

    Full Text Available In the solvated title complex, [Ni(C46H47N6O2]ClO4·2CH4O, the coordination sphere around the NiII ion can be described as distorted cis-NiO2N4 octahedral defined by two phenolate O atoms and four N atoms from the hexadentate ligand. An intramolecular bifurcated N—H...(N,O hydrogen bond helps to establish the conformation of the complex molecule. In the crystal, the components are connected by O—H...O and C—H...O hydrogen bonds.

  12. Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reverses subcronic PCP-induced deficits in the novel object recognition task in rats

    DEFF Research Database (Denmark)

    Nielsen, Trine Damgaard; Larsen, Dorrit Bjerg; Hansen, Suzanne Lisbet;

    2010-01-01

    deficit in female Lister hooded rats in teh novel object recognition (NOR) task. Here we show that positive modulation of AMPA receptor (AMPAR) mediated glutamate transmission alleviates cognitive deficits induced by sub-chronic PCP treatment. Female Lister hooded rats were treated sub......-cbronic PCP treatment induced a significant decrease in the discrimination index (DI) and both ampakines CX546 and CX516 were able to reverse this diruption of object memory in rats in the novel object recognition task. These data suggest that positive AMPAR modulation may represent a mechanism for treatment...

  13. An efficient synthesis of novel 3’-substituted 2-aryl-5-methyl-5'thioxo-[4,4'-bi-4H-1,2,4-triazol]-3(1'H, 2H-ones

    Directory of Open Access Journals (Sweden)

    RAVINDRA R. KAMBLE

    2006-04-01

    Full Text Available Asimple and high yieldingmethod for the integration of two 1,2,4-triazole rings (10a–l has been developed starting from 3-arylsydnones (1a–d. Confirmation for the structures of the newly synthesised compounds was provided by their physical, analytical and spectral data (IR, 1H NMR, 13C NMR and MS.

  14. Early Growth Response 1 (Egr-1) Regulates N-Methyl-d-aspartate Receptor (NMDAR)-dependent Transcription of PSD-95 and α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor (AMPAR) Trafficking in Hippocampal Primary Neurons*

    Science.gov (United States)

    Qin, Xike; Jiang, Yongjun; Tse, Yiu Chung; Wang, Yunling; Wong, Tak Pan; Paudel, Hemant K.

    2015-01-01

    The N-methyl-d-aspartate receptor (NMDAR) controls synaptic plasticity and memory function and is one of the major inducers of transcription factor Egr-1 in the hippocampus. However, how Egr-1 mediates the NMDAR signal in neurons has remained unclear. Here, we show that the hippocampus of mice lacking Egr-1 displays electrophysiology properties and ultrastructure that are similar to mice overexpressing PSD-95, a major scaffolding protein of postsynaptic density involved in synapse formation, synaptic plasticity, and synaptic targeting of AMPA receptors (AMPARs), which mediate the vast majority of excitatory transmission in the CNS. We demonstrate that Egr-1 is a transcription repressor of the PSD-95 gene and is recruited to the PSD-95 promoter in response to NMDAR activation. Knockdown of Egr-1 in rat hippocampal primary neurons blocks NMDAR-induced PSD-95 down-regulation and AMPAR endocytosis. Likewise, overexpression of Egr-1 in rat hippocampal primary neurons causes reduction in PSD-95 protein level and promotes AMPAR endocytosis. Our data indicate that Egr-1 is involved in NMDAR-mediated PSD-95 down-regulation and AMPAR endocytosis, a process important in the expression of long term depression. PMID:26475861

  15. Interaction of the M4 Segment with Other Transmembrane Segments Is Required for Surface Expression of Mammalian α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors*

    Science.gov (United States)

    Salussolia, Catherine L.; Corrales, Alexandra; Talukder, Iehab; Kazi, Rashek; Akgul, Gulcan; Bowen, Mark; Wollmuth, Lonnie P.

    2011-01-01

    Ionotropic glutamate receptors (GluRs) are ligand-gated ion channels with a modular structure. The ion channel itself shares structural similarity, albeit an inverted membrane topology, with P-loop channels. Like P-loop channels, prokaryotic GluR subunits (e.g. GluR0) have two transmembrane segments. In contrast, eukaryotic GluRs have an additional transmembrane segment (M4), located C-terminal to the ion channel core. However, the structural/functional significance of this additional transmembrane segment is poorly defined. Although topologically similar to GluR0, mammalian AMPA receptor (GluA1) subunits lacking the M4 segment do not display surface expression. This lack of expression is not due to the M4 segment serving as an anchor to the ligand-binding domain because insertion of an artificial polyleucine transmembrane segment does not rescue surface expression. Specific interactions between M4 and the ligand-binding domain are also unlikely because insertion of polyglycines into the linker connecting them has no deleterious effects on function or surface expression. However, tryptophan and cysteine scanning mutagenesis of the M4 segment, as well as recovery of function in the polyleucine background, defined a unique face of the M4 helix that is required for GluR surface expression. In the AMPA receptor structure, this face forms intersubunit contacts with the transmembrane helices of the ion channel core (M1 and M3) from another subunit within the homotetramer. Thus, our experiments show that a highly specific interaction of the M4 segment with an adjacent subunit is required for surface expression of AMPA receptors. This interaction may represent a mechanism for regulating AMPA receptor biogenesis. PMID:21930708

  16. (±)-N-[4-Acetyl-5-methyl-5-(4-methyl-cyclo-hex-3-en-yl)-4,5-dihydro-1,3,4-thia-diazol-2-yl]acetamide.

    Science.gov (United States)

    Mohammed, Tebbaa; Mazoir, Noureddine; Daran, Jean-Claude; Berraho, Moha; Benharref, Ahmed

    2008-02-20

    The new title thiadiazole compound, C(14)H(21)N(3)O(2)S, was semi-synthesized starting from 1-(4-methyl-cyclo-hex-3-en-yl)ethanone, a natural product isolated from Cedrus atlantica essential oil. The stereochemistry has been confirmed by single-crystal X-ray diffraction. The thia-diazo-line ring is roughly planar, although it may be regarded as having a half-chair conformation. The cyclo-hexenyl ring has a half-chair conformation. The most inter-esting feature is the formation of a pseudo-ring formed by four mol-ecules associated through N-H⋯O hydrogen bonds around a fourfold inversion axis, forming an R(4) (4)(28) motif.

  17. [Pharmacological studies of antispasmodics. III. Antispasmodic activity of 3-(di-2-thienylmethylene)-5-methyl-trans-quino-lizidinium bromide (HRS-902) on smooth muscle organs and its organ selectivity (author's transl)].

    Science.gov (United States)

    Kubo, S; Morikawa, K; Matsubara, I; Yamazaki, M; Kato, H

    1981-01-01

    Pharmacological activities of HSR-902, a new antispasmodic agent, in gastrointestinal tract, biliary and urinary systems were compared with those of atropine, butylscopolamine bromide, timepidium bromide, prifinium bromide and diphemanil methylsulfate. In isolated smooth muscle organs (stomach, duodenum, ileum, colon, gall bladder and urinary bladder), anti-acetylcholine activities of HSR-902 were the most potent among these agents but its activity in urinary bladder, similar to findings in the cases of atropine and diphemanil methylsulfate, was relatively less potent than that of prifinium bromide, timepidium bromide and butylscopolamine bromide. Regarding the contractions of stomach, jejunum and ileum, which were induced by vagus nerve stimulation or acetylcholine, and on the ileum spontaneous motility, antispasmodic activities of HSR-902 were almost equal to or somewhat more potent than those of atropine, and its activities were more potent than those of prifinium bromide, timepidium bromide, diphemanil methylsulfate and butylscopolamine bromide. On the gall bladder pressure and the counts of perfusion through Oddi's Sphincter, these agents exhibited a similar inhibition and enhancement, respectively. In the case of urinary bladder contractions induced by pelvic nerve stimulation, these agents exhibited a weak inhibition. The inhibitory effect of HSR-902 was relatively less potent than that of other agents except atropine, which had little effect. HSR-902 was similar to atropine in this so-called "atropine-resistance".

  18. Novel photodynamic effect of a psoralen-conjugated oligonucleotide for the discrimination of the methylation of cytosine in DNA.

    Science.gov (United States)

    Yamayoshi, Asako; Matsuyama, Yohei; Kushida, Mikihiko; Kobori, Akio; Murakami, Akira

    2014-01-01

    DNA methylation and demethylation significantly affect the deactivation and activation processes of gene expression significantly. In particular, C-5-methylation of cytosine in the CpG islands is important for the epigenetic modification in genes, which plays a key role in regulating gene expression. The determination of the location and frequency of DNA methylation is important for the elucidation of the mechanisms of cell differentiation and carcinogenesis. Here we designed a psoralen-conjugated oligonucleotide (PS-oligo) for the discrimination of 5-methylcytosine (5-mC) in DNA. The cross-linking behavior of psoralen derivatives with pyrimidine bases, such as thymine, uracil and cytosine has been well discussed, but there are no reports which have examined whether cross-linking efficiency of psoralen with cytosine would be changed with or without C-5 methylation. We found that the cross-linking efficiency of PS-oligo with target-DNA containing 5-mC was greatly increased compared to the case of target-DNA without 5-mC, approximately seven-fold higher. Here we report a new aspect of the photocross-linking behavior of psoralen with 5-mC that is applicable to a simple, sequence-specific and quantitative analysis for the discrimination of 5-mC in DNA, which can be applicable to study the epigenetic behavior of gene expressions.

  19. Overexpression of transcription factor AP-2 stimulates the PA promoter of the human uracil-DNA glycosylase (UNG) gene through a mechanism involving derepression

    DEFF Research Database (Denmark)

    Aas, Per Arne; Pena Diaz, Javier; Liabakk, Nina Beate

    2009-01-01

    within the region of DNA marked by PA. Footprinting analysis and electrophoretic mobility shift assays of PA and putative AP-2 binding regions with HeLa cell nuclear extract and recombinant AP-2alpha protein indicate that AP-2 transcription factors are central in the regulated expression of UNG2 m......alpha, lacking the activation domain but retaining the DNA binding and dimerization domains, stimulated PA to a level approaching that of full-length AP-2, suggesting that AP-2 overexpression stimulates PA activity by a mechanism involving derepression rather than activation, possibly by neutralizing...

  20. Accurate Dna Assembly And Direct Genome Integration With Optimized Uracil Excision Cloning To Facilitate Engineering Of Escherichia Coli As A Cell Factory

    DEFF Research Database (Denmark)

    Cavaleiro, Mafalda; Kim, Se Hyeuk; Nørholm, Morten

    2015-01-01

    Plants produce a vast diversity of valuable compounds with medical properties, but these are often difficult to purify from the natural source or produce by organic synthesis. An alternative is to transfer the biosynthetic pathways to an efficient production host like the bacterium Escherichia co......-excision-based cloning and combining it with a genome-engineering approach to allow direct integration of whole metabolic pathways into the genome of E. coli, to facilitate the advanced engineering of cell factories....

  1. Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small cell lung cancer-specific cytotoxicity and tumor growth delay

    DEFF Research Database (Denmark)

    Christensen, Camilla L; Gjetting, Torben; Poulsen, Thomas Tuxen

    2010-01-01

    Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine de...

  2. Monoclonal B-cell hyperplasia and leukocyte imbalance precede development of B-cell malignancies in uracil-DNA glycosylase deficient mice

    DEFF Research Database (Denmark)

    Andersen, Sonja; Ericsson, Madelene; Dai, Hong Yan;

    2005-01-01

    causes a significant reduction of T-helper cells, and 50% of the young Ung(-/-) mice investigated have no detectable NK/NKT-cell population in their spleen. The immunological imbalance is confirmed in experiments with spleen cells where the production of the cytokines interferon gamma, interleukin 6...

  3. Synthesis and DNA cleavage activities of mononuclear macrocyclic polyamine zinc(II), copper(II), cobalt(II) complexes which linked with uracil.

    Science.gov (United States)

    Wang, Xiao-Yan; Zhang, Ji; Li, Kun; Jiang, Ning; Chen, Shan-Yong; Lin, Hong-Hui; Huang, Yu; Ma, Li-Jian; Yu, Xiao-Qi

    2006-10-01

    Mononuclear macrocyclic polyamine zinc(II), copper(II), cobalt(II) complexes, which could attach to peptide nucleic acid (PNA), were synthesized as DNA cleavage agents. The structures of these new mononuclear complexes were identified by MS and (1)H NMR spectroscopy. The catalytic activities on DNA cleavage of these mononuclear complexes with different central metals were subsequently studied, which showed that copper complex was better catalyst in the DNA cleavage process than zinc and cobalt complexes. The effects of reaction time, concentration of complexes were also investigated. The results indicated that the copper(II) complexes could catalyze the cleavage of supercoiled DNA (pUC 19 plasmid DNA) (Form I) under physiological conditions to produce selectively nicked DNA (Form II, no Form III produced) with high yields. The mechanism of the cleavage process was also studied.

  4. Clay catalysis of oligonucleotide formation: kinetics of the reaction of the 5'-phosphorimidazolides of nucleotides with the non-basic heterocycles uracil and hypoxanthine

    Science.gov (United States)

    Kawamura, K.; Ferris, J. P.

    1999-01-01

    The montmorillonite clay catalyzed condensation of activated monocleotides to oligomers of RNA is a possible first step in the formation of the proposed RNA world. The rate constants for the condensation of the phosphorimidazolide of adenosine were measured previously and these studies have been extended to the phosphorimidazolides of inosine and uridine in the present work to determine of substitution of neutral heterocycles for the basic adenine ring changes the reaction rate or regioselectivity. The oligomerization reactions of the 5'-phosphoromidazolides of uridine (ImpU) and inosine (ImpI) on montmorillonite yield oligo(U)s and oligo(I)s as long as heptamers. The rate constants for oligonucleotide formation were determined by measuring the rates of formation of the oligomers by HPLC. Both the apparent rate constants in the reaction mixture and the rate constants on the clay surface were calculated using the partition coefficients of the oligomers between the aqueous and clay phases. The rate constants for trimer formation are much greater than those dimer synthesis but there was little difference in the rate constants for the formation of trimers and higher oligomers. The overall rates of oligomerization of the phosphorimidazolides of purine and pyrimidine nucleosides in the presence of montmorillonite clay are the same suggesting that RNA formed on the primitive Earth could have contained a variety of heterocyclic bases. The rate constants for oligomerization of pyrimidine nucleotides on the clay surface are significantly higher than those of purine nucleotides since the pyrimidine nucleotides bind less strongly to the clay than do the purine nucleotides. The differences in the binding is probably due to Van der Waals interactions between the purine bases and the clay surface. Differences in the basicity of the heterocyclic ring in the nucleotide have little effect on the oligomerization process.

  5. Crystal Structure and Conformation of [1-(β-D-lyxofuranosyl)uracil]-2′-spiro-5″-[4″-(S)-(diethoxyphosphinyl)-2″-oxazoline

    Institute of Scientific and Technical Information of China (English)

    迟国臣; 陈茹玉; 王宏根; 姚心侃

    2002-01-01

    The title compound, C15H22N3O9P·2H2O, Mr=455.36, crystallizes in orthorhombic, space group P212121, with a =9.193(2), b =14.681(3), c =15.201(3)A, V =2501(1)A3, Z =4, Dx=1.474g/cm3, λ(MoKα)=0.71073A, μ=0.1894mm-1, T=299±1K, F(000)=960, R=0.061 and Rw=0.068 for 1899 observed reflections with I≥3σ(I). The analysis results indicate that the title compound is of lyxo-configuration and the configuration at C4″ is S. In the crystal state the molecule has anti conformation about glycosidic bond with the torsion angle-151.7°, the sugar ring is puckered with C3′-endo-C2′-exo, and the conformation of the C4′-C5′ bond is-sc.

  6. Predictive factors for survival after bi-fractionated radiotherapy with or without cisplatin and 5-fluoro-uracil (BiRCF trial) for a unresectable pharyngeal cancer; Facteurs predictifs pour la survie apres radiotherapie bifractionnee avec ou sans cisplatine et 5-fluoro-uracile (essai BiRCF) pour cancer pharynge non resecable

    Energy Technology Data Exchange (ETDEWEB)

    Borchiellini, D.; Benezery, K.; Dassonville, O.; Marcy, P.Y.; Chateau, Y.; Poissonnet, G.; Etienne-Grimaldi, M.C.; Peyrade, F.; Thariat, J. [Centre Antoine-Lacassagne, 06 - Nice (France); Bensadoun, R. [CHU, 86 - Poitiers (France)

    2010-10-15

    The objective of this study was to determine the predictive factors for a long term survival and local-areal control for patients suffering from an unresectable pharyngeal cancer and treated according to the BiRCF trial. The authors indicate the different types of tumours among the 59 concerned patients, the different treatments, and analyse the tumour and ganglionary response, the cancer steadiness or advance, late effects, the relapse rates (global, local, areal), the survival rate by 5 years, the late toxicity. A uni-factorial analysis is performed. Short communication

  7. Effects of 1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone on renal fibroblast in rats%1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮对鼠肾成纤维细胞的影响

    Institute of Scientific and Technical Information of China (English)

    陶立坚; 张军; 胡高云; 陈卓; 龚娟

    2004-01-01

    目的:探讨1- (3-氟苯基)-5-甲基-2-(1H)吡啶酮对鼠肾纤维化的治疗作用. 方法:采用MTT法和ELISA法分别检测1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮和pirfenidone对鼠肾成纤维细胞(BHK-21)增殖和分泌纤维结合蛋白(Fn)表达的影响. 结果:1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮作用于鼠肾成纤维细胞48 h后能明显抑制细胞增殖及分泌Fn,1 000 μg/ml的1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮作用于BHK-21后24 h即可明显抑制BHK-21细胞增殖. 结论:1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮可明显抑制鼠肾成纤维细胞增殖,在肾间质纤维化防治药物研制方面显示出良好的前景.

  8. Synthesis of New Pyrazolo[1,5-a]pyrimidine, Triazolo[4,3-a]pyrimidine Derivatives, and Thieno[2,3-b]pyridine Derivatives from Sodium 3-(5-Methyl-1-phenyl-1H-pyrazol-4-yl-3-oxoprop-1-en-1-olate

    Directory of Open Access Journals (Sweden)

    Abdou O. Abdelhamid

    2013-01-01

    Full Text Available Condensation of sodium 3-oxo-3-(1-phenyl-1H-pyrazol-4-ylprop-1-en-1-olate (2 with several heterocyclic amines, cyanoacetamide, cyanothioacetamide, and 2-cyanoacetohydrazide gives pyrazolo[1,5-a]pyrimidines (5a–d, pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (9, benzo[4,5]imidazo[1,2-a]pyrimidine (10, [1,2,4]triazolo[1,5-a]pyrimidine (11, and pyridine derivatives (12–14. Also, thieno[2,3-b]pyridines (15–18 were synthesized via pyridinethione (13 with α-halo ketones and α-halo ester. Structures of the newly synthesized compounds were elucidated by elemental analysis, spectral data, alternative synthetic routes, and chemical transformation whenever possible.

  9. 嗜酸嗜热古菌Sulfolobus acidocaldarius编码尿嘧啶DNA糖苷酶表达,纯化与酶学特征%Cloning, expression, purification and characterization of two uracil-DNA glycosylases from Sulfolobus acidocaldarius

    Institute of Scientific and Technical Information of China (English)

    王婧; 易刚顺; 欧杰; 刘建华; 刘喜朋

    2015-01-01

    [目的]嗜高温微生物面临dC脱氨基生成dU损伤的巨大压力,鉴定嗜酸嗜热古菌S.acidocaldarius来源的尿嘧啶DNA糖苷酶(UDG)切除dU损伤的酶学活性.[方法]重组表达来源于S.acidocaldarius的Ⅳ和Ⅴ型UDG,经亲和纯化得到电泳纯重组蛋白.然后利用人工合成的dU (deoxyuracil)修饰寡核苷酸片段作为底物,体外鉴定两种重组UDG的酶学特性.[结果]来源于S.acidocaldarius的Ⅳ和Ⅴ型重组UDG具有相似的酶学特性.Ⅳ型UDG催化效率更高,比活性是Ⅴ型重组UDG的750倍左右.作为来自嗜热微生物的蛋白,S.acidocaldarius的Ⅳ和Ⅴ型UDG的最适反应温度为65-75℃.[结论]Ⅳ型UDG比Ⅴ型UDG水解dU碱基和脱氧核糖之间糖苷键的能力更强.

  10. Amino acid substitutions in HIV-1 reverse transcriptase with corresponding residues from HIV-2. Effect on kinetic constants and inhibition by non-nucleoside analogs.

    Science.gov (United States)

    Bacolla, A; Shih, C K; Rose, J M; Piras, G; Warren, T C; Grygon, C A; Ingraham, R H; Cousins, R C; Greenwood, D J; Richman, D

    1993-08-05

    Nevirapine is a highly potent and specific inhibitor of human immunodeficiency virus type 1 (HIV-1) polymerase, but is inactive against HIV-2 and other polymerase. Previous studies demonstrated that residues 176-190 of HIV-1 reverse transcriptase (RT) can confer nevirapine sensitivity to HIV-2 RT. To better characterize the role of this sequence in HIV-1 RT, we have progressively substituted residues 176-190 of HIV-2 RT for those of HIV-1 RT and monitored the impact on the kinetic properties; inhibitory activity of nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[2,3-b:2',3'-e] [1,4]diazepin-6-one), E-BPU (5-ethyl-1-benzyloxymethyl-6-(phenylthio)-uracil), and TIBO-R82150 ((+)-S-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-j k] [1,4]benzodiazepin-2(1H)-thione); and inhibitor-induced fluorescence changes of the mutant enzymes. The study revealed that in addition to Try-181 and Tyr-188, a new amino acid residue (Gly-190) plays an important role in determining susceptibility to nevirapine and E-BPU, but not to TIBO-R82150. These data argue that these non-nucleoside inhibitors fit differently, even though they share a common binding pocket. Nevirapine was seen to exert inhibitory activity by altering the interaction of the enzyme with the template-primer. Kinetic parameters were modulated by the template (DNA versus RNA) as well as by some of the mutations.

  11. Synthesis of triazole-nucleoside phosphoramidites and their use in solid-phase oligonucleotide synthesis.

    Science.gov (United States)

    Peel, Brandon J; Efthymiou, Tim C; Desaulniers, Jean-Paul

    2014-12-19

    Triazole-backbone oligonucleotides are macromolecules that have one or more triazole units that are acting as a backbone mimic. Triazoles within the backbone have been used within oligonucleotides for a variety of applications. This unit describes the preparation and synthesis of two triazole-nucleoside phosphoramidites [uracil-triazole-uracil (UtU) and cytosine-triazole-uracil (CtU)] based on a PNA-like scaffold, and their incorporation within oligonucleotides.

  12. Drug: D02131 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available nations D02131 Tegafur - uracil mixt Antineoplastics [BR:br08308] Antimetabolites Pyrimidine analogues Tegaf...3 Therapeutic category of drugs in Japan [BR:br08301] 4 Agents affecting cellular function 42 Antineoplast...ics 422 Antimetabolites 4229 Others D02131 Tegafur - uracil mixt Anatomical Therape

  13. NCBI nr-aa BLAST: CBRC-PABE-24-0030 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PABE-24-0030 ref|YP_927793.1| uracil-xanthine permease [Shewanella amazonensis... SB2B] gb|ABM00124.1| uracil-xanthine permease [Shewanella amazonensis SB2B] YP_927793.1 3.4 27% ...

  14. NCBI nr-aa BLAST: CBRC-CREM-01-1290 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CREM-01-1290 ref|YP_048084.1| putative uracil transport protein (NCS2 family) [Acinetobacter... sp. ADP1] emb|CAG70262.1| putative uracil transport protein (NCS2 family) [Acinetobacter sp. ADP1] YP_048084.1 1e-116 82% ...

  15. Arabidopsis CDS blastp result: AK106879 [KOME

    Lifescience Database Archive (English)

    Full Text Available AK106879 002-118-E09 At5g03555.1 permease, cytosine/purines, uracil, thiamine, allan...toin family protein contains Pfam PF02133: permease, cytosine/purines, uracil, thiamine, allantoin family 1e-161 ...

  16. Repair of U/G and U/A in DNA by UNG2-associated repair complexes takes place predominantly by short-patch repair both in proliferating and growth-arrested cells

    DEFF Research Database (Denmark)

    Akbari, Mansour; Otterlei, Marit; Pena Diaz, Javier

    2004-01-01

    Nuclear uracil-DNA glycosylase UNG2 has an established role in repair of U/A pairs resulting from misincorporation of dUMP during replication. In antigen-stimulated B-lymphocytes UNG2 removes uracil from U/G mispairs as part of somatic hypermutation and class switch recombination processes. Using...

  17. NCBI nr-aa BLAST: CBRC-RMAC-01-0032 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-RMAC-01-0032 ref|YP_703453.1| possible xanthine/uracil permease [Rhodococcus s...p. RHA1] gb|ABG95295.1| possible xanthine/uracil permease [Rhodococcus sp. RHA1] YP_703453.1 0.37 21% ...

  18. NCBI nr-aa BLAST: CBRC-CREM-01-1369 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CREM-01-1369 ref|YP_001086345.1| Xanthine/uracil permease family [Acinetobacter baum...annii ATCC 17978] gb|ABO13743.1| Xanthine/uracil permease family [Acinetobacter baumannii ATCC 17978] YP_001086345.1 2e-87 66% ...

  19. NCBI nr-aa BLAST: CBRC-CREM-01-1290 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CREM-01-1290 ref|ZP_01562587.1| uracil-xanthine permease [Burkholderia cenocep...acia MC0-3] gb|EAV59325.1| uracil-xanthine permease [Burkholderia cenocepacia MC0-3] ZP_01562587.1 2e-94 68% ...

  20. NCBI nr-aa BLAST: CBRC-TBEL-01-2511 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-TBEL-01-2511 ref|YP_001115799.1| Xanthine/uracil/vitamin C permease [Burkholderia vietnam...iensis G4] gb|ABO56334.1| Xanthine/uracil/vitamin C permease [Burkholderia vietnamiensis G4] YP_001115799.1 0.027 22% ...

  1. NCBI nr-aa BLAST: CBRC-CREM-01-1290 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CREM-01-1290 ref|YP_001478049.1| uracil-xanthine permease [Serratia proteamacu...lans 568] gb|ABV40921.1| uracil-xanthine permease [Serratia proteamaculans 568] YP_001478049.1 3e-95 65% ...

  2. Syntheses of haptens containing dioxaphosphorinan methoxyacetic acid linker arms for the production of antibodies to organophosphate pesticides

    NARCIS (Netherlands)

    tenHoeve, W; Wynberg, H; Jones, WT; Harvey, D; Ryan, GB; Reynolds, PHS

    1997-01-01

    Four generic heterobifunctional reagents, namely 2-(2-chloro-5-methyl-1,3,2-dioxaphosphorinan-5-yl)methoxyacetic acid methyl ester, p-sulfide, 2-(2-chloro-5-methyl-1,3,2-dioxaphosphorinan-5-yl)methoxyacetic acid methyl ester, p-oxide, 2-(2-mercapto-5-methyl-1,3,2-dioxaphosphorinan-5-yl)methoxyacetic

  3. Herpes simplex virus thymidine kinase imaging in mice with (1-(2'-deoxy-2'-[{sup 18}F]fluoro-1-{beta}-D-arabinofuranosyl)-5-iodouracil) and metabolite (1-(2'-deoxy-2'-[{sup 18}F]fluoro-1-{beta}-D-arabinofuranosyl)-5-uracil)

    Energy Technology Data Exchange (ETDEWEB)

    Nimmagadda, Sridhar; Lawhorn-Crews, Jawana M.; Shields, Anthony F. [Wayne State University, Karmanos Cancer Institute, Detroit, MI (United States); Wayne State University, Department of Medicine, Detroit, MI (United States); Mangner, Thomas J. [Wayne State University, Karmanos Cancer Institute, Detroit, MI (United States); Wayne State University, Department of Radiology, Detroit, MI (United States); Haberkorn, Uwe [University of Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany)

    2009-12-15

    FIAU, (1-(2{sup '}-deoxy-2{sup '}-fluoro-1-{beta}-D-arabinofuranosyl)-5-iodouracil) has been used as a substrate for herpes simplex virus thymidine kinases (HSV-TK and HSV-tk, for protein and gene expression, respectively) and other bacterial and viral thymidine kinases for noninvasive imaging applications. Previous studies have reported the formation of a de-iodinated metabolite of {sup 18}F-FIAU. This study reports the dynamic tumor uptake, biodistribution, and metabolite contribution to the activity of {sup 18}F-FIAU seen in HSV-tk gene expressing tumors and compares the distribution properties with its de-iodinated metabolite {sup 18}F-FAU. CD-1 nu/nu mice with subcutaneous MH3924A and MH3924A-stb-tk+ xenografts on opposite flanks were used for the biodistribution and imaging studies. Mice were injected IV with either {sup 18}F-FIAU or {sup 18}F-FAU. Mice underwent dynamic imaging with each tracer for 65 min followed by additional static imaging up to 150 min post-injection for some animals. Animals were sacrificed at 60 or 150 min post-injection. Samples of blood and tissue were collected for biodistribution and metabolite analysis. Regions of interest were drawn over the images obtained from both tumors to calculate the time-activity curves. Biodistribution and imaging studies showed the highest uptake of {sup 18}F-FIAU in the MH3924A-stb-tk+ tumors. Dynamic imaging studies revealed a continuous accumulation of {sup 18}F-FIAU in HSV-TK expressing tumors over 60 min. The mean biodistribution values (SUV {+-} SE) for MH3924A-stb-tk+ were 2.07 {+-} 0.40 and 6.15 {+-} 1.58 and that of MH3924A tumors were 0.19 {+-} 0.07 and 0.47 {+-} 0.06 at 60 and 150 min, respectively. In {sup 18}F-FIAU injected mice, at 60 min nearly 63% of blood activity was present as its metabolite {sup 18}F-FAU. Imaging and biodistribution studies with {sup 18}F-FAU demonstrated no specific accumulation in MH3924A-stb-tk+ tumors and SUVs for both the tumors were similar to those observed with muscle. {sup 18}F-FIAU shows a continuous accumulation of activity in HSV-TK expressing tumors. {sup 18}F-FAU does not show any preferential accumulation in HSV-TK expressing tumors. In the {sup 18}F-FIAU treated mice, the {sup 18}F-FAU contribution to the total uptake seen in HSV-TK positive tumors is minimal. (orig.)

  4. Optimization of selective conditions for the selection of uracil auxotrophs of thermophilic archaea Sulfolobus tokodaii%超嗜热古菌Sulfolobus tokodaii尿嘧啶营养缺陷型筛选条件的最适化及初步筛选

    Institute of Scientific and Technical Information of China (English)

    黄奇洪; 申玉龙; 倪金凤

    2008-01-01

    超嗜热古菌Sulfolobus tokodaii隶属于古菌中的泉古菌(Crenarchaea),硫化叶菌属(Sulfolobus).野生型S.tokodaii*$尿嘧啶相关基因表达的乳清核苷酸转移酶和乳清苷单磷酸脱羧酶可以将5-氟乳清酸(5-FOA)转化成有毒物质5-氟尿嘧啶核苷酸,导致野生型S.tokodaii无法正常生长.根据此原理,通过对筛选条件如5-FOA的质量浓度、紫外诱变时间等的最适化,运用微生物的自发突变或对其进行紫外照射等诱变方法,初步筛选出S.tokodaii的尿嘧啶营养缺陷型菌株.

  5. Chemo radioimmunotherapy with 5-fluorouracil, cisplatin and interferon-{alpha} in pancreatic and peri-ampullary cancer: Results of a feasibility study; Chimioradiotherapie et immunotherapie avec 5-fluoro-uracile, cisplatine et interferon-{alpha} dans les cancers du pancreas et periampullaires: resultats d'une etude de faisabilite

    Energy Technology Data Exchange (ETDEWEB)

    Nitsche, M.; Christiansen, H.; Hermann, R.M.; Hess, C.F. [Goettingen Univ., Dept. of Radiation Oncology (Germany); Horstmann, O.; Becker, H. [Goettingen Univ., Dept. of Surgery (Germany); Pradier, O. [Centre Hospitalier Universitaire, Dept. de cancerologie, 29 - Brest (France); Schmidberger, H. [Mainz Univ., Dept. of Radiation Oncology (Germany)

    2008-12-15

    Background: Recent studies give rise to the hypothesis, that adjuvant chemo radioimmunotherapy with 5-fluorouracil (5-F.U.), cisplatin and interferon-a (I.F.N.-a) might be a possible new treatment of pancreatic cancer in resected patients. We report the up-to-now experience at our institution. Patients and methods: Eleven patients with histological diagnosis of localized carcinoma of the pancreas (n = 7) or peri-ampullary (n = 4) were prospectively analyzed. Four patients were deemed unresectable because of local invasion of adjacent organs (neo-adjuvant setting) and seven patients underwent curative resection (adjuvant setting). Eight patients were classified as T3 carcinomas and three T4 carcinomas. Fifty-five per cent (6/11) of the patients presented with positive lymph node involvement. One histological Grade I, six Grade II and three Grade III were detected. External conformal irradiation to a total dose of 50.4 Gy with 1.8 Gy per day was delivered. All patients received a concomitant chemotherapy with continuous 5-F.U. 200 mg/m{sup 2} per day on 28 treatment days and intravenous bolus cisplatin 30 mg/m{sup 2} per week (Day 2, 9, 16, 23, 30). A recombinant r-I.F.N.-a was administered on three days weekly during Week one to five of the radiotherapy course as subcutaneous injections with 3*3 Mio. I.U. weekly. Results: The four-year overall survival rate for all patients was 55%. In the neo-adjuvant group, three of four patients died due to progressive disease; in the adjuvant group, combined chemo radioimmunotherapy lead to controlled disease in five of seven patients. The overall toxicity was well-managed. Conclusion: Our data strengthens the hypothesis of concomitant chemo radioimmunotherapy with 5-F.U., I.F.N.-a and cisplatin as a possible new treatment of pancreatic cancer in resected patients. (authors)

  6. Concomitant bid radiotherapy with cisplatin and 5-fluorouracil in unresectable carcinoma of the pharynx: 10 year's experience at the Centre Antoine Lacassagne; Radiotherapie bifractionnee et chimiotherapie par cisplatine et 5-fluoro-uracile concomitantes dans les carcinomes epidermoides localement evolues non resecables du pharynx: dix ans d'experience au centre Antoine Lacassagne

    Energy Technology Data Exchange (ETDEWEB)

    Magne, N.; Pivot, X.; Marcy, P.Y.; Chauvel, P.; Courdi, A.; Dassonville, O.; Possonnet, G.; Vallicioni, J.; Ettore, F.; Falewee, M.N.; Milano, G.; Santini, J.; Lagrange, J.L.; Schneider, M.; Demard, F.; Bensadoun, R.J. [Centre Antoine-Lacassagne, 06 - Nice (France)

    2001-08-01

    Patients suffering from locally advanced unresectable squamous cell carcinoma of the oropharynx and hypopharynx treated with radiotherapy alone have a poor prognosis. More than 70% of patients die within 5 years mainly due to local recurrences. The aim of this study was to evaluate retrospectively the Antoine Lacassagne Cancer Center's experience in a treatment by concomitant bid radiotherapy and chemotherapy. Evaluation was based on analysis of the toxicity, the response rates, the survival, and the clinical prognostic factors. From 1992 to 2000, 92 consecutive patients were treated in our single institution. All of them had stage IV, unresectable squamous cell carcinoma of the pharynx and they received continuous bid radiotherapy (two daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal internal between fractions). Total radiotherapy dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Two or three chemotherapy courses of cisplatin (CP)-5-fluorouracil (5FU) were given during radiotherapy at 21 -day intervals (third not delivered after the end of the radiotherapy). CP dose was 100 mg/m{sup 2} (day 1) and 5-FU was given as 6-day continuous infusion (750 mg/m{sup 2}/day at 1. course; 430 mg/m{sup 2}/day at 2. and 3. courses). Special attention was paid to supportive care, particularly in terms of enteral nutrition and mucositis prevention by low-level laser energy. Acute toxicity was marked and included WHO grade III/IV mucositis (89%, 16% of them being grade IV), WHO grade III dermatitis (72%) and grade III/IV neutropenia (61%). This toxicity was significant but manageable with optimised supportive care, and never led to interruption of treatment for more than 1 week, although there were two toxic deaths. Complete global response rate at 6 months was 74%. Overall global survival at 1 and 3 years was 72% and 50% respectively, with a median follow-up of 17 months. Prognostic factors for overall were the Karnofsky index (71% survival at 3 years for patients with a Karnofsky index of 90-100% versus 30% for patients with a Karnofsky index of 80% versus 0% for patients with a Karnofsky index of 60-70%, p = 0.0001) and tumor location (55% at years for oropharynx versus 37% for pan-pharynx versus 28% for hypopharynx, p=0.009). These results confirm the efficacy of concomitant bid radiotherapy and chemotherapy in advanced unresectable tumor of the pharynx. The improvement in results will essentially depend on our capacity to restore in a good nutritional status the patients before beginning this heavy treatment. (author)

  7. The Selection of Uracil Auxotroph Strain of Rhodotorula benthica S8 Treated by UV-induced Mutation%紫外诱变筛选海洋红酵母S8的尿嘧啶缺陷型菌株

    Institute of Scientific and Technical Information of China (English)

    王宇光; 雷禄旺; 孙建波; 卢雪花; 夏启玉; 张昕

    2010-01-01

    本课题组从海南天然海域筛选到一株高产类胡萝卜素的海洋红酵母菌株S8,该菌株对鱼无毒害,并与鱼共生,欲将其应用于盐诱导表达外源蛋白的海洋红酵母工程菌的构建.本研究利用紫外诱变筛选的方法处理S8菌株,通过统计其UV致死率、5-氟乳清酸致死率等筛选S8的尿嘧啶营养缺陷型突变株.研究结果表明,供试菌株通过紫外线诱变、5-氟乳清酸致死和回复突变率的实验筛选,共获得16株稳定的尿嘧啶缺陷型突变株,突变菌株在基本培养基中培养了8 d仍不能生长.选择了其中的一株ST5进行了产胡萝卜素能力的测定,结果表明,在同样的培养条件下,野生型S8菌株细胞生物产量可达87.55 g/L,类胡萝卜素含量可达520μg/g,突变株ST5的细胞生物产量为85.45 g/L,类胡萝卜素含量为512μg/g;ST5的产胡萝卜素能力方面与野生型S8无明显差异.因此,尿嘧啶缺陷型菌株ST5可为下一步海洋红酵母工程菌的构建提供受体菌.

  8. Synthesis and molecular modelling of unsaturated exomethylene pyranonucleoside analogues with antitumor and antiviral activities.

    Science.gov (United States)

    Agelis, George; Tzioumaki, Niki; Tselios, Theodore; Botić, Tanja; Cencic, Avrelija; Komiotis, Dimitri

    2008-07-01

    This report describes the total and facile synthesis of the unsaturated keto and exomethylene pyranonucleoside analogues, 1-(2,3,4-trideoxy-4-methylene-6-O-trityl-alpha-D-glycero-hex-2-enopyranosyl)uracil (10), 1-(2,3-dideoxy-alpha-D-glycero-hex-2-enopyranosyl-4-ulose)uracil (17) and 1-(2,3,4-trideoxy-4-methylene-alpha-D-glycero-hex-2-enopyranosyl)uracil (18). Commercially available 1,2,3,4,6-penta-O-acetyl-alpha-D-mannopyranose (1) was condensed with silylated uracil, deacetylated and acetalated to afford 1-(2,3-O-isopropylidene-alpha-D-mannopyranosyl)uracil (4). Two different synthetic routes were investigated for the conversion of 4 into the olefinic derivative 1-(2,3,4-trideoxy-4-methylene-6-O-trityl-alpha-D-glycero-hex-2-enopyranosyl)uracil (10). Although the two procedures are quite similar with respect to yields and final products, the second also leads to the keto-2',3'-unsaturated analogue (17). The new analogues were evaluated for their anticancer and antiviral activities using several tumor cell lines and gastrointestinal rotavirus. All of the compounds showed direct antiviral effect against rotavirus infectivity in Caco-2 cell line. Moreover, 1-(2,3,4-trideoxy-4-methylene-6-O-trityl-alpha-D-glycero-hex-2-enopyranosyl)uracil (10) was found to be potent in MCF-7 breast carcinoma cell line.

  9. 1775-IJBCS-Article-Odin Monday

    African Journals Online (AJOL)

    hp

    Epoxidation of aminometradin (l-allyl-3-ethyl-6-amino uracil) using tetraoxochromate(VI) acid, trifloroperacetic acid and hydrogen peroxide as oxidants, catalyzed by ... is a diuretic drug which increases urine and solute excretion from the.

  10. 5-Arylaminouracil Derivatives: New Inhibitors of Mycobacterium tuberculosis.

    Science.gov (United States)

    Matyugina, Elena; Novikov, Mikhail; Babkov, Denis; Ozerov, Alexander; Chernousova, Larisa; Andreevskaya, Sofia; Smirnova, Tatiana; Karpenko, Inna; Chizhov, Alexander; Murthu, Pravin; Lutz, Stefan; Kochetkov, Sergei; Seley-Radtke, Katherine L; Khandazhinskaya, Anastasia L

    2015-12-01

    Three series of 5-arylaminouracil derivatives, including 5-(phenylamino)uracils, 1-(4'-hydroxy-2'-cyclopenten-1'-yl)-5-(phenylamino)uracils, and 1,3-di-(4'-hydroxy-2'-cyclopenten-1'-yl)-5-(phenylamino)uracils, were synthesized and screened for potential antimicrobial activity. Most of compounds had a negative effect on the growth of the Mycobacterium tuberculosis H37Rv strain, with 100% inhibition observed at concentrations between 5 and 40 μg/mL. Of those, 1-(4'-hydroxy-2'-cyclopenten-1'-yl)-3-(4‴-hydroxy-2‴-cyclopenten-1‴-yl)-5-(4″-butyloxyphenylamino)uracil proved to be the most active among tested compounds against the M. tuberculosis multidrug-resistant strain MS-115 (MIC90 5 μg/mL). In addition, the thymidylate kinase of M. tuberculosis was evaluated as a possible enzymatic target.

  11. Synthesis of New Bis-Alkylated Phosphono Alkenyl Acyclonucleosides : (Z) and (E)-Diethyl-2-(3-alkyl pyrimidin-1-yl)ethylen-1-yl Phosphonate

    OpenAIRE

    Imbach, J L; J. L. Barascut; Lazrek, H B; Taourirte, M.; Rochdi, A.

    2000-01-01

    The E- and Z- phosphonoalkenyl acyclonucleosides of uracil and thymine were synthesized under Michael addition conditions. Introduction of an alkyl, alkenyl or alkynyl group at the N-3 position of the pyrimidine moiety was accomplished using potassium carbonate in DMF.

  12. Powerful methods to establish chromosomal markers in Lactococcus lactis: an analysis of pyrimidine salvage pathway mutants obtained by positive selections

    DEFF Research Database (Denmark)

    Martinussen, Jan; Hammer, Karin

    1995-01-01

    phosphoribosyltransferase (upp), uridindcytidine kinase (udk), pyrimidine nucleoside phosphorylase (pdp), cytidine/deoxycytidine deaminase (dd), thymidine kinase (tdk) and purine nucleoride phosphorylase (pup). Based on an analysis of the mutants obtained, the pathways by which L. lactis metabolizes uracil...

  13. Genetic code correlations - Amino acids and their anticodon nucleotides

    Science.gov (United States)

    Weber, A. L.; Lacey, J. C., Jr.

    1978-01-01

    The data here show direct correlations between both the hydrophobicity and the hydrophilicity of the homocodonic amino acids and their anticodon nucleotides. While the differences between properties of uracil and cytosine derivatives are small, further data show that uracil has an affinity for charged species. Although these data suggest that molecular relationships between amino acids and anticodons were responsible for the origin of the code, it is not clear what the mechanism of the origin might have been.

  14. Transport Selectivity of a Diethylene Glycol Dimethacrylate-Based Thymine-imprinted Polymeric Membrane over a Cellulose Support for Nucleic Acid Bases

    Institute of Scientific and Technical Information of China (English)

    QU Xiang-Jin; CHEN Chang-Bao; ZHOU Jie; WU Chun-Hui

    2007-01-01

    The binding mechanism between 9-vinyladenine and pyrimidine base thymine in methanol was studied with UV-visible spectrophotometric method. Based on this study, using thymine as a template molecule, 9-vinyladenine as a novel functional monomer and diethylene glycol dimethacrylate as a new cross-linker, a specific diethylene glycol dimethacrylate-based molecularly imprinted polymeric membrane was prepared over a cellulose support.Then, the resultantly polymeric membrane morphologies were visualized with scanning electron microscopy and its permselectivity was examined using thymine, uracil, cytosine, adenine and guanine as substrates. This result showed that the imprinting polymeric membrane prepared with diethylene glycol dimethacrylate exhibited higher transport capacity for the template molecule thymine and its optimal analog uracil than other nucleic acid bases. The membrane also took on higher permselectivity than the imprinted membrane made with ethylene glycol dimethacrylate as a cross-linker. When a mixture including five nucleic acid bases thymine, uracil, cytosine, adenine and guanine passed through the diethylene glycol dimethacrylate-based thymine-imprinted polymeric membrane,recognition of the membrane for the template molecule thymine and its optimal analog uracil was demonstrated. It was predicted that the molecularly imprinted membrane prepared with diethylene glycol dimethacrylate as cross-linker might be applicable to thymine assay of absolute hydrolysates of DNA or uracil assay of absolute hydrolysates of RNA in biological samples because of its high selectivity for the template molecule thymine and its optimal analog uracil.

  15. Mapping the UV Photophysics of Platinum Metal Complexes Bound to Nucleobases

    Science.gov (United States)

    Sen, Ananya; Dessent, Caroline

    2015-03-01

    We report the first UV laser spectroscopic study of isolated gas-phase complexes of Platinum metal complex anions bound to a nucleobase as model systems for exploring at the molecular level the key photophysical processes involved in photodynamic therapy. Spectra of the PtIV CN 6 2 - • Uracil and PtII CN 4 2 - • Uracil complexes were acquired across the 220 -320 nm range using mass-selective photodepletion and photofragment action spectroscopy. The spectra of both complexes reveal prominent UV absorption bands that we assign primarily to excitation of the Uracil π - π * localized chromophore. Distinctive UV photofragments are observed for the complexes, with PtIV CN 6 2 - • Uracil photoexcitation resulting in complex fission, while PtII CN 4 2 - • Uracil photoexcitation initiates a nucleobase proton-transfer reaction across 4.4 -5.2 eV and electron detachment above 5.2 eV. The observed photofragments are consistent with ultrafast decay of a Uracil localized excited state back to the electronic ground state followed by intramolecular vibrational relaxation and ergodic complex fragmentation. In addition, we present recent results to explore how the photophysics of the Platinum complex-nucleobase clusters evolves as a function of nucleobase. Results are presented for PtII CN 4 2 - • Uracil complexed to Cytosine, Thymine and Adenine, reveal distinctive decay dynamics which we attribute to the intrinsic decay dynamics of the nucleobase. JPC. Lett. 2014, 5, 3281 to 3285 and PCCP 2014, 16, 15490 to 15500.

  16. 76 FR 23898 - Mefenpyr-diethyl; Pesticide Tolerances

    Science.gov (United States)

    2011-04-29

    ...-dihydro-5-methyl-1H-pyrazole-3,5- dicarboxylic acid, diethyl ester) and its dichlorophenyl-pyrazoline...,5- dihydro-5-methyl-1H-pyrazole-3,5-dicarboxylic acid, diethyl ester) and its dichlorophenyl...-pyrazole-3,5-dicarboxylic acid, diethyl ester) and its 2,4-dichlorophenyl-pyrazoline...

  17. Structure-Function Relationship of a Plant NCS1 Member – Homology Modeling and Mutagenesis Identified Residues Critical for Substrate Specificity of PLUTO, a Nucleobase Transporter from Arabidopsis

    Science.gov (United States)

    Witz, Sandra; Panwar, Pankaj; Schober, Markus; Deppe, Johannes; Pasha, Farhan Ahmad; Lemieux, M. Joanne; Möhlmann, Torsten

    2014-01-01

    Plastidic uracil salvage is essential for plant growth and development. So far, PLUTO, the plastidic nucleobase transporter from Arabidopsis thaliana is the only known uracil importer at the inner plastidic membrane which represents the permeability barrier of this organelle. We present the first homology model of PLUTO, the sole plant NCS1 member from Arabidopsis based on the crystal structure of the benzyl hydantoin transporter MHP1 from Microbacterium liquefaciens and validated by molecular dynamics simulations. Polar side chains of residues Glu-227 and backbones of Val-145, Gly-147 and Thr-425 are proposed to form the binding site for the three PLUTO substrates uracil, adenine and guanine. Mutational analysis and competition studies identified Glu-227 as an important residue for uracil and to a lesser extent for guanine transport. A differential response in substrate transport was apparent with PLUTO double mutants E227Q G147Q and E227Q T425A, both of which most strongly affected adenine transport, and in V145A G147Q, which markedly affected guanine transport. These differences could be explained by docking studies, showing that uracil and guanine exhibit a similar binding mode whereas adenine binds deep into the catalytic pocket of PLUTO. Furthermore, competition studies confirmed these results. The present study defines the molecular determinants for PLUTO substrate binding and demonstrates key differences in structure-function relations between PLUTO and other NCS1 family members. PMID:24621654

  18. Structure-function relationship of a plant NCS1 member--homology modeling and mutagenesis identified residues critical for substrate specificity of PLUTO, a nucleobase transporter from Arabidopsis.

    Science.gov (United States)

    Witz, Sandra; Panwar, Pankaj; Schober, Markus; Deppe, Johannes; Pasha, Farhan Ahmad; Lemieux, M Joanne; Möhlmann, Torsten

    2014-01-01

    Plastidic uracil salvage is essential for plant growth and development. So far, PLUTO, the plastidic nucleobase transporter from Arabidopsis thaliana is the only known uracil importer at the inner plastidic membrane which represents the permeability barrier of this organelle. We present the first homology model of PLUTO, the sole plant NCS1 member from Arabidopsis based on the crystal structure of the benzyl hydantoin transporter MHP1 from Microbacterium liquefaciens and validated by molecular dynamics simulations. Polar side chains of residues Glu-227 and backbones of Val-145, Gly-147 and Thr-425 are proposed to form the binding site for the three PLUTO substrates uracil, adenine and guanine. Mutational analysis and competition studies identified Glu-227 as an important residue for uracil and to a lesser extent for guanine transport. A differential response in substrate transport was apparent with PLUTO double mutants E227Q G147Q and E227Q T425A, both of which most strongly affected adenine transport, and in V145A G147Q, which markedly affected guanine transport. These differences could be explained by docking studies, showing that uracil and guanine exhibit a similar binding mode whereas adenine binds deep into the catalytic pocket of PLUTO. Furthermore, competition studies confirmed these results. The present study defines the molecular determinants for PLUTO substrate binding and demonstrates key differences in structure-function relations between PLUTO and other NCS1 family members.

  19. Structure-function relationship of a plant NCS1 member--homology modeling and mutagenesis identified residues critical for substrate specificity of PLUTO, a nucleobase transporter from Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Sandra Witz

    Full Text Available Plastidic uracil salvage is essential for plant growth and development. So far, PLUTO, the plastidic nucleobase transporter from Arabidopsis thaliana is the only known uracil importer at the inner plastidic membrane which represents the permeability barrier of this organelle. We present the first homology model of PLUTO, the sole plant NCS1 member from Arabidopsis based on the crystal structure of the benzyl hydantoin transporter MHP1 from Microbacterium liquefaciens and validated by molecular dynamics simulations. Polar side chains of residues Glu-227 and backbones of Val-145, Gly-147 and Thr-425 are proposed to form the binding site for the three PLUTO substrates uracil, adenine and guanine. Mutational analysis and competition studies identified Glu-227 as an important residue for uracil and to a lesser extent for guanine transport. A differential response in substrate transport was apparent with PLUTO double mutants E227Q G147Q and E227Q T425A, both of which most strongly affected adenine transport, and in V145A G147Q, which markedly affected guanine transport. These differences could be explained by docking studies, showing that uracil and guanine exhibit a similar binding mode whereas adenine binds deep into the catalytic pocket of PLUTO. Furthermore, competition studies confirmed these results. The present study defines the molecular determinants for PLUTO substrate binding and demonstrates key differences in structure-function relations between PLUTO and other NCS1 family members.

  20. Structure-function relationship of a plant NCS1 member - Homology modeling and mutagenesis identified residues critical for substrate specificity of PLUTO, a nucleobase transporter from arabidopsis

    KAUST Repository

    Witz, Sandra

    2014-03-12

    Plastidic uracil salvage is essential for plant growth and development. So far, PLUTO, the plastidic nucleobase transporter from Arabidopsis thaliana is the only known uracil importer at the inner plastidic membrane which represents the permeability barrier of this organelle. We present the first homology model of PLUTO, the sole plant NCS1 member from Arabidopsis based on the crystal structure of the benzyl hydantoin transporter MHP1 from Microbacterium liquefaciens and validated by molecular dynamics simulations. Polar side chains of residues Glu-227 and backbones of Val-145, Gly-147 and Thr-425 are proposed to form the binding site for the three PLUTO substrates uracil, adenine and guanine. Mutational analysis and competition studies identified Glu-227 as an important residue for uracil and to a lesser extent for guanine transport. A differential response in substrate transport was apparent with PLUTO double mutants E227Q G147Q and E227Q T425A, both of which most strongly affected adenine transport, and in V145A G147Q, which markedly affected guanine transport. These differences could be explained by docking studies, showing that uracil and guanine exhibit a similar binding mode whereas adenine binds deep into the catalytic pocket of PLUTO. Furthermore, competition studies confirmed these results. The present study defines the molecular determinants for PLUTO substrate binding and demonstrates key differences in structure-function relations between PLUTO and other NCS1 family members. 2014 Witz et al.

  1. Spectrofluorimetric determination of 5-fluorouracil by fluorescence quenching of 9-anthracenecarboxylic acid

    Science.gov (United States)

    Khot, M. S.; Bhattar, S. L.; Kolekar, G. B.; Patil, S. R.

    2010-09-01

    Photo-induced intermolecular electron transfer (PET) interaction between excited singlet (S 1) state of 9-anthracene carboxylic acid (9-ANCA) and DNA bases of pyrimidines as uracil and 5-fluorouracil (5-FU) has been studied in water and ethanol solutions using steady-state fluorescence spectroscopy. The intensity of all emission bands of 9-ANCA was quenched in presence of uracil and 5-FU by electron transfer reaction without formation of an exciplex. It was found that uracil and 5-fluorouracil acts as effective electron donors and simultaneously quench the fluorescence of electron-accepting sensitizer 9-ANCA. The quenching by diffusion-controlled rate coincides well with the dynamic Stern-Volmer correlation. The bimolecular quenching rate constant (kqss) and electron transfer rate constant ( ket) observed are seen to be much higher for 5-fluorouracil than those for uracil. The thermodynamic parameters estimated by using the Rehm-Weller equation were used to propose a suitable mechanism for PET occurring between uracils and 9-ANCA. The proposed method was used to determine 5-fluorouracil from pharmaceutical samples with satisfactory results. The technique is more selective, sensitive and relatively free from coexisting substances.

  2. Photoelectron spectroscopy and density functional theory studies on the uridine homodimer radical anions

    Science.gov (United States)

    Jae Ko, Yeon; Storoniak, Piotr; Wang, Haopeng; Bowen, Kit H.; Rak, Janusz

    2012-11-01

    We report the photoelectron spectrum (PES) of the homogeneous dimer anion radical of uridine, (rU)2•-. It features a broad band consisting of an onset of ˜1.2 eV and a maximum at the electron binding energy (EBE) ranging from 2.0 to 2.5 eV. Calculations performed at the B3LYP/6-31++G** level of theory suggest that the PES is dominated by dimeric radical anions in which one uridine nucleoside, hosting the excess charge on the base moiety, forms hydrogen bonds via its O8 atom with hydroxyl of the other neutral nucleoside's ribose. The calculated adiabatic electron affinities (AEAGs) and vertical detachment energies (VDEs) of the most stable homodimers show an excellent agreement with the experimental values. The anionic complexes consisting of two intermolecular uracil-uracil hydrogen bonds appeared to be substantially less stable than the uracil-ribose dimers. Despite the fact that uracil-uracil anionic homodimers are additionally stabilized by barrier-free electron-induced proton transfer, their relative thermodynamic stabilities and the calculated VDEs suggest that they do not contribute to the experimental PES spectrum of (rU)2•-.

  3. Attempted prebiotic synthesis of pseudouridine

    Science.gov (United States)

    Dworkin, J. P.; Miller, S. L. (Principal Investigator)

    1997-01-01

    Pseudouridine is a modified base found in all tRNA and rRNA. Hence, it is reasonable to think that pseudouridine was important in the early evolution, if not the origin, of life. Since uracil reacts rapidly with formaldehyde and other aldehydes at the C-5 position, it is plausible that pseudouridine could be synthesized in a similar way by the reaction of the C-5 of uracil with the C-1 of ribose. The determining factor is whether the ribose could react with the uracil faster than ribose decomposes. However, both rates are determined by the amount of free aldehyde in the ribose. Various plausible prebiotic reactions were investigated and none showed pseudouridine above the detection limit (prebiotic conditions. Unless efficient non-biological catalysts for any of these reactions exist, pseudouridine would not have been synthesized to any significant extent without the use of biologically produced enzymes.

  4. Secondary structure prediction of protein constructs using random incremental truncation and vacuum-ultraviolet CD spectroscopy

    CERN Document Server

    Pukáncsik, M; Matsuo, K; Gekko, K; Hart, D; Kézsmárki, I; Vértessy, B G

    2014-01-01

    A novel uracil-DNA degrading protein factor (termed UDE) was identified in Drosophila melanogaster with no significant structural and functional homology to other uracil-DNA binding or processing factors. Determination of the 3D structure of UDE will be a true breakthrough in description of the molecular mechanism of action of UDE catalysis, as well as in general uracil-recognition and nuclease action. The revolutionary ESPRIT technology was applied to the novel protein UDE to overcome problems in identifying soluble expressing constructs given the absence of precise information on domain content and arrangement. Nine specimen from the created numerous truncated constructs of UDE were choosen to dechiper structural and functional relationships. VUVCD with neural network was performed to define the secondary structure content and location of UDE and its truncated variants. The quantitative analysis demonstrated exclusive {\\alpha}-helical content for the full-length protein, which is preserved in the truncated ...

  5. TrpA1 Regulates Defecation of Food-Borne Pathogens under the Control of the Duox Pathway.

    Directory of Open Access Journals (Sweden)

    Eun Jo Du

    2016-01-01

    Full Text Available Pathogen expulsion from the gut is an important defense strategy against infection, but little is known about how interaction between the intestinal microbiome and host immunity modulates defecation. In Drosophila melanogaster, dual oxidase (Duox kills pathogenic microbes by generating the microbicidal reactive oxygen species (ROS, hypochlorous acid (HOCl in response to bacterially excreted uracil. The physiological function of enzymatically generated HOCl in the gut is, however, unknown aside from its anti-microbial activity. Drosophila TRPA1 is an evolutionarily conserved receptor for reactive chemicals like HOCl, but a role for this molecule in mediating responses to gut microbial content has not been described. Here we identify a molecular mechanism through which bacteria-produced uracil facilitates pathogen-clearing defecation. Ingestion of uracil increases defecation frequency, requiring the Duox pathway and TrpA1. The TrpA1(A transcript spliced with exon10b (TrpA1(A10b that is present in a subset of midgut enteroendocrine cells (EECs is critical for uracil-dependent defecation. TRPA1(A10b heterologously expressed in Xenopus oocytes is an excellent HOCl receptor characterized with elevated sensitivity and fast activation kinetics of macroscopic HOCl-evoked currents compared to those of the alternative TRPA1(A10a isoform. Consistent with TrpA1's role in defecation, uracil-excreting Erwinia carotovora showed higher persistence in TrpA1-deficient guts. Taken together, our results propose that the uracil/Duox pathway promotes bacteria expulsion from the gut through the HOCl-sensitive receptor, TRPA1(A10b, thereby minimizing the chances that bacteria adapt to survive host defense systems.

  6. Spontaneous Oligomerization of Nucleotide Alternatives in Aqueous Solutions

    Science.gov (United States)

    Smith, Karen E.; House, Christopher H.; Dworkin, Jason P.; Callahan, Michael P.

    2017-03-01

    On early Earth, a primitive polymer that could spontaneously form from likely available precursors may have preceded both RNA and DNA as the first genetic material. Here, we report that heated aqueous solutions containing 5-hydroxymethyluracil (HMU) result in oligomers of uracil, heated solutions containing 5-hydroxymethylcytosine (HMC) result in oligomers of cytosine, and heated solutions containing both HMU and HMC result in mixed oligomers of uracil and cytosine. Oligomerization of hydroxymethylated pyrimidines, which may have been abundant on the primitive Earth, might have been important in the development of simple informational polymers.

  7. The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

    National Research Council Canada - National Science Library

    Lipina, Tatiana; Weiss, Karin; Roder, John

    2007-01-01

    ...) as measured in a thirst-motivated conditioned emotional response procedure. Administration of the positive modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPAR...

  8. 76 FR 53372 - Receipt of Several Pesticide Petitions Filed for Residues of Pesticide Chemicals in or on Various...

    Science.gov (United States)

    2011-08-26

    ... for residues of the insecticide thiamethoxam [3-[(2-chloro-5- thiazolyl)methyl]tetrahydro-5-methyl-N... of thiamethoxam in or on raw agricultural commodities. This method is based on crop specific...

  9. 75 FR 48667 - Notice of Receipt of Several Pesticide Petitions Filed for Residues of Pesticide Chemicals in or...

    Science.gov (United States)

    2010-08-11

    ... for residues of the insecticide thiamethoxam, (3- tetrahydro-5-methyl-N- nitro-4H-1,3,5-oxadiazin-4... practical analytical methodology for detecting and measuring levels of thiamethoxam in or on...

  10. Ionotropic excitatory amino acid receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antagonist

    DEFF Research Database (Denmark)

    Madsen, U; Sløk, F A; Stensbøl, T B;

    2000-01-01

    We have previously described the potent and selective (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), and the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4......-isoxazolyl]propionic acid (AMOA). Using these AMPA receptor ligands as leads, a series of compounds have been developed as tools for further elucidation of the structural requirements for activation and blockade of AMPA receptors. The synthesized compounds have been tested for activity at ionotropic...... excitatory amino acid (EAA) receptors using receptor binding and electrophysiological techniques, and for activity at metabotropic EAA receptors using second messenger assays. Compounds 1 and 4 were essentially inactive. (RS)-2-Amino-3-[3-(2-carboxyethyl)-5-methyl-4-isoxazolyl]propionic acid (ACMP, 2...

  11. Phenotypical difference in deamination of cytarabine is not evident in induction therapy for acute myeloid leukemia

    DEFF Research Database (Denmark)

    Krogh-Madsen, Mikkel; Hansen, Steen Honore'; Jensen, Morten Krogh

    2013-01-01

    Objective To investigate the uracil arabinoside/cytarabine (Ara-U/Ara-C) ratios with the lower dose in adult acute myeloid leukaemia (AML) induction therapy (100 mg/m2 Ara-C) where no enzyme saturation is expected. Methods A precise and robust high-performance liquid chromatography (HPLC) method ...

  12. N-1-Alkylated Pyrimidine Films as a New Potential Optical Data Storage Medium

    DEFF Research Database (Denmark)

    Lohse, Brian; Hvilsted, Søren; Berg, Rolf Henrik;

    2006-01-01

    We investigate several compounds of the type 1,1’-(a,w-alkanediyl)bis[pyrimidinej and 1-(w- bromoalkyl)uracil, which can undergo photoinduced (2jr + 2n) cycloaddition reactions on exposure to UV light at 254 and 257 nm, which have been synthesized for application in high capacity optical data...

  13. Immunohistological expression of HIF-1α, GLUT-1, Bcl-2 and Ki-67 in consecutive biopsies during chemoradiotherapy in patients with rectal cancer

    DEFF Research Database (Denmark)

    Havelund, Birgitte Mayland; Sørensen, Flemming Brandt; Pløen, John;

    2013-01-01

    receiving preoperative CRT (>50.4 Gy and Uracil/Tegafur). Immunohistological expressions of HIF-1α, GLUT-1, Bcl-2 and Ki-67 were investigated in biopsies taken before treatment, after 2, 4 and 6 weeks of CRT and in specimens from the operation. Decreasing expressions of HIF-1α, Bcl-2 and Ki-67 were observed...

  14. Repression of the pyr operon in Lactobacillus plantarum prevents its ability to grow at low carbon dioxide levels

    DEFF Research Database (Denmark)

    Nicoloff, Hervé; Elagöz, Aram; Arsène-Ploetze, Florence

    2005-01-01

    (encoding CPS-A) responds to arginine availability, whereas pyrAaAb (encoding CPS-P) is part of the pyrR1BCAaAbDFE operon coding for the de novo pyrimidine pathway repressed by exogenous uracil. The pyr operon is regulated by transcription attenuation mediated by a trans-acting repressor that binds...

  15. A versatile expression vector system for mammalian cell factories

    DEFF Research Database (Denmark)

    Lund, Anne Mathilde; Kildegaard, Helene Faustrup; Hansen, Bjarne Gram

    The development of the field of mammalian cell factories requests fast and high-throughput methods which means high need for simpler and more efficient cloning techniques. This project applies the ligation-free USERTM (uracil-specific excision reagent) cloning technique to construct mammalian...

  16. Analysis of 6912 unselected somatic hypermutations in human VDJ rearrangements reveals lack of strand specificity and correlation between phase II substitution rates and distance to the nearest 3' activation-induced cytidine deaminase target

    DEFF Research Database (Denmark)

    Ohm-Laursen, Line; Barington, Torben

    2007-01-01

    The initial event of somatic hypermutation (SHM) is the deamination of cytidine residues by activation-induced cytidine deaminase (AID). Deamination is followed by the replication over uracil and/or different error-prone repair events. We sequenced 659 nonproductive human IgH rearrangements (IGHV...

  17. Anti-wrinkle and anti-inflammatory effects of active garlic components and the inhibition of MMPs via NF-κB signaling.

    Directory of Open Access Journals (Sweden)

    So Ra Kim

    Full Text Available Skin aging is a multisystem degenerative process caused by several factors, such as, UV irradiation, stress, and smoke. Furthermore, wrinkle formation is a striking feature of photoaging and is associated with oxidative stress and inflammatory response. In the present study, we investigated whether caffeic acid, S-allyl cysteine, and uracil, which were isolated from garlic, modulate UVB-induced wrinkle formation and effect the expression of matrix-metalloproteinase (MMP and NF-κB signaling. The results obtained showed that all three compounds significantly inhibited the degradation of type І procollagen and the expressions of MMPs in vivo and attenuated the histological collagen fiber disorder and oxidative stress in vivo. Furthermore, caffeic acid and S-allyl cysteine were found to decrease oxidative stress and inflammation by modulating the activities of NF-κB and AP-1, and uracil exhibited an indirect anti-oxidant effect by suppressing cyclooxygenase-2 (COX-2 and inducible nitric oxide synthase (iNOS expressions levels and downregulating transcriptional factors. These results suggest that the anti-wrinkle effects of caffeic acid, S-allyl cysteine, and uracil are due to anti-oxidant and/or anti-inflammatory effects. Summarizing, caffeic acid, S-allyl cysteine, and uracil inhibited UVB-induced wrinkle formation by modulating MMP via NF-κB signaling.

  18. Dicty_cDB: Contig-U03277-1 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available 87 5e-46 (B0B8I2) RecName: Full=Uracil-DNA glycosylase; Short=UD... 187 7e-46 EU885419_1( EU885419 |pid:none) Duck enteritis...e) Melanoplus sanguinipes entomopox... 88 6e-16 EF449516_2( EF449516 |pid:none) Duck enteritis virus viron g

  19. High-resolution photoelectron spectra of the pyrimidine-type nucleobases.

    Science.gov (United States)

    Fulfer, K D; Hardy, D; Aguilar, A A; Poliakoff, E D

    2015-06-14

    High-resolution photoelectron spectra of the gas phase pyrimidine-type nucleobases, thymine, uracil, and cytosine, were collected using synchrotron radiation over the photon energy range 17 ≤ hν ≤ 150 eV. These data provide the highest resolution photoelectron spectra of thymine, uracil, and cytosine published to date. By comparing integrated regions of the energy dependent photoelectron spectra of thymine, the ionization potentials of the first four ionic states of thymine were estimated to be 8.8, 9.8, 10.3, and 10.8 eV. The thymine data also show evidence for low energy shape resonances in three of the outermost valence electronic states. Comparing the uracil spectrum with the thymine spectrum, the four outermost valence electronic states of uracil likely begin at binding energies 9.3, 9.9, 10.5, and 11.0 eV. High-resolution spectra indicate only one tautomeric form of cytosine contributes significantly to the spectrum with the four outermost valence electronic states beginning at binding energies 8.9, 9.9, 10.4, and 10.85 eV.

  20. High-resolution photoelectron spectra of the pyrimidine-type nucleobases

    Energy Technology Data Exchange (ETDEWEB)

    Fulfer, K. D.; Hardy, D.; Poliakoff, E. D., E-mail: epoliak@lsu.edu [Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803 (United States); Aguilar, A. A. [Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, California 94720 (United States)

    2015-06-14

    High-resolution photoelectron spectra of the gas phase pyrimidine-type nucleobases, thymine, uracil, and cytosine, were collected using synchrotron radiation over the photon energy range 17 ≤ hν ≤ 150 eV. These data provide the highest resolution photoelectron spectra of thymine, uracil, and cytosine published to date. By comparing integrated regions of the energy dependent photoelectron spectra of thymine, the ionization potentials of the first four ionic states of thymine were estimated to be 8.8, 9.8, 10.3, and 10.8 eV. The thymine data also show evidence for low energy shape resonances in three of the outermost valence electronic states. Comparing the uracil spectrum with the thymine spectrum, the four outermost valence electronic states of uracil likely begin at binding energies 9.3, 9.9, 10.5, and 11.0 eV. High-resolution spectra indicate only one tautomeric form of cytosine contributes significantly to the spectrum with the four outermost valence electronic states beginning at binding energies 8.9, 9.9, 10.4, and 10.85 eV.

  1. Yeast Interacting Proteins Database: YBR135W, YBR252W [Yeast Interacting Proteins Database

    Lifescience Database Archive (English)

    Full Text Available bait as prey (0) YBR252W DUT1 dUTPase, catalyzes hydrolysis of dUTP to dUMP and PPi, thereby...ription dUTPase, catalyzes hydrolysis of dUTP to dUMP and PPi, thereby preventing incorporation of uracil in

  2. Tunable Hydrophobicity in DNA Micelles : Design, Synthesis, and Characterization of a New Family of DNA Amphiphiles

    NARCIS (Netherlands)

    Anaya, Milena; Kwak, Minseok; Musser, Andrew J.; Muellen, Klaus; Herrmann, Andreas; Müllen, Klaus

    2010-01-01

    This work describes the synthesis and characterization of a new family of DNA amphiphiles containing modified nucleobases. The hydrophobicity was imparted by the introduction of a dodec-1-yne chain at the 5-position of the uracil base, which allowed precise and simple tuning of the hydrophobic

  3. Efficient N-Arylation and N-Alkenylation of the Five DNA/RNANucleobases

    DEFF Research Database (Denmark)

    Jacobsen, Mikkel Fog; Knudsen, Martin M.; Gothelf, Kurt Vesterager

    2006-01-01

    -substituted pyrimidin-2(1H)-one served as both a cytosine and a uracil precursor and was N-arylated and N-alkenylated in high yields. Adenine was efficiently and selectively N-arylated and N-alkenylated at the N9 position by employing a bis-Boc-protected adenine derivative, while a bis-Boc-protected 2-amino-6...

  4. Product release mechanism and the complete enzyme catalysis cycle in yeast cytosine deaminase (yCD): A computational study.

    Science.gov (United States)

    Zhao, Yuan; She, Nai; Zhang, Xin; Wang, Chaojie; Mo, Yirong

    2017-08-01

    Yeast cytosine deaminase (yCD) is critical in gene-directed enzyme prodrug therapy as it catalyzes the hydrolytic deamination of cytosine. The product (uracil) release process is considered as rate-limiting in the whole enzymatic catalysis and includes the cleavage of the uracil-metal bond and the delivery of free uracil out of the reactive site. Herein extensive combined random acceleration molecular dynamics (RAMD) and molecular dynamics (MD) simulations coupled with the umbrella sampling technique have been performed to study the product transport mechanism. Five channels have been identified, and the thermodynamic and dynamic characterizations for the two most favorable channels have been determined and analyzed. The free energy barrier for the most beneficial pathway is about 13kcal/mol and mainly results from the cleavage of hydrogen bonds between the ligand uracil and surrounding residues Asn51, Glu64, and Asp155. The conjugated rings of Phe114 and Trp152 play gating and guiding roles in the product delivery via π⋯π van der Waals interactions with the product. Finally, the full cycle of the enzymatic catalysis has been determined, making the whole process computationally more precise. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Nucleobase assemblies supported by uranyl cation coordination and other non-covalent interactions

    Indian Academy of Sciences (India)

    Jitendra Kumar; Sandeep Verma

    2011-11-01

    We describe synthesis and solid state structural description of uranyl complexes of carboxylate functionalized adenine and uracil derivatives. The metal coordination through carboxylate pendant leads to the formation of dimeric assemblies, whereas the directional nature of hydrogen bonding interaction supported by nucleobases and aqua ligands, result in the generation of complex 3-D architectures containing embedded nucleobase ribbons.

  6. Formation of Nucleobases from the UV Irradiation of Pyrimidine in Astrophysical Ice Analogs

    Science.gov (United States)

    Sandford, Scott A.; Nuevo, Michel; Materese, Christopher K.

    2014-01-01

    Nucleobases are the informational subunits of DNA and RNA. They consist of Nheterocycles that belong to either the pyrimidine-base group (uracil, cytosine, and thymine) or the purinebase group (adenine and guanine). Several nucleobases, mostly purine bases, have been detected in meteorites [1-3], with isotopic signatures consistent with an extraterrestrial origin [4]. Uracil is the only pyrimidine-base compound formally reported in meteorites [2], though the presence of cytosine cannot be ruled out [5,6]. However, the actual process by which the uracil was made and the reasons for the non-detection of thymine in meteorites have yet to be fully explained. Although no N-heterocycles have ever been observed in the ISM [7,8], the positions of the 6.2-µm interstellar emission features suggest a population of such molecules is likely to be present [9]. In this work we study the formation of pyrimidine-based molecules, including the three nucleobases uracil, cytosine, and thymine from the ultraviolet (UV) irradiation of pyrimidine in ices consisting of several combinations of H(sub2)O, NH(sub3), CH(sub3)OH, and CH(sub4) at low temperature, in order to simulate the astrophysical conditions under which prebiotic species may be formed in the interstellar medium, in the protosolar nebula, and on icy bodies of the Solar System.

  7. The effect of food on the pharmacokinetics of S-1 after single oral administration to patients with solid tumors.

    NARCIS (Netherlands)

    Peters, G.J.; Noordhuis, P.; Groeningen, van C.J.; Giaccone, G.; Holwerda, U.; Voorn, D.; Schrijvers, A; Schornagel, J.H.; Beijnen, J.H.; Fumoleau, P; Schellens, JH

    2004-01-01

    0.0005), and for cyanuric acid, the breakdown product of oxonic acid, was 5.1 (P = 0.019). Accumulation of uracil, indicative for dihydropyrimidine dehydrogenase inhibition, was not affected, as well as the T(1/2) of FT, 5FU, CDHP, and oxonic acid. Evaluation of the log-transformed data demonstrated

  8. Cell cycle-specific UNG2 phosphorylations regulate protein turnover, activity and association with RPA

    DEFF Research Database (Denmark)

    Hagen, Lars; Kavli, Bodil; Sousa, Mirta M L

    2008-01-01

    Human UNG2 is a multifunctional glycosylase that removes uracil near replication forks and in non-replicating DNA, and is important for affinity maturation of antibodies in B cells. How these diverse functions are regulated remains obscure. Here, we report three new phosphoforms of the non-cataly...

  9. Effects of β-alanine administration on selected parameters of oxidative stress and phosphoryltransfer network in cerebral cortex and cerebellum of rats

    NARCIS (Netherlands)

    Gemelli, Tanise; de Andrade, Rodrigo Binkowski; Rojas, Denise Bertin; Bonorino, Nariélle Ferner; Mazzola, Priscila Nicolao; Tortorelli, Lucas Silva; Funchal, Cláudia; Filho, Carlos Severo Dutra; Wannmacher, Clovis Milton Duval

    2013-01-01

    β-Alanine is a β-amino acid derivative of the degradation of pyrimidine uracil and precursor of the oxidative substrate acetyl-coenzyme A (acetyl-CoA). The accumulation of β-alanine occurs in β-alaninemia, an inborn error of metabolism. Patients with β-alaninemia may develop neurological abnormaliti

  10. A novel method to generate unmarked gene deletions in the intracellular pathogen Rhodococcus equi using 5-fluorocytosine conditional lethality

    NARCIS (Netherlands)

    van der Geize, R.; de Jong, W.; Hessels, G. I.; Grommen, A. W. F.; Jacobs, A. A. C.; Dijkhuizen, L.

    2008-01-01

    A novel method to efficiently generate unmarked in-frame gene deletions in Rhodococcus equi was developed, exploiting the cytotoxic effect of 5-fluorocytosine (5-FC) by the action of cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) enzymes. The opportunistic, intracellular

  11. Tunable Hydrophobicity in DNA Micelles : Design, Synthesis, and Characterization of a New Family of DNA Amphiphiles

    NARCIS (Netherlands)

    Anaya, Milena; Kwak, Minseok; Musser, Andrew J.; Muellen, Klaus; Herrmann, Andreas; Müllen, Klaus

    2010-01-01

    This work describes the synthesis and characterization of a new family of DNA amphiphiles containing modified nucleobases. The hydrophobicity was imparted by the introduction of a dodec-1-yne chain at the 5-position of the uracil base, which allowed precise and simple tuning of the hydrophobic prope

  12. Immunoglobulin genes: generating diversity with AID and UNG.

    Science.gov (United States)

    Storb, Ursula; Stavnezer, Janet

    2002-10-29

    Somatic hypermutation and switch recombination of immunoglobulin genes require the activity of the activation-induced deaminase, AID. Recent studies of mice deficient for the uracil-DNA glycosylase UNG, which removes U from DNA, suggest that AID catalyses the deamination of dC to dU during antibody diversification.

  13. Optical absorption and magnetic circular dichroism spectra of thiouracils: a quantum mechanical study in solution

    DEFF Research Database (Denmark)

    Martínez-Fernández, L.; Fahleson, Tobias; Norman, Patrick

    2017-01-01

    The excited electronic states of 2-thiouracil, 4-thiouracil and 2,4-dithiouracil, the analogues of uracil where the carbonyl oxygens are substituted by sulphur atoms, have been investigated by computing the magnetic circular dichroism (MCD) and one-photon absorption (OPA) spectra at the time...

  14. In vivo reshaping the catalytic site of nucleoside 2'-deoxyribosyltransferase for dideoxy- and didehydronucleosides via a single amino acid substitution.

    Science.gov (United States)

    Kaminski, Pierre Alexandre; Dacher, Priscilla; Dugué, Laurence; Pochet, Sylvie

    2008-07-18

    Nucleoside 2'-deoxyribosyltransferases catalyze the transfer of 2-deoxyribose between bases and have been widely used as biocatalysts to synthesize a variety of nucleoside analogs. The genes encoding nucleoside 2'-deoxyribosyltransferase (ndt) from Lactobacillus leichmannii and Lactobacillus fermentum underwent random mutagenesis to select variants specialized for the synthesis of 2',3'-dideoxynucleosides. An Escherichia coli strain, auxotrophic for uracil and unable to use 2',3'-dideoxyuridine, cytosine, and 2',3'-dideoxycytidine as a source of uracil was constructed. Randomly mutated lactobacilli ndt libraries from two species, L. leichmannii and L. fermentum, were screened for the production of uracil with 2',3'-dideoxyuridine as a source of uracil. Several mutants suitable for the synthesis of 2',3'-dideoxynucleosides were isolated. The nucleotide sequence of the corresponding genes revealed a single mutation (G --> A transition) leading to the substitution of a small aliphatic amino acid by a nucleophilic one, A15T (L. fermentum) or G9S (L. leichmannii), respectively. We concluded that the "adaptation" of the nucleoside 2'-deoxyribosyltransferase activity to 2,3-dideoxyribosyl transfer requires an additional hydroxyl group on a key amino acid side chain of the protein to overcome the absence of such a group in the corresponding substrate. The evolved proteins also display significantly improved nucleoside 2',3'-didehydro-2',3'-dideoxyribosyltransferase activity.

  15. Genetic and Physiological Studies of Bacillus anthracis Related to Development of An Improved Vaccine

    Science.gov (United States)

    1989-07-01

    streptomycin resistance. Ura, uracil; Pur, purine; Rib, riboflavin ; Aro, aromatic; Gua, guanine; Pig, pigment ; Ant, anthranilic acid; Leu, leucine; Spo...one was a pigmented mutant). A description of the characterizable mutants isolated is given in Table 2. To determine whether the mutants resulted from

  16. Akt1 protects against germ cell apoptosis in the post natal mouse testis following lactational exposure to 6-N-propylthiouracil

    Science.gov (United States)

    Lactational exposure to 6-propyl-2-thio-uracil (PTU), a neonatal goitrogen, leads to increased testis size and sperm production in rodents. Aktl, a gene involved in cell survival and proliferation is also phosphorylated by thyroxine (T4). Therefore, we examined the requirement f...

  17. Preparation of next-generation sequencing libraries from damaged DNA.

    Science.gov (United States)

    Briggs, Adrian W; Heyn, Patricia

    2012-01-01

    Next-generation sequencing (NGS) has revolutionized ancient DNA research, especially when combined with high-throughput target enrichment methods. However, attaining high sequencing depth and accuracy from samples often remains problematic due to the damaged state of ancient DNA, in particular the extremely low copy number of ancient DNA and the abundance of uracil residues derived from cytosine deamination that lead to miscoding errors. It is therefore critical to use a highly efficient procedure for conversion of a raw DNA extract into an adaptor-ligated sequencing library, and equally important to reduce errors from uracil residues. We present a protocol for NGS library preparation that allows highly efficient conversion of DNA fragments into an adaptor-ligated form. The protocol incorporates an option to remove the vast majority of uracil miscoding lesions as part of the library preparation process. The procedure requires only two spin column purification steps and no gel purification or bead handling. Starting from an aliquot of DNA extract, a finished, highly amplified library can be generated in 5 h, or under 3 h if uracil removal is not required.

  18. Nucleotide metabolism in Lactococcus lactis: Salvage pathways of exogenous pyrimidines

    DEFF Research Database (Denmark)

    Martinussen, Jan; Andersen, Paal Skytt; Hammer, Karin

    1994-01-01

    By measuring enzyme activities in crude extracts and studying the effect of toxic analogs (5-fluoropyrimidines) on cell growth, the metabolism of pyrimidines in Lactococcus lactis was analyzed. Pathways by which uracil, uridine, deoxyuridine, cytidine, and deoxycytidine are metabolized in L. lact...

  19. Infrared multiple photon dissociation action spectroscopy of sodium cationized halouracils: Effects of sodium cationization and halogenation on gas-phase conformation

    NARCIS (Netherlands)

    Kaczan, C.M.; Rathur, A.I.; Wu, R.R.; Chen, Y.; Austin, C.A.; Berden, G.; Oomens, J.; Rodgers, M.T.

    2015-01-01

    The gas-phase structures of sodium cationized complexes of 5- and 6-halo-substituted uracils are examined via infrared multiple photon dissociation (IRMPD) action spectroscopy and theoretical electronic structure calculations. The halouracils examined in this investigation include: 5-flourouracil, 5

  20. Potential formation of three pyrimidine bases in interstellar regions

    CERN Document Server

    Majumdar, Liton; Das, Ankan; Chakrabarti, Sandip K

    2015-01-01

    Work on the chemical evolution of pre-biotic molecules remains incomplete since the major obstacle is the lack of adequate knowledge of rate coefficients of various reactions which take place in interstellar conditions. In this work, we study the possibility of forming three pyrimidine bases, namely, cytosine, uracil and thymine in interstellar regions. Our study reveals that the synthesis of uracil from cytosine and water is quite impossible under interstellar circumstances. For the synthesis of thymine, reaction between uracil and :CH2 is investigated. Since no other relevant pathways for the formation of uracil and thymine were available in the literature, we consider a large gas-grain chemical network to study the chemical evolution of cytosine in gas and ice phases. Our modeling result shows that cytosine would be produced in cold, dense interstellar conditions. However, presence of cytosine is yet to be established. We propose that a new molecule, namely, C4N3OH5 could be observable in the interstellar ...

  1. Effects of capecitabine treatment on the uptake of thymidine analogs using exploratory PET imaging agents: 18F-FAU, 18F-FMAU, and 18F-FLT

    National Research Council Canada - National Science Library

    Christopher I McHugh; Jawana M Lawhorn-Crews; Dipenkumar Modi; Kirk A Douglas; Steven K Jones; Thomas J Mangner; Jerry M Collins; Anthony F Shields

    2016-01-01

    ...: 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT), 1-(2'-deoxy-2'-[18F]fluoro-β-D-arabinofuranosyl) thymidine (18F-FMAU), and 1-(2'-deoxy-2'-[18F]fluoro-β-D-arabinofuranosyl) uracil (18F-FAU) in patients with advanced cancer...

  2. A second pathway to degrade pyrimidine nucleic acid precursors in eukaryotes

    DEFF Research Database (Denmark)

    Andersen, Gorm; Bjornberg, Olof; Polakova, Silvia;

    2008-01-01

    Pyrimidine bases are the central precursors for RNA and DNA, and their intracellular pools are determined by de novo, salvage and catabolic pathways. In eukaryotes, degradation of uracil has been believed to proceed only via the reduction to dihydrouracil. Using a yeast model, Saccharomyces kluyv...

  3. Sulfonamide bearing oligonucleotides: Simple synthesis and efficient RNA recognition

    DEFF Research Database (Denmark)

    Kumar, P.; Chandak, N.; Nielsen, P.;

    2012-01-01

    Four pyrimidine nucleosides wherein a benzensulfonamide group is linked to the C-5 position of the uracil nucleobase through a triazolyl or an alkynyl linker were prepared by Cu(I)-assisted azide-alkyne cycloadditions (CuAAC) or Sonogashira reactions, respectively, and incorporated into oligonucl...

  4. Synthesis of New Bis-Alkylated Phosphono Alkenyl Acyclonucleosides : (Z and (E-Diethyl-2-(3-alkyl pyrimidin-1-ylethylen-1-yl Phosphonate

    Directory of Open Access Journals (Sweden)

    J. L. Imbach

    2000-10-01

    Full Text Available The E- and Z- phosphonoalkenyl acyclonucleosides of uracil and thymine were synthesized under Michael addition conditions. Introduction of an alkyl, alkenyl or alkynyl group at the N-3 position of the pyrimidine moiety was accomplished using potassium carbonate in DMF.

  5. Identification of Two Candidate Tumor Suppressor Genes on Chromosome 17p13.3: Assessment of Their Roles in Breast and Ovarian Carcinogenesis

    Science.gov (United States)

    2001-07-01

    the RNA. In Sxl this residue is an isoleu- lar interactions between these side chains and RNA. cine , making a hydrophobic interaction with a uracil For...interested in testing it at the National Center for Toxicogenomics). The results will be passed to the analysis system, which presently handles ImaGene

  6. UPP1 — EDRN Public Portal

    Science.gov (United States)

    UPP1, or uridine phosphorylase 1, is a pyrimidine nucleoside phosphorylase. UPP1, in the presence of orthophosphate, catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to uracil and ribose- or deoxyribose-1-phosphate. Pyrimidine nucleoside phosphorylases can add ribose or deoxyribose to pyrimidine bases to form nucleosides that can be incorporated into RNA or DNA.

  7. Artifactual mutations resulting from DNA lesions limit detection levels in ultrasensitive sequencing applications.

    Science.gov (United States)

    Arbeithuber, Barbara; Makova, Kateryna D; Tiemann-Boege, Irene

    2016-12-01

    The need in cancer research or evolutionary biology to detect rare mutations or variants present at very low frequencies (DNA lesions introduce important error sources in ultrasensitive technologies such as single molecule PCR (smPCR) applications (e.g. droplet-digital PCR), or next-generation sequencing (NGS) based methods. Using templates with known amplifiable lesions (8-oxoguanine, deaminated 5-methylcytosine, uracil, and DNA heteroduplexes), we assessed with smPCR and duplex sequencing that templates with these lesions were amplified very efficiently by proofreading polymerases (except uracil), leading to G->T, and to a lesser extent, to unreported G->C substitutions at 8-oxoguanine lesions, and C->T transitions in amplified uracil containing templates. Long heat incubations common in many DNA extraction protocols significantly increased the number of G->T substitutions. Moreover, in ∼50-80% smPCR reactions we observed the random amplification preference of only one of both DNA strands explaining the known 'PCR jackpot effect', with the result that a lesion became indistinguishable from a true mutation or variant. Finally, we showed that artifactual mutations derived from uracil and 8-oxoguanine could be significantly reduced by DNA repair enzymes. © The Author 2016. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

  8. DNA duplex stability of the thio-iso-guanine•methyl-iso-Cytosine base pair.

    Science.gov (United States)

    Lee, Dongkye; Switzer, Christopher

    2015-01-01

    We report the synthesis, incorporation into oligonucleotides, and base-pairing properties of the 2-thio-variant of iso-guanine. Iso-guanine is the purine component of a nonstandard base pair with 5-methyl-iso-cytosine. The 2-thio-iso-guanine • 5-methyl-iso-cytosine base pair is found to have similar stability to an adenine • thymine pair.

  9. A new and efficient method for the synthesis of isoquinoline-3-carboxylate

    Institute of Scientific and Technical Information of China (English)

    Xiang Wei Liao; Bao He Guan; Zhan Zhu Liu

    2008-01-01

    An isoquinoline-3-carboxylate compound 3 was obtained with a moderate yield of 40% when N-acetyl-(3'-hydroxy-4'-methoxy-5'-methyl)phenylalanine methyl ester 1 was refluxed in HMTA/TFA. However, the anticipated product N-acetyl-(3'-hydroxy-4'-rnethoxy-5'-methyl-6'-formyl)phenylalanine methyl ester 2 could not be found. The possible mechanism was discussed in this article.

  10. Phenotypic and clinical implications of variants in the dihydropyrimidine dehydrogenase gene.

    Science.gov (United States)

    Kuilenburg, André B P van; Meijer, Judith; Tanck, Michael W T; Dobritzsch, Doreen; Zoetekouw, Lida; Dekkers, Lois-Lee; Roelofsen, Jeroen; Meinsma, Rutger; Wymenga, Machteld; Kulik, Wim; Büchel, Barbara; Hennekam, Raoul C M; Largiadèr, Carlo R

    2016-04-01

    Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil, thymine and the antineoplastic agent 5-fluorouracil. Genetic variations in the gene encoding DPD (DPYD) have emerged as predictive risk alleles for 5FU-associated toxicity. Here we report an in-depth analysis of genetic variants in DPYD and their consequences for DPD activity and pyrimidine metabolites in 100 Dutch healthy volunteers. 34 SNPs were detected in DPYD and 15 SNPs were associated with altered plasma concentrations of pyrimidine metabolites. DPD activity was significantly associated with the plasma concentrations of uracil, the presence of a specific DPYD mutation (c.1905+1G>A) and the combined presence of three risk variants in DPYD (c.1905+1G>A, c.1129-5923C>G, c.2846A>T), but not with an altered uracil/dihydrouracil (U/UH2) ratio. Various haplotypes were associated with different DPD activities (haplotype D3, a decreased DPD activity; haplotype F2, an increased DPD activity). Functional analysis of eight recombinant mutant DPD enzymes showed a reduced DPD activity, ranging from 35% to 84% of the wild-type enzyme. Analysis of a DPD homology model indicated that the structural effect of the novel p.G401R mutation is most likely minor. The clinical relevance of the p.D949V mutation was demonstrated in a cancer patient heterozygous for the c.2846A>T mutation and a novel nonsense mutation c.1681C>T (p.R561X), experiencing severe grade IV toxicity. Our studies showed that the endogenous levels of uracil and the U/UH2 ratio are poor predictors of an impaired DPD activity. Loading studies with uracil to identify patients with a DPD deficiency warrants further investigation.

  11. [Development of Eimeria tenella in MDBK cell culture with a note on enhancing effect of preincubation with chicken spleen cells].

    Science.gov (United States)

    Chai, J Y; Lee, S H; Kim, W H; Yun, C K

    1989-06-01

    Eimeria tenella, an intracellular protozoan parasite infecting the epithelial cells of the ceca of chickens, causes severe diarrhea and bleeding that can lead its host to death. It is of interest that E. tenella first penetrate into the mucosal intraepithelial lymphocytes (IEL) before they parasitize crypt or villous epithelial cells. This in vitro study was undertaken to know whether the penetration of E. tenella into such a lymphoid cell is a beneficial step for the parasite survival and development. Three sequential experiments were performed. First, the in vitro established bovine kidney cell line, MDBK cells, were evaluated for use as host cells for E. tenella, through morphological observation. Second, the degree of parasite development and multiplication in MDBK cells was quantitatively assayed using radioisotope-labelled uracil (3H-uracil). Third, the E. tenella sporozoites viability was assayed after preincubation of them with chicken spleen cells. E. tenella oöcysts obtained from the ceca of the infected chickens were used for the source of the sporozoites. Spleen cells (E) obtained from normal chickens (FP strain) were preincubated with the sporozoites (T) at the E:T ratio of 100:1, 50:1 or 25:1 for 4 or 12 hours, and then the mixture was inoculated into the MDBK cell monolayer. Morphologically the infected MDBK cells revealed active schizogonic cycle of E. tenella in 3-4 days, which was characterized by the appearance of trophozoites, and immature and mature schizonts containing merozoites. The 3H-uracil uptake by E. tenella increased gradually in the MDBK cells, which made a plateau after 48-60 hours, and decreased thereafter. The uptake amount of 3H-uracil depended not only upon the inoculum size of the sporozoites but also on the degree of time delay (preincubation; sporozoites only) from excystation to inoculation into MDBK cells. The 3H-uracil uptake became lower as the preincubation time was prolonged. In comparison, after preincubation of

  12. (E-tert-Butyl 2-(5-{[4-(dimethylaminophenyl]diazenyl}-2,6-dioxo-1H-pyrimidin-3-ylacetate dichloromethane monosolvate

    Directory of Open Access Journals (Sweden)

    Robert H. E. Hudson

    2014-05-01

    Full Text Available In the title compound, C18H23N5O4·CH2Cl2, the dichloromethane solvent molecule is disordered over two sets of sites in a 0.630 (13:0.370 (13 ratio. The dihedral angle between the uracil and phenyl rings is 30.2 (1°. In the crystal, the principal interactions are N—H...O hydrogen bonds, which link uracil units across centres of symmetry, forming eight-membered rings with an R22(8 graph-set motif. The structure also displays C—H...O and C—H...Cl hydrogen bonds. Intramolecular C—H...O short contacts are also observed.

  13. Uptake and incorporation of pyrimidines in Euglena gracilis.

    Science.gov (United States)

    Wasternack, C H

    1976-08-01

    In photoorganotrophically grown cells of Euglena gracilis the uptake and incorporation degree of 12 different pyrimidines were tested. The rate of uptake of pyrimidines has distinct maxima in the late log phase and in the stationary phase of cell multiplication. The kinetics of uptake are linear in the first 2 h, do not show saturation at various concentrations and increase with the concetrations. No accumulation of the pyrimidines at various concentrations could be observed in the first 2 h of incubation. Membrane inhibitors as uranyl acetate inhibit the uptake of the reference substance alpha-AIB, which is wellknown transported by an active transport mechanism, but have no effect on uptake rate of uracil and cytosine. It could not be observed an energy requirement tested in temperature dependence and with electron transport inhibitors. Uptake of uridine, uracil, barbituric acid and alpha-AIB is inhibited by cycloheximide in a different manner after 5 - 10 min.

  14. Meteorites and the RNA World: A Thermodynamic Model of Nucleobase Synthesis within Planetesimals

    CERN Document Server

    Pearce, Ben K D

    2016-01-01

    The possible meteorite parent body origin of Earth's pregenetic nucleobases is substantiated by the guanine (G), adenine (A) and uracil (U) measured in various meteorites. Cytosine (C) and thymine (T) however are absent in meteorites, making the emergence of a RNA and later RNA/DNA/protein world problematic. We investigate the meteorite parent body (planetesimal) origin of all nucleobases by computationally modeling 18 reactions that potentially contribute to nucleobase formation in such environments. Out of this list, we identify the two most important reactions for each nucleobase and find that these involve small molecules such as HCN, CO, NH3, and water that ultimately arise from the protoplanetary disks in which planetesimals are built. The primary result of this study is that cytosine is unlikely to persist within meteorite parent bodies due to aqueous deamination. Thymine has a thermodynamically favourable reaction pathway from uracil, formaldehyde and formic acid, but likely did not persist within pla...

  15. Catalysis of a Flavoenzyme-Mediated Amide Hydrolysis

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, Tathagata; Zhang, Yang; Abdelwahed, Sameh; Ealick, Steven E.; Begley, Tadhg P. (Cornell); (TAM)

    2010-09-13

    A new pyrimidine catabolic pathway (the Rut pathway) was recently discovered in Escherichia coli K12. In this pathway, uracil is converted to 3-hydroxypropionate, ammonia, and carbon dioxide. The seven-gene Rut operon is required for this conversion. Here we demonstrate that the flavoenzyme RutA catalyzes the initial uracil ring-opening reaction to give 3-ureidoacrylate. This reaction, while formally a hydrolysis reaction, proceeds by an oxidative mechanism initiated by the addition of a flavin hydroperoxide to the C4 carbonyl. While peroxide-catalyzed amide hydrolysis has chemical precedent, we are not aware of a prior example of analogous chemistry catalyzed by flavin hydroperoxides. This study further illustrates the extraordinary catalytic versatility of the flavin cofactor.

  16. Resonant electron capture by orotic acid molecules

    Science.gov (United States)

    Muftakhov, M. V.; Shchukin, P. V.; Khatymov, R. V.

    2017-09-01

    Resonant electron attachment by orotic acid molecules (6-COOH-uracil) are studied in the energy range of 0-14 eV via negative ion mass spectrometry. Molecular ions, whose lifetimes relative to electron autodetachment are found to be 300 μs are recorded in the region of thermal electron energies; they form in the valence state through a vibration-excited resonance mechanism. Unlike unsubstituted uracil, most dissociative processes occur in the low-energy region of <4 eV and are due to carboxylic anions. An absolute cross section of 2.4 × 10-17 cm2 is found for the most intense fragment ions [M-H]- at an output energy of 1.33 eV. The kinetics of decarboxylation is considered for these ions. This could be a model reaction for the last stage of uridine monophosphate biosynthesis.

  17. The pyrimidine operon pyrRPB-carA from Lactococcus lactis

    DEFF Research Database (Denmark)

    Martinussen, Jan; Schallert, J.; Andersen, Birgit;

    2001-01-01

    The four genes pyrR, pyrP, pyrB, and carA were found to constitute an operon in Lactococcus lactis subsp, lactis MG1363. The functions of the different genes were established by mutational analysis. The first gene in the operon is the pyrimidine regulatory gene, pyrR, which is responsible...... for the regulation of the expression of the pyrimidine biosynthetic genes leading to UMP formation. The second gene encodes a membrane-bound high-affinity uracil permease, required for utilization of exogenous uracil. The last two genes in the operon, pyrB and carA, encode pyrimidine biosynthetic enzymes; aspartate....... The expression of the pyrimidine biosynthetic genes including the pyrRPB-carA operon is subject to control at the transcriptional level, most probably by an attenuator mechanism in which PyrR acts as the regulatory protein....

  18. Construction of a UGA suppressor tRNA by modification in vitro of yeast tRNACys.

    Science.gov (United States)

    Vacher, J; Grosjean, H; de Henau, S; Finelli, J; Buckingham, R H

    1984-01-02

    In this paper we describe the construction of a yeast tRNACys UGA suppressor. After specific hydrolysis of the parent molecule, the first base of the anticodon GCA was replaced by a uracil. The resulting molecule, harboring a UCA anticodon, was injected into Xenopus laevis oocytes in order to test its biological activities. The level of aminoacylation was similar to that of the parent molecule. Readthrough of the UGA termination codon in beta-globin mRNA, coinjected with the tRNA, indicated suppressor activity; however, tRNACys (anticodon UCA) was a much less efficient suppressor than others tested under the same conditions. We see no post-transcriptional modification of the uracil in the anticodon wobble position after injection into oocytes. This may be related to the low suppressor activity; however, it is also possible that other features of tRNACys structure may be unadapted to efficient UCA anticodon function.

  19. Modified 5'-trityl nucleosides as inhibitors of Plasmodium falciparum dUTPase.

    Science.gov (United States)

    Ruda, Gian Filippo; Nguyen, Corinne; Ziemkowski, Przemysław; Felczak, Krzysztof; Kasinathan, Ganasan; Musso-Buendia, Alexander; Sund, Christian; Zhou, Xiao Xiong; Kaiser, Marcel; Ruiz-Pérez, Luis M; Brun, Reto; Kulikowski, Tadeusz; Johansson, Nils Gunnar; González-Pacanowska, Dolores; Gilbert, Ian H

    2011-02-07

    2'-Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this Plasmodium falciparum enzyme. Herein we report further structure-activity studies; in particular, variations of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base. Compounds were tested against both the enzyme and the parasite. Variations of the 5'-trityl group and of the 3'-substituent were well tolerated and yielded active compounds. However, there is a clear requirement for the uracil base for activity, because modifications of the uracil ring result in loss of enzyme inhibition and significant decreases in antiplasmodial action. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. An electrochemical evidence of free radicals formation from flutamide and its reactivity with endo/xenobiotics of pharmacological relevance.

    Science.gov (United States)

    Núñez-Vergara, L J; Farias, D; Bollo, S; Squella, J A

    2001-01-01

    This paper reports the feasibility of free radicals formation from flutamide by using cyclic voltammetry. The electrochemical characteristics and the reactivity of the one-electron reduction product from flutamide in mixed media with thiol compounds and the nuclei acid bases are characterized. Results from this paper show the thermodynamic feasibility of free radical formation expressed for both the cathodic peak potential and the second-order rate constant values. The reactivity of the radical towards thiol compounds (glutathione, cysteamine, N-acetylcysteine) and the nuclei acid base, adenine, thymine and uracil were quantitatively assessed through the calculation of the respective interaction rate constants. Based on these results, the following tentative order of reactivity towards the xeno/endobiotics is as follows: cysteamine > uracil > glutathione > adenine > N-acetylcysteine > thymine. The stability of the nitro radical anion electrochemically generated from flutamide showed a linear dependence with pH.

  1. Electron Attachment to DNA and RNA Nucleobases: An EOMCC Investigation

    CERN Document Server

    Dutta, Chintya Kumar; Vaval, Nayana; Pal, Sourav

    2014-01-01

    We report a benchmark theoretical investigation of both adiabatic and vertical electron affinities of five DNA and RNA nucleobases: adenine, guanine, cytosine, thymine and uracil using state-of-the-art equation of motion coupled cluster (EOMCC) method. We have calculated the vertical electron affinity values of first five electron attached states of the DNA and RNA nucleobases and only the first electron attached state is found to be energetically accessible in gas phase. An analysis of the natural orbitals shows that the first electron attached states of uracil and thymine are valence-bound type and undergo significant structural changes on attachment of excess electron, which is reflected in the deviation of the adiabatic electron affinity from the vertical one. On the other hand, the first electron attached state of cytosine, adenine and guanine are dipole-bound type and their structure remain unaffected on attachment of an extra electron, which results in small deviation of adiabatic electron affinity fro...

  2. USER-derived cloning methods and their primer design.

    Science.gov (United States)

    Salomonsen, Bo; Mortensen, Uffe H; Halkier, Barbara A

    2014-01-01

    Uracil excision-based cloning through USER™ (Uracil-Specific Excision Reagent) is an efficient ligase-free cloning technique that comprises USER cloning, USER fusion, and USER cassette-free (UCF) USER fusion. These USER-derived cloning techniques enable seamless assembly of multiple DNA fragments in one construct. Though governed by a few simple rules primer design for USER-based fusion of PCR fragments can prove time-consuming for inexperienced users. The Primer Help for USER (PHUSER) software is an easy-to-use primer design tool for USER-based methods. In this chapter, we present a PHUSER software protocol for designing primers for USER-derived cloning techniques.

  3. A strategy for developing a hammerhead ribozyme for selective RNA cleavage depending on substitutional RNA editing

    OpenAIRE

    Fukuda, Masatora; Kurihara, Kei; Tanaka, Yasuyoshi; Deshimaru, Masanobu

    2012-01-01

    Engineered site-specific RNA cleavage is widely used for gene regulation, RNA mapping, and synthetic RNA production. Here the authors extend the range of engineered recognition selectivity to include cleavage of sequence motifs containing naturally occurring base modifications. They describe and implement a designer hammerhead ribozyme that cleaves a target sequence 1 nt from a site of adenosine to inosine (A-to-I) or cytosine to uracil (C-to-U) editing in synthetic or physiological mRNA cont...

  4. 1-(2-Bromo-2-deoxy-β-d-xylofuranosyluracil

    Directory of Open Access Journals (Sweden)

    Chun-Feng Wang

    2011-01-01

    Full Text Available In the title compound, C9H11BrN2O5, the ribofuranose ring has a C2-exo, C3-endo twist configuration and is attached to the uracil unit via a β-N1-glycosidic bond. The crystal structure is stabilized by two intermolecular O—H...O interactions and one intermolecular N—H...O interaction.

  5. The Crystal Structure of Streptococcus pyogenes Uridine Phosphorylase Reveals a Distinct Subfamily of Nucleoside Phosphorylases

    Energy Technology Data Exchange (ETDEWEB)

    Tran, Timothy H.; Christoffersen, S.; Allan, Paula W.; Parker, William B.; Piskur, Jure; Serra, I.; Terreni, M.; Ealick, Steven E. (Cornell); (Pavia); (Lund); (Southern Research)

    2011-09-20

    Uridine phosphorylase (UP), a key enzyme in the pyrimidine salvage pathway, catalyzes the reversible phosphorolysis of uridine or 2'-deoxyuridine to uracil and ribose 1-phosphate or 2'-deoxyribose 1-phosphate. This enzyme belongs to the nucleoside phosphorylase I superfamily whose members show diverse specificity for nucleoside substrates. Phylogenetic analysis shows Streptococcus pyogenes uridine phosphorylase (SpUP) is found in a distinct branch of the pyrimidine subfamily of nucleoside phosphorylases. To further characterize SpUP, we determined the crystal structure in complex with the products, ribose 1-phosphate and uracil, at 1.8 {angstrom} resolution. Like Escherichia coli UP (EcUP), the biological unit of SpUP is a hexamer with an ?/? monomeric fold. A novel feature of the active site is the presence of His169, which structurally aligns with Arg168 of the EcUP structure. A second active site residue, Lys162, is not present in previously determined UP structures and interacts with O2 of uracil. Biochemical studies of wild-type SpUP showed that its substrate specificity is similar to that of EcUP, while EcUP is {approx}7-fold more efficient than SpUP. Biochemical studies of SpUP mutants showed that mutations of His169 reduced activity, while mutation of Lys162 abolished all activity, suggesting that the negative charge in the transition state resides mostly on uracil O2. This is in contrast to EcUP for which transition state stabilization occurs mostly at O4.

  6. The Nucleoside Uridine Isolated in the Gas Phase**

    Science.gov (United States)

    Peña, Isabel; Cabezas, Carlos; Alonso, José L.

    2016-01-01

    Herein we present the first experimental observation of the isolated nucleoside uridine, placed in the gas phase by laser ablation and characterized by Fourier transform microwave techniques. Free from the bulk effects of their native environments, anti/C2’-endo-g+ conformation has been revealed as the most stable form of uridine. Intramolecular hydrogen bonds involving uracil and ribose moieties have been found to play an important role in the stabilization of the nucleoside. PMID:25683559

  7. A source for microhydrated biomolecules

    Energy Technology Data Exchange (ETDEWEB)

    Förstel, M.; Hergenhahn, U., E-mail: uwe.hergenhahn@ipp.mpg.de [Max-Planck-Institut für Plasmaphysik, Wendelsteinstraße 1, 17491 Greifswald (Germany); Neustetter, M.; Denifl, S. [Institut für Ionenphysik und Angewandte Physik, Technikerstraße 25, 6020 Innsbruck (Austria); Lelievre, F. [Max-Planck-Institut für Plasmaphysik, Wendelsteinstraße 1, 17491 Greifswald (Germany); University Paris-Sud 11, Faculté des Science d’Orsay, 91405 Orsay (France)

    2015-07-15

    We describe the construction of an apparatus for the production of a molecular jet of microhydrated biomolecules. Our design uses a water reservoir producing water vapour, which then passes through a separate reservoir containing a vapour of a sublimated biomolecule. The mixture coexpands into a molecular beam apparatus through a conical nozzle. Mass spectra showing water-adenin and water-uracil complexes are shown as typical examples. Suitable expansion conditions are reached without the use of an inert carrier gas.

  8. Distribution of Nucleosides in Populations of Cordyceps cicadae

    OpenAIRE

    Wen-Bo Zeng; Hong Yu; Feng Ge; Jun-Yuan Yang; Zi-Hong Chen; Yuan-Bing Wang; Yong-Dong Dai; Alison Adams

    2014-01-01

    A rapid HPLC method had been developed and used for the simultaneous determination of 10 nucleosides (uracil, uridine, 2'-deoxyuridine, inosine, guanosine, thymidine, adenine, adenosine, 2'-deoxyadenosine and cordycepin) in 10 populations of Cordyceps cicadae, in order to compare four populations of Ophicordyceps sinensis and one population of Cordyceps militaris. Statistical analysis system (SAS) 8.1 was used to analyze the nucleoside data. The pattern of nucleoside distribution was analyzed...

  9. Compound list: propylthiouracil [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available propylthiouracil PTU 00029 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/propylthio...uracil.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/propylthi...ST/Rat/in_vivo/Liver/Single/propylthiouracil.Rat.in_vivo.Liver.Single.zip ftp://f...tp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/propylthiouracil.Rat.in_vivo.Liver.Repeat.zip ...

  10. ACTA-EVER lecture 2007 - The retinal pigment epithelium: friend or foe?

    DEFF Research Database (Denmark)

    La Cour, Morten

    2008-01-01

    far. We report on a drug delivery system under development where a prodrug of the antimetabolite 5-fluoro-uracil (5-FU) is suspended in the silicone oil used as a surgical device in the treatment of proliferative vitreoretinopathy (PVR). The theoretical advantage of this approach is that it allows...... for long contact times between therapeutic, and non-toxic, concentrations of 5-FU and the RPE Udgivelsesdato: 2008/9...

  11. CHEMOTHERAPEUTIC POLYMERS ⅩⅩⅢ SYNTHESIS AND ANTITUMOR ACTIVITY OF POLYPHOSPHATES CONTAINING BOTH NUCLEIC ACID BASE AND PHOSPHONOACETIC ACID ETHYL ESTER

    Institute of Scientific and Technical Information of China (English)

    ZHUO Renxi; LIU Zhenghua; LI Li

    1989-01-01

    Eight new polyphosphates containing both nucleic acid base and phosphonoacetic acid ethyl ester were synthesized by the polycondensation of P, P- dichloride of phosphonoacetic acid ethyl ester with 1, 3-dihydroxyalkyl - 5 - fluorouracil, 1,3 - dihydroxyalkyl - uracil and 1, 3 - dihydroxyalkylthymine. These polyphosphates were tested against Ehrlich Ascites Carcinoma in mice. Polymer Ⅱa and Ⅱc exhibited excellent antitumor activity. Ⅱc also showed lower toxicity.

  12. Past and present achievements, and future direction of the Gastrointestinal Oncology Study Group (GIOSG), a Division of Japan Clinical Oncology Group (JCOG).

    Science.gov (United States)

    Boku, Narikazu

    2011-12-01

    Initially, Gastrointestinal Study Group in Japan Clinical Oncology Group (GIOSG/JCOG) focused on gastric cancer. In 1980s, fluoropyrimidine, cisplatin and mitomycin C were key drugs. A randomized Phase II trial (JCOG8501) comparing futrafur plus mitomycin C and uracil plus futrafur and mitomycin C showed a higher response rate of uracil plus futrafur and mitomycin C than futrafur plus mitomycin C. From the results of two Phase II trials of etoposide, adriamycin and cisplatin, and cisplatin plus 5-fluorouracil, uracil plus futrafur and mitomycin C and cisplatin plus 5-fluorouracil were adopted for the test arms of the Phase III trial (JCOG9205) comparing with continuous infusion of 5-fluorouracil as a control arm. Neither cisplatin plus 5-fluorouracil nor uracil plus futrafur and mitomycin C showed a survival benefit over continuous infusion of 5-fluorouracil. In late 1990s, new agents, irinotecan and S-1, were developed for gastric cancer in Japan. GIOSG conducted a Phase III trial (JCOG9912) investigating superiority of irinotecan plus cisplatin and non-inferiority of monotherapy with S-1 compared with continuous infusion of 5-fluorouracil, and S-1 succeeded in showing non-inferiority. Then, SPIRITS trial showed a survival benefit of S-1 plus cisplatin over S-1, resulting in the establishment of a standard care for advanced gastric cancer in Japan. GIOSG have merged with Gastric Cancer Study Group as the Stomach Cancer Study Group (SCSG) from 2011. Recent progress in the development of new drugs has been remarkable. From the point of the roles shared with many other study groups for clinical trials, including registration trials of new drugs conducted by pharmaceutical companies, SCSG should recognize its role and conduct clinical trials with high quality for establishing new standard treatment.

  13. Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity

    Energy Technology Data Exchange (ETDEWEB)

    Fenech, Michael, E-mail: michael.fenech@csiro.au [CSIRO Food and Nutritional Sciences, PO Box 10041 Adelaide BC, SA 5000 (Australia)

    2012-05-01

    Folate plays a critical role in the prevention of uracil incorporation into DNA and hypomethylation of DNA. This activity is compromised when vitamin B12 concentration is low because methionine synthase activity is reduced, lowering the concentration of S-adenosyl methionine (SAM) which in turn may diminish DNA methylation and cause folate to become unavailable for the conversion of dUMP to dTMP. The most plausible explanation for the chromosome-breaking effect of low folate is excessive uracil misincorporation into DNA, a mutagenic lesion that leads to strand breaks in DNA during repair. Both in vitro and in vivo studies with human cells clearly show that folate deficiency causes expression of chromosomal fragile sites, chromosome breaks, excessive uracil in DNA, micronucleus formation, DNA hypomethylation and mitochondrial DNA deletions. In vivo studies show that folate and/or vitamin B12 deficiency and elevated plasma homocysteine (a metabolic indicator of folate deficiency) are significantly correlated with increased micronucleus formation and reduced telomere length respectively. In vitro experiments indicate that genomic instability in human cells is minimised when folic acid concentration in culture medium is greater than 100 nmol/L. Intervention studies in humans show (a) that DNA hypomethylation, chromosome breaks, uracil incorporation and micronucleus formation are minimised when red cell folate concentration is greater than 700 nmol/L and (b) micronucleus formation is minimised when plasma concentration of vitamin B12 is greater than 300 pmol/L and plasma homocysteine is less than 7.5 {mu}mol/L. These concentrations are achievable at intake levels at or above current recommended dietary intakes of folate (i.e. >400 {mu}g/day) and vitamin B12 (i.e. >2 {mu}g/day) depending on an individual's capacity to absorb and metabolise these vitamins which may vary due to genetic and epigenetic differences.

  14. Insight into the mechanism of the initial reaction of a OH-radical with DNA/RNA nucleobases

    DEFF Research Database (Denmark)

    Milhøj, Birgitte Olai; Sauer, Stephan P. A.

    2015-01-01

    through hydrogen abstraction and OH radical addition onto carbon sites, using DFT at the ωB97X-D/6-311++G(2df,2pd) level with the Eckart tunneling correction. The overall rate constants for the reaction with adenine, guanine, thymine, and uracil are found to be 2.17×10−12, 5.64×10−11, 2.01×10−11, and 5...

  15. Synthesis and characterization of novel biodegradable poly(carbonate ester)s with photolabile protecting groups.

    Science.gov (United States)

    Xie, Zhigang; Hu, Xiuli; Chen, Xuesi; Sun, Jing; Shi, Quan; Jing, Xiabin

    2008-01-01

    Novel biodegradable poly(carbonate ester)s with photolabile protecting groups were synthesized by ring-opening copolymerization of L-lactide (LA) with 5-methyl-5-(2-nitro-benzoxycarbonyl)-1,3-dioxan-2-one (MNC) with diethyl zinc (Et2Zn) as catalyst. The poly(L-lactide-co-5-methyl-5-carboxyl-1,3-dioxan-2-one) (P(LA-co-MCC)) was obtained by UV irradiation of poly(L-lactide acid-co-5-methyl-5-(2-nitro-benzoxycarbonyl)-1,3-dioxan-2-one) (P(LA-co-MNC)) to remove the protective 2-nitrobenzyl group. The free carboxyl groups on the copolymers P(LA-co-MCC) were reacted with paclitaxel, a common antitumor drug. Gel permeation chromatography and NMR studies confirmed the copolymer structures and successful attachment of paclitaxel to the copolymer.

  16. De novo pyrimidine nucleotide synthesis mainly occurs outside of plastids, but a previously undiscovered nucleobase importer provides substrates for the essential salvage pathway in Arabidopsis.

    Science.gov (United States)

    Witz, Sandra; Jung, Benjamin; Fürst, Sarah; Möhlmann, Torsten

    2012-04-01

    Nucleotide de novo synthesis is highly conserved among organisms and represents an essential biochemical pathway. In plants, the two initial enzymatic reactions of de novo pyrimidine synthesis occur in the plastids. By use of green fluorescent protein fusions, clear support is provided for a localization of the remaining reactions in the cytosol and mitochondria. This implies that carbamoyl aspartate, an intermediate of this pathway, must be exported and precursors of pyrimidine salvage (i.e., nucleobases or nucleosides) are imported into plastids. A corresponding uracil transport activity could be measured in intact plastids isolated from cauliflower (Brassica oleracea) buds. PLUTO (for plastidic nucleobase transporter) was identified as a member of the Nucleobase:Cation-Symporter1 protein family from Arabidopsis thaliana, capable of transporting purine and pyrimidine nucleobases. A PLUTO green fluorescent protein fusion was shown to reside in the plastid envelope after expression in Arabidopsis protoplasts. Heterologous expression of PLUTO in an Escherichia coli mutant lacking the bacterial uracil permease uraA allowed a detailed biochemical characterization. PLUTO transports uracil, adenine, and guanine with apparent affinities of 16.4, 0.4, and 6.3 μM, respectively. Transport was markedly inhibited by low concentrations of a proton uncoupler, indicating that PLUTO functions as a proton-substrate symporter. Thus, a protein for the absolutely required import of pyrimidine nucleobases into plastids was identified.

  17. Effects of Hypoxanthine Substitution in Peptide Nucleic Acids Targeting KRAS2 Oncogenic mRNA Molecules: Theory and Experiment

    Science.gov (United States)

    Sanders, Jeffrey M.; Wampole, Matthew E.; Chen, Chang-Po; Sethi, Dalip; Singh, Amrita; Dupradeau, François-Yves; Wang, Fan; Gray, Brian D.; Thakur, Mathew L.; Wickstrom, Eric

    2013-01-01

    Genetic disorders can arise from single base substitutions in a single gene. A single base substitution for wild type guanine in the twelfth codon of KRAS2 mRNA occurs frequently to initiate lung, pancreatic, and colon cancer. We have observed single base mismatch specificity in radioimaging of mutant KRAS2 mRNA in tumors in mice by in vivo hybridization with radiolabeled peptide nucleic acid (PNA) dodecamers. We hypothesized that multi-mutant specificity could be achieved with a PNA dodecamer incorporating hypoxanthine, which can form Watson-Crick basepairs with adenine, cytosine, thymine, and uracil. Using molecular dynamics simulations and free energy calculations, we show that hypoxanthine substitutions in PNAs are tolerated in KRAS2 RNA-PNA duplexes where wild type guanine is replaced by mutant uracil or adenine in RNA. To validate our predictions, we synthesized PNA dodecamers with hypoxanthine, and then measured the thermal stability of RNA-PNA duplexes. Circular dichroism thermal melting results showed that hypoxanthine-containing PNAs are more stable in duplexes where hypoxanthine-adenine and hypoxanthine-uracil base pairs are formed than single mismatch duplexes or duplexes containing hypoxanthine-guanine opposition. PMID:23972113

  18. Secondary Structure Prediction of Protein Constructs Using Random Incremental Truncation and Vacuum-Ultraviolet CD Spectroscopy

    Science.gov (United States)

    Pukáncsik, Mária; Orbán, Ágnes; Nagy, Kinga; Matsuo, Koichi; Gekko, Kunihiko; Maurin, Damien; Hart, Darren; Kézsmárki, István; Vertessy, Beata G.

    2016-01-01

    A novel uracil-DNA degrading protein factor (termed UDE) was identified in Drosophila melanogaster with no significant structural and functional homology to other uracil-DNA binding or processing factors. Determination of the 3D structure of UDE is excepted to provide key information on the description of the molecular mechanism of action of UDE catalysis, as well as in general uracil-recognition and nuclease action. Towards this long-term aim, the random library ESPRIT technology was applied to the novel protein UDE to overcome problems in identifying soluble expressing constructs given the absence of precise information on domain content and arrangement. Nine constructs of UDE were chosen to decipher structural and functional relationships. Vacuum ultraviolet circular dichroism (VUVCD) spectroscopy was performed to define the secondary structure content and location within UDE and its truncated variants. The quantitative analysis demonstrated exclusive α-helical content for the full-length protein, which is preserved in the truncated constructs. Arrangement of α-helical bundles within the truncated protein segments suggested new domain boundaries which differ from the conserved motifs determined by sequence-based alignment of UDE homologues. Here we demonstrate that the combination of ESPRIT and VUVCD spectroscopy provides a new structural description of UDE and confirms that the truncated constructs are useful for further detailed functional studies. PMID:27273007

  19. Blockage of the pyrimidine biosynthetic pathway affects riboflavin production in Ashbya gossypii.

    Science.gov (United States)

    Silva, Rui; Aguiar, Tatiana Q; Domingues, Lucília

    2015-01-10

    The Ashbya gossypii riboflavin biosynthetic pathway and its connection with the purine pathway have been well studied. However, the outcome of genetic alterations in the pyrimidine pathway on riboflavin production by A. gossypii had not yet been assessed. Here, we report that the blockage of the de novo pyrimidine biosynthetic pathway in the recently generated A. gossypii Agura3 uridine/uracil auxotrophic strain led to improved riboflavin production on standard agar-solidified complex medium. When extra uridine/uracil was supplied, the production of riboflavin by this auxotroph was repressed. High concentrations of uracil hampered this (and the parent) strain growth, whereas excess uridine favored the A. gossypii Agura3 growth. Considering that the riboflavin and the pyrimidine pathways share the same precursors and that riboflavin overproduction may be triggered by nutritional stress, we suggest that overproduction of riboflavin by the A. gossypii Agura3 may occur as an outcome of a nutritional stress response and/or of an increased availability in precursors for riboflavin biosynthesis, due to their reduced consumption by the pyrimidine pathway.

  20. Response of biological uv dosimeters to the simulated extraterrestrial uv radiation

    Science.gov (United States)

    Bérces, A.; Rontó, G.; Kerékgyártó, T.; Kovács, G.; Lammer, H.

    In the Laboratory polycrystalline uracil thin layer and bacteriophage T7 detectors have been developed for UV dosimetry on the EarthSs surface. Exponential response of the uracil polycrystal has been detected both by absorption spectroscopy and measurements of the refractive index under the influence of terrestrial solar radiation or using UV-C sources. In UV biological dosimetry the UV dose scale is additive starting at a value of zero according to the definition of CIE (Technical Report TC-6-18). The biological dose can be defined by a measured end-effect. In our dosimeters (phage T7 and uracil dosimeter) exposed to natural (terrestrial) UV radiation the proportion of pyrimidin photoproducts among the total photoproducts is smaller than 0.1 and the linear correlation between the biological and physical dose is higher than 0.9. According to the experimental data this linear relationship is often not valid. We observed that UV radiation did not only induce dimerisation but shorter wavelengths caused monomerisation of pyrimidin dimers. Performing the irradiation in oxygen free environment and using a Deuterium lamp as UV source, we could increase monomerisation against dimerisation thus the DNA-based dosimetrySs additivity rule is not fulfilled in these conditions. In this study we will demonstrate those non-linear experiments which constitute the basis of our biological experiments on the International Space Station.

  1. Identification and antifungal activity of novel organic compounds found in cuticular and internal lipids of medically important flies.

    Science.gov (United States)

    Gołębiowski, Marek; Cerkowniak, Magdalena; Urbanek, Aleksandra; Dawgul, Małgorzata; Kamysz, Wojciech; Boguś, Mieczysława I; Stepnowski, Piotr

    2015-01-01

    Novel organic compounds found in the cuticular and internal lipids of medically important flies were identified. Uracil, 9-tricosene, 1-oleoyl glycerol, dimethyl suberate and butyl stearate were tested for their potential antifungal activity. Minimal inhibitory concentrations of the compounds against reference strains of fungi were determined. Uracil and dimethyl suberate slightly inhibited the growth of entomopathogenic fungi. The cuticular and internal lipids of Calliphora vicina, Calliphora vomitoria, Sarcophaga carnaria and Musca domestica were studied by gas chromatography (GC) combined with mass spectrometry (GC/MS). A comparison of the lipid extracts between the preimaginal and mature stages showed adults flies contained a higher total content of the identified components. Furthermore, their amounts distinctly predominated in the internal lipids of all the species. The amount of 9-tricosene was the highest in adults of C. vicina, while the larvae and pupae had a definitively lower amount of this compound. Uracil was found to be the most abundant component in extracts obtained from C. vomitoria especially in the internal lipids of adults. 1-oleoyl glycerol was detected in all of the examined species of flies. It was most abundant in the internal extracts isolated from the larvae of C. vicina and the pupae of C. vomitoria. Suberic acid dimethyl ester was found in the larval and pupal internal lipids of C. vicina and S. carnaria in low amounts. Butyl stearate was identified only in the internal lipids of the larvae and adults of houseflies.

  2. Minutes of the 48. meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO); Compte-rendu de la 48. reunion de l'American Society for Therapeutic Radiology and Oncology (ASTRO)

    Energy Technology Data Exchange (ETDEWEB)

    Simon, J.M.; Mazeron, J.J. [Groupe Hospitalier de la Pitie-Salpetriere, APHP, Service de Radiotherapie Oncologique, 75 - Paris (France)

    2007-05-15

    Four parts are treated in this article: Cancers of the O.R.L. sphere, prostate cancers, breast cancer and anal channel. About the O.R.L. sphere cancers, Comparison between several works are made: american and European tests that conclude to the superiority of a chemotherapy using cisplatin on a classical radiotherapy after excision of epidermoid carcinomas of the O.R.L. sphere. Two other tests, one from Hong Kong and the other one from Singapore, are related; The first test studied a concomitant chemotherapy face to an adjuvant chemotherapy in locally evolved nasopharynx cancer. The second one ( Singapore) has compared radiotherapy and radiotherapy with concomitant chemotherapy by cisplatin. Concerning the prostate cancer, the question of dose escalation is developed, followed by a comparison between radiotherapy and hormonotherapy with goserelin. About the breast cancer, two canadian tests are related: the first one concerns the comparison between a conformal radiotherapy with intensity modulation a classical radiotherapy with two tangential beams. The results are in favour of R.C.M.I ( conformal radiotherapy with intensity modulation). The second tests compared a chemotherapy with tamoxifen with and without radiotherapy, the conclusions are in favour of chemotherapy with radiotherapy. The last part was devoted to the anal channel, and compared two chemotherapy with radiotherapy, one using 5-fluoro-uracil and mitomycin, the second one 5-fluoro-uracil and cisplatin. The treatment with 5-fluoro-uracil and mitomycin stays the preferred one. (N.C.)

  3. The pyrimidine nucleotide biosynthetic pathway modulates production of biofilm determinants in Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Marco Garavaglia

    Full Text Available Bacteria are often found in multicellular communities known as biofilms, which constitute a resistance form against environmental stresses. Extracellular adhesion and cell aggregation factors, responsible for bacterial biofilm formation and maintenance, are tightly regulated in response to physiological and environmental cues. We show that, in Escherichia coli, inactivation of genes belonging to the de novo uridine monophosphate (UMP biosynthetic pathway impairs production of curli fibers and cellulose, important components of the bacterial biofilm matrix, by inhibiting transcription of the csgDEFG operon, thus preventing production of the biofilm master regulator CsgD protein. Supplementing growth media with exogenous uracil, which can be converted to UMP through the pyrimidine nucleotide salvage pathway, restores csgDEFG transcription and curli production. In addition, however, exogenous uracil triggers cellulose production, particularly in strains defective in either carB or pyrB genes, which encode enzymes catalyzing the first steps of de novo UMP biosynthesis. Our results indicate the existence of tight and complex links between pyrimidine metabolism and curli/cellulose production: transcription of the csgDEFG operon responds to pyrimidine nucleotide availability, while cellulose production is triggered by exogenous uracil in the absence of active de novo UMP biosynthesis. We speculate that perturbations in the UMP biosynthetic pathways allow the bacterial cell to sense signals such as starvation, nucleic acids degradation, and availability of exogenous pyrimidines, and to adapt the production of the extracellular matrix to the changing environmental conditions.

  4. Nutrition Condition of Hyaluronic Acid Fermentation with Streptococcus zooepidemicus%营养条件对兽疫链球菌发酵生产透明质酸的影响

    Institute of Scientific and Technical Information of China (English)

    高海军; 陈坚; 章燕芳; 堵国成

    2000-01-01

    Based on the analysis of metabolic pathway Streptococcous zooepidemicus for hyaluronic acid (HA) synthesis, nucleotide,especially uracil, was considered to be important to cell growth and metabolism. When 0.005 g·L-1 uracil added in the media in which yeast extract as complex nitrogen source, cell growth and HA production were increased by 32 % and 34 % respectively. From analysis of amino acid in fermentation process, it was show that arginine(Arg) was needed for cell metabolism,and concentration of free Arg maintained at 0 g·L-1 in fermentation process, which was proposed to limit cell growth and HA production. By shake-flask experiment HA concentration reached 0.510 g·L-1 whene 0.06 g·L-1 Arg added,in the fermentation with 2.5 L fermentor, when uracil 0.005 g·L-1 and Arg 0.06 g·L-1 were added, the rate of cell growth increased, maximum of specific growth rate, concentration of HA and HA molecular weight reached 0.67 h-1 ,5.2 g·L-1 and 2.15×106 Da from 0.54 h-1,4.2 g·L-1,2.0×106 Da,respectively.

  5. Supramolecular Functionalities Influence the Thermal Properties, Interactions and Conductivity Behavior of Poly(ethylene glycol/LiAsF6 Blends

    Directory of Open Access Journals (Sweden)

    Shiao-Wei Kuo

    2013-07-01

    Full Text Available In this study, we tethered terminal uracil groups onto short-chain poly(ethylene glycol (PEG to form the polymers, uracil (U-PEG and U-PEG-U. Through AC impedance measurements, we found that the conductivities of these polymers increased upon increasing the content of the lithium salt, LiAsF6, until the Li-to-PEG ratio reached 1:4, with the conductivities of the LiAsF6/U-PEG blends being greater than those of the LiAsF6/U-PEG-U blends. The ionic conductivity of the LiAsF6/U-PEG system reached as high as 7.81 × 10−4 S/cm at 30 °C. Differential scanning calorimetry, wide-angle X-ray scattering, 7Li nuclear magnetic resonance spectroscopy and Fourier transform infrared spectroscopy revealed that the presence of the uracil groups in the solid state electrolytes had a critical role in tuning the glass transition temperatures and facilitating the transfer of Li+ ions.

  6. An Efficient and Short Route for the Synthesis of Reverse Pyrrole Ribonucleosides

    Directory of Open Access Journals (Sweden)

    Pereira Letícia O. R.

    2002-01-01

    Full Text Available The synthesis of reverse pyrrole ribonucleosides methyl 5-C-(4-acetyl-5-methyl-pyrrol-1-yl-2,3-O-isopropylidene-5-deoxy- beta-D-ribofuranoside (10, methyl 5-C-(4-ethoxycarbonyl-5-methyl-pyrrol-1-yl-2,3-O-isopropylidene-5-deoxy- beta-D-ribofuranoside (11, methyl 5-C-(4-acetyl-5-methyl-pyrrol-1-yl-5-deoxy-beta-D-ribofuranoside (12, methyl 5-C-(4-ethoxycarbonyl-5-methyl-pyrrol-1-yl-5-deoxy- beta-D-ribofuranoside (13, methyl 5-deoxy-5-C-(3'-formyl-4'-hydroxypropyl-pyrrol-1'-yl-2,3-O-isopropylidene- beta-D-ribofuranoside (16 and methyl 5-deoxy-5-C-(3'-formyl-pyrrol-1'-yl-2,3-O-isopropylidene- beta-D-ribofuranoside (18 are described starting from readily available methyl 5-amino-5-deoxy-2,3-O-isopropylidene-beta-D-ribofuranoside (9. The synthetic strategy for the construction of the heterocyclic ring was based on the nucleophilic attack of (9 to 4-acetyl-2-n-butoxy-5-methyl-4,5-dihydrofuran (4, 4-carbetoxy-2-n-butoxy-5-methyl-4,5-dihydrofuran (5, 4-formyl-2-n-butoxy-4,5-dihydrofuran (6 and 4-formyl-1-methyl dioxabyciclo[3.3.0]oct-3-en (8, in situ. The later compounds were obtained from reaction between 3-diazo-2,4-pentadione (1, ethyl 2-diazoacetoacetate (2 or diazomalonaldehyde (3 and enol ethers using dirhodium tetraacetate as a catalyst.

  7. Role of desensitization and subunit expression for kainate receptor-mediated neurotoxicity in murine neocortical cultures

    DEFF Research Database (Denmark)

    Jensen, J B; Schousboe, A; Pickering, D S

    1999-01-01

    ) toxicity mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, and (3) toxicity that can be mediated by kainate receptors when desensitization of the receptors is blocked. The indirect action at NMDA receptors was discovered because (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H...... nedioxy-5H-2,3-benzodiazepine (GYKI 53655), a selective AMPA receptor antagonist, abolished the remaining toxicity. These results indicated that kainate- and domoate-mediated toxicity involves both the NMDA and the AMPA receptors. Pretreatment of the cultures with concanavalin A to prevent desensitization...

  8. AMPA receptor ligands

    DEFF Research Database (Denmark)

    Strømgaard, Kristian; Mellor, Ian

    2004-01-01

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player in the f......Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player...

  9. EFSA CEF Panel (EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids), 2014. Scientific Opinion on Flavouring Group Evaluation 300, Revision 1 (FGE.300Rev1): One cyclo-aliphatic amide from chemical group 33

    DEFF Research Database (Denmark)

    Beltoft, Vibe Meister; Frandsen, Henrik Lauritz; Nørby, Karin Kristiane

    The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate a flavouring substance,cyclopropanecarboxylic acid (2-isopropyl-5-methyl-cyclohexyl)-amide [FL-no: 16.115] in the Flavouring Group Evaluation 300, Revision 1...... (FGE.300Rev1) using the Procedure in Commission Regulation (EC) No 1565/2000. This revision is made due to a re-evaluation of the flavouring substance, cyclopropanecarboxylic acid (2-isopropyl-5-methyl-cyclohexyl)-amide [FL-no: 16.115], as a 90-day dietary study in rats has become available...

  10. The Combination of 4-Hydroxythiazoles with Azaheterocycles: Efficient bidentate Ligands for novel Ruthenium Complexes

    OpenAIRE

    Beckert, Rainer; Weiss, Dieter

    2010-01-01

    Abstract We report here on the synthesis of three novel ligands in which an azaheterocycle is connected with a thiazole subunit: 4-methoxy-5-methyl-2-pyridine-2-yl-1,3-thiazole (1), 4-methoxy-5-methyl-2-pyrimidine-2-yl-1,3-thiazole (2) and 4-methoxy-5-phenyl-2-pyridine-2-yl-1,3-thiazole (3). Being cyclic versions of 1,4-diazadienes, they offer good prerequisites for the synthesis of metal complexes and have been employed as chelating ligands. Three novel heteroleptic cationic compl...

  11. Evaluation of ascorbic acid in protecting labile folic acid derivatives.

    OpenAIRE

    1983-01-01

    The use of ascorbic acid as a reducing agent to protect labile, reduced derivatives of folic acid has been evaluated by high-performance liquid chromatographic separations and Lactobacillus casei microbiological assay of eluate fractions. Upon heating for 10 min at 100 degrees C, solutions of tetrahydropteroylglutamic acid (H4PteGlu) in 2% sodium ascorbate gave rise to 5,10-methylene-H4PteGlu and 5-methyl-H4PteGlu. H2PteGlu acid gave rise to 5-methyl-H4PteGlu and PteGlu. 10-Formyl-H4PteGlu ga...

  12. 产紫杉醇真菌N8菌株URA-3基因的敲除%Disruption of URA-3 gene of a paclitaxel-producing fungus N8

    Institute of Scientific and Technical Information of China (English)

    颜菲

    2014-01-01

    目的 为了解决产紫杉醇小孢拟盘多毛孢真菌N8基因操作的筛选标记缺乏的问题,构建N8菌株营养缺陷型菌株.方法 通过基因同源重组的方法定向敲除N8菌株中尿嘧啶合成途径中关键基因URA-3基因,然后利用分子生物学方法和添加一定浓度5-氟乳清酸(5-FOA)、尿嘧啶的基本培养基筛选获得转化子.结果 尿嘧啶营养缺陷型菌株在含有5-FOA和尿嘧啶的培养基上可以正常生长而野生型N8菌株无法生长.结论 成功构建产紫杉醇真菌N8菌株的尿嘧啶营养缺陷型菌株,可为其后续的基因功能研究奠定基础.%Objective In order to get genetic markers,an auxotrophic paclitaxel-producing fungus named Pestalotiopsis malicola N8 strain was isolated by genetic modification.Methods Based on the homologous recombination,URA-3 which is the key gene for uracil synthetic route of Pestalotiopsis malicola N8 strain was knocked out.The transformants were screened by minimal medium with the combination of 5-fluoroorotic acid (5-FOA) and uracil.Results The results showed that the uracil auxotrophic strain was able to grow in the minimal medium containing 5-FOA and uracil while the wild type strain was not.Conclusions The uracil auxotrophic strain can be used as a new selection marker for future gene function studies of N8 strain.

  13. The effect of some α-adrenoceptor antagonists on spontaneous myogenic activity in the rat portal vein and the putative involvement of ATP-sensitive K+channels

    NARCIS (Netherlands)

    Schwietert, R.; Wilhelm, D.; Wilffert, B.; Van Zwieten, P.A.

    1992-01-01

    In the present study we showed that the α-adrenoceptor antagonists phentolamine, yohimbine, prazosin, corynanthine and idazoxan, when cumulatively applied in high concentrations (1-100 μmol/l), can increase spontaneous myogenic activity in the rat portal vein. 5-Methyl-urapidil and rauwolscine were

  14. THE EFFECT OF SOME ALPHA-ADRENOCEPTOR ANTAGONISTS ON SPONTANEOUS MYOGENIC ACTIVITY IN THE RAT PORTAL-VEIN AND THE PUTATIVE INVOLVEMENT OF ATP-SENSITIVE K+ CHANNELS

    NARCIS (Netherlands)

    SCHWIETERT, R; WILHELM, D; WILFFERT, B; VANZWIETEN, PA

    1992-01-01

    In the present study we showed that the alpha-adrenoceptor antagonists phentolamine, yohimbine, prazosin, corynanthine and idazoxan, when cumulatively applied in high concentrations (1-100-mu-mol/l), can increase spontaneous myogenic activity in the rat portal vein. 5-Methyl-urapidil and rauwolscine

  15. Autoimmun synaptisk encefalitis er en underdiagnosticeret sygdomsgruppe

    DEFF Research Database (Denmark)

    Nielsen, Signe Modvig; Høi-Hansen, Christina Engel; Uldall, Peter;

    2012-01-01

    The term autoimmune synaptic encephalitis (ASE) comprises encephalitides associated with autoantibodies against structures of the neuronal synapse. We review four types of ASE (anti-N-methyl-D-aspartate receptor encephalitis, anti-α-amine-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor enc...

  16. AMPA antagonist ZK200775 in patients with acute ischemic stroke - Possible glial cell toxicity detected by monitoring of S-100B serum levels

    NARCIS (Netherlands)

    Elting, JW; Kaste, M; Lees, KR; Diener, HC; Hommel, M; Versavel, M; Teelken, AW; De Keyser, J; Sulter, G.

    2002-01-01

    Background and Purpose-S-100B and neuron-specific enolase (NSE) serum concentrations can be used as peripheral markers of glial cell and neuronal damage, respectively. We investigated these markers in a clinical trial with the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) antagonist Z

  17. Novel 1-hydroxyazole bioisosteres of glutamic acid. Synthesis, protolytic properties, and pharmacology

    DEFF Research Database (Denmark)

    Stensbøl, Tine B; Uhlmann, Peter; Morel, Sandrine

    2002-01-01

    A number of 1-hydroxyazole derivatives were synthesized as bioisosteres of (S)-glutamic acid (Glu) and as analogues of the AMPA receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 3b). All compounds were subjected to in vitro pharmacological studies, including...

  18. Molecular pharmacology of the AMPA agonist, (S)-2-amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid [(S)-APPA] and the AMPA antagonist, (R)-APPA

    DEFF Research Database (Denmark)

    Ebert, B; Madsen, U; Lund, Trine Meldgaard

    1994-01-01

    The heterocyclic analogue of (S)-glutamic acid, (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [(S)-AMPA] is a potent and selective AMPA receptor agonist, whereas the enantiomeric compound, (R)-AMPA, is virtually inactive. We have previously characterized (RS)-2-amino-3-(3-hydroxy-...

  19. Synthesis, Characterisation and Structural Studies of Complexes Containing Different Schiff Bases with Mn (Lll And Mn (Ii Transition Metals

    Directory of Open Access Journals (Sweden)

    Gulrez Nizami

    2014-01-01

    Full Text Available The Schiff bases 5-methyl2-hydroxyacetophenonemorpholine-N-thiohydrazide, 5-methyl2-hydroxyacetophenoneantipyrine 5-chloro2-hydroxyacetophenonemorpholine-N-thiohydrazone has reacted with MnII and MnIII to form co-ordination compounds having general formula [M (C14H19O2N3S 3H2O] Cl; [M (C14H19O2N3S.3H2O]; [M (C20H20N3O2 2] Cl; [M (C20H20N3O2 2];[M(C13H14O2N3SCl.3H2O]Cl and [M(C13H14O2N3SCl].3H2 O] respectively. Where M=Mn III and Mn II. The adducts have been characterized on the basis of elemental analyses molar conductance, I.R , visible spectra, magnetic susceptibility measurement and TGA. The ligands behave in dibasic tridentate manner in 5-methyl2-hydroxyacetophenonemorpholine-N-thiohydrazone and 5-chloro2-hydroxyacetophenonemorpholine-N-thiohydrazone.While5-methyl2hydroxyacetophenoneantipyrine behaves in monobasic tridentate manner. All these compounds are paramagnetic in nature and have octahedral geometry.

  20. Synthesis and photoluminescence properties of an unprecedented phosphinine-Cu4Br4 cluster

    NARCIS (Netherlands)

    Roesch, Philipp; Nitsch, Jörn; Lutz, Martin; Wiecko, Jelena; Steffen, Andreas; Müller, Christian

    2014-01-01

    A hitherto unprecedented polynuclear phosphinine-Cu(I) complex has been prepared and crystallographically characterized. The molecular structure in the crystal verifies the presence of the heterocubanetype tetrameric cluster [LCuBr]4 (L = 2,4-diphenyl-5-methyl-6-(2,3- dimethylphenyl)phosphinine),

  1. Pharmacological properties of homomeric and heteromeric GluR1o and GluR3o receptors

    DEFF Research Database (Denmark)

    Nielsen, B S; Banke, T G; Schousboe, A

    1998-01-01

    Homomeric and heteromeric alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunits GluR1o and GluR3o were expressed in Spodoptera frugiperda (Sf9) insect cells. Membranes containing the recombinant receptors showed a doublet of bands of the expected size (99-109 kDa) after...

  2. Synthesis and antisense properties of 2'-O-(2S-methoxypropyl)-RNA-modified gapmer antisense oligonucleotides.

    Science.gov (United States)

    Yu, Jinghua; Pandey, Sanjay K; Khatri, Hetal; Prakash, Thazha P; Swayze, Eric E; Seth, Punit P

    2014-09-01

    To ascertain whether increasing hydrophobicity can enhance the activity of second-generation antisense oligonucleotides (ASOs) in muscle, we investigated the antisense properties of 2'-O-(2S-methoxypropyl)-RNA (2S-MOP)-modified ASOs. Synthesis of the 2S-MOP 5-methyl uridine phosphoramidite was accomplished on a multi-gram scale by Lewis-acid-catalyzed ring opening of 5'-O-tert-butyldiphenylsilyl ether-protected 2,2'-anhydro-5-methyl uridine with 2S-methoxy-1-propanol. Synthesis of the 2S-MOP 5-methyl cytidine nucleoside from the corresponding 5-methyl uridine nucleoside was accomplished by formation and displacement of a 4-triazolide intermediate with aqueous ammonia. 2S-MOP-modified oligonucleotides were prepared on an automated DNA synthesizer and showed similar enhancements in duplex thermal stability as 2'-O-methoxyethyl RNA (MOE)-modified oligonucleotides. 2S-MOP-containing antisense oligonucleotides were evaluated in Balb-c mice and showed good activity for decreasing the expression levels of scavenger receptor B1 (Srb1) and phosphatase and tensin homologue (PTEN) mRNA in liver and muscle tissue. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. The purification, crystallization and preliminary structural characterization of FAD-dependent monooxygenase PhzS, a phenazine-modifying enzyme from Pseudomonas aeruginosa

    Science.gov (United States)

    The blue chloroform-soluble bacterial metabolite pyocyanin (1-hydroxy-5-methyl-phenazine) contributes to the survival and virulence of Pseudomonas aeruginosa, an important Gram-negative opportunistic pathogen of humans and animals. Little is known about the two enzymes, designated PhzM and PhzS, tha...

  4. AMPA and GABA receptor antagonists and their interaction in rats with a genetic form of absence epilepsy

    NARCIS (Netherlands)

    Kaminski, R.M.; Rijn, C.M. van; Turski, W.A.; Czuczwar, S.J.; Luijtelaar, E.L.J.M. van

    2001-01-01

    The effects of combined and single administration of the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, 7,8-methylenedioxy-1-(4-aminophenyl)-4-methyl-3-acetyl-4,5-dihydro-2,3 -benzodiazepine (LY 300164), and of the GABAB receptor antagonist -aminopropyl-n-butyl-phosp

  5. The Teratogenic Potencies of Valproic Acid Derivatives and Their Effects on Biological End-points are Related to Changes in Histone Deacetylase and Erk1/2 Activities

    DEFF Research Database (Denmark)

    Gotfryd, Kamil; Hansen, Maria; Kawa, Anna;

    2011-01-01

    Valproic acid (VPA) is a known teratogen. In the present study, the effects of VPA and seven VPA derivatives with different teratogenic potencies (isobutyl-, 5-methyl-, ethyl-, propyl-, butyl-, pentyl- and hexyl-4-yn-VPA) were investigated in L929 cells in vitro. Evaluated end-points included cha...

  6. The First Total Synthesis of Triprenylquinone and Hydroquinones

    Institute of Scientific and Technical Information of China (English)

    Chun Hong LI; Xue Song CHEN; Guang Lian ZHOU; Zhi Xiang XIE; Ying LI

    2005-01-01

    First total synthesis of triprenylquinone and hydroquinones, three naturally occurring compound 1, 2 and (±) 3, have been achieved from readily available 2-bromo-5-methyl-1,4-dimethoxybenzene 4 and geranyl bromide. The triprenylquinone and hydroquinones precursor were readily prepared with use of a Julia reaction.

  7. Monoclonal antibodies specific for the organophosphate pesticide azinphos-methyl

    NARCIS (Netherlands)

    Jones, WT; Harvey, D; Jones, SD; Ryan, GB; Wynberg, H; TenHoeve, W; Reynolds, PHS

    1995-01-01

    2-(2-Mercapto-5-methyl-1,3,2-dioxaphosphorinan-5-yl,2-sulphide) methoxyacetic acid has been synthesized and used to prepare an azinphos hapten and protein conjugates. Monoclonal antibodies of high affinity against the pesticide azinphos-methyl were prepared from mice immunized with the

  8. Complexity, Robustness, and Network Thermodynamics in Large-Scale and Multiagent Systems: A Hybrid Control Approach

    Science.gov (United States)

    2012-01-11

    involve filtered versions of the control input and system state in the update laws nor does it involve a least-squares exponential forgetting factor...including receptors for glycine, serotonin type 2 and 3, N- methyl-d-aspartate (NMDA), α-2 adrenoreceptors, α-amino-3-hydroxy-5-methyl-4- isoxazo

  9. Evaluation of PhTX-74 as Subtype-Selective Inhibitor of GluA2-Containing AMPA Receptors

    DEFF Research Database (Denmark)

    Poulsen, Mette Homann; Lucas, Simon; Strømgaard, Kristian

    2014-01-01

    The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are glutamate-gated cation channels that mediate fast excitatory synaptic transmission in the central nervous system. AMPARs are tetramers formed by homo- or heteromeric assembly of GluA1-4 subunits to produce multiple s...

  10. Modification of the philanthotoxin-343 polyamine moiety results in different structure-activity profiles at muscle nicotinic ACh, NMDA and AMPA receptors

    DEFF Research Database (Denmark)

    Mellor, I R; Brier, T J; Pluteanu, F

    2003-01-01

    Voltage-dependent, non-competitive inhibition by philanthotoxin-343 (PhTX-343) analogues, with reduced charge or length, of nicotinic acetylcholine receptors (nAChR) of TE671 cells and ionotropic glutamate receptors (N-methyl-D-aspartate receptors (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isox...

  11. Inhibition of AMPA Receptors by Polyamine Toxins is Regulated by Agonist Efficacy and Stargazin

    DEFF Research Database (Denmark)

    Poulsen, Mette H; Lucas, Simon; Strømgaard, Kristian

    2014-01-01

    The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are glutamate-gated cation channels mediating the majority of fast excitatory synaptic transmission in the central nervous system (CNS). Polyamine toxins derived from spiders and wasps are use- and voltage-dependent chan...

  12. Encephalitis and AMPA receptor antibodies Novel findings in a case series of 22 patients

    NARCIS (Netherlands)

    R. Höftberger (Romana); A. van Sonderen (Agnes); F. Leypoldt (Frank); D. Houghton (David); M. Geschwind (Michael); J. Gelfand (Jeffrey); M. Paredes (Mercedes); L. Sabater (Lidia); A. Saiz (Albert Abe); M.J. Titulaer (Maarten); F. Graus (Francesc); J. Dalmau (Josep)

    2015-01-01

    textabstractObjective: We report the clinical features, comorbidities, and outcome of 22 newly identified patients with antibodies to the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Methods: This was a retrospective review of patients diagnosed between May 2009 and March 2

  13. Retrieval Is Not Necessary to Trigger Reconsolidation of Object Recognition Memory in the Perirhinal Cortex

    Science.gov (United States)

    Santoyo-Zedillo, Marianela; Rodriguez-Ortiz, Carlos J.; Chavez-Marchetta, Gianfranco; Bermudez-Rattoni, Federico; Balderas, Israela

    2014-01-01

    Memory retrieval has been considered as requisite to initiate memory reconsolidation; however, some studies indicate that blocking retrieval does not prevent memory from undergoing reconsolidation. Since N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors in the perirhinal cortex have…

  14. Role of astrocytes in depolarization-coupled release of glutamate in cerebellar cultures

    DEFF Research Database (Denmark)

    Bak, Lasse K; Waagepetersen, Helle S; Schousboe, Arne

    2004-01-01

    Release of preloaded D-[3H]aspartate in response to depolarization induced by high potassium, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) or the endogenous agonist glutamate was studied using cultured glutamatergic cerebellar granule neurons, cerebell...

  15. Identification of the methyltransferase targeting C2499 in Deinococcus radiodurans 23S ribosomal RNA

    DEFF Research Database (Denmark)

    Nielsen, Julie Mundus; Flyvbjerg, Karen Freund; Kirpekar, Finn

    2016-01-01

    The bacterium Deinococcus radiodurans-like all other organisms-introduces nucleotide modifications into its ribosomal RNA. We have previously found that the bacterium contains a Carbon-5 methylation on cytidine 2499 of its 23S ribosomal RNA, which is so far the only modified version of cytidine 2...

  16. Spectroscopy, Crystal and Molecular Structures of New 4-Acylpyrazolone Dinitrophenylhydrazones

    Directory of Open Access Journals (Sweden)

    Omoruyi G. Idemudia

    2016-10-01

    Full Text Available Still looking at the development of new materials with unique properties and taking advantage of the nucleophilic properties of amines to form stable azomethines, dinitrophenylhydrazine was reacted with 4-ethyl-5-methyl-2-phenyl-pyrazol-3-one and then with 4-propyl-5-methyl-2-phenyl-pyrazol-3-one to get 4-ethyl-5-methyl-2-phenyl-pyrazol-3-one dinitrophenylhydrazone (Empp-Dh and 4-propyl-5-methyl-2-phenyl-pyrazol-3-one dinitrophenylhydrazone (Pmpp-Dh, respectively, via a simple condensation reaction in a one-pot synthesis system. Careful interpretations of results from elemental analysis, mass and NMR spectroscopy were in agreement with single-crystal X-ray diffraction data. Reported Schiff bases in their single-crystal solid state exist in imine keto tautomer form, each crystallizing in a monoclinic crystal system, with a space group of C2/c (No. 15 in Empp-Dh and P21/c (No. 14 in Pmpp-Dh. They have extensive intra- and inter-molecular hydrogen as well as C–H···π-ring interactions.

  17. On the total synthesis of terpenes containing quaternary stereocenters : Stereoselective synthesis of the taiwaniaquinoids, mastigophorene A, and tuberculosinyl adenosine

    NARCIS (Netherlands)

    Buter, Jeffrey

    2016-01-01

    Dit proefschrift beschrijft de stereoselectieve synthese van natuurstoffen. Allereerst is de synthese van mycoketide beschreven, en de daaropvolgende analyse met NMR-spectroscopie. De analyse heeft bijgedragen aan het opstellen van een voorspelmodel voor natuurproducten die het 1,5-methyl raamwerk b

  18. [C-11]FMAU and [F-18]FHPG as PET tracers for herpes simplex virus thymidine kinase enzyme activity and human cytomegalovirus infections

    NARCIS (Netherlands)

    de Vries, EFJ; van Waarde, A; Harmsen, MC; Mulder, NH; Vaalburg, W; Hospers, GAP

    [C-11]-2'-Fluoro-5-methyl-1-beta-D-arabinofuranosyluracil ([C-11]FMAU) and [F-18]-9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]guanine ([F-18]FHPG), radiolabeled representatives of two classes of antiviral agents, were evaluated as tracers for measuring herpes simplex virus thymidine kinase (HSV-tk)

  19. Synthesis and characterization of related substances of Azilsartan Kamedoxomil

    Directory of Open Access Journals (Sweden)

    Maddi N. V. D. Harikiran

    2017-03-01

    Full Text Available Azilsartan Kamedoxomil is an AT1-subtype angiotensin II receptor blocker (ARB. During the laboratory synthesis of Azilsartan Kamedoxomil, four related substances of Azilsartan Kamedoxomil were observed and identified. These were 2-Ethoxy-3-[[4-[2- [4-[(5-methyl-2-oxo-1,3-dioxol-4-ylmethyl]-5-oxo-1,2,4-oxadiazol-3-yl]phenyl]phenyl] methyl] benzimidazole-4-carboxylic acid (azilsartan N-medoxomil, 9, (5-methyl-2-oxo- 1,3-dioxol-4-ylmethyl 2-ethoxy-3-[[4-[2-[4-[(5-methyl-2-oxo-1,3-dioxol-4-ylmethyl]-5- oxo-1,2,4-oxadiazol-3-yl]phenyl]phenyl] methyl] benzimidazole-4-carboxylate (azilsartan dimedoxomil, 10, (5-methyl-2-oxo-1,3-dioxo-4-ylmethyl 1-[2’-(4,5-dihydro-5-oxo-4H- 1,2,4-oxadiazol-3-ylbiphenyl-4-yl]methyl]-2-methoxy-1H-benzimidazole-7-carboxylate (methoxy analogue of azilsartan medoxomil, 11, Methyl 1-((2’-amidobiphenyl-4-yl methyl-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (amide methyl ester, 12. The present work describes the origin, synthesis and characterization of these related substances.

  20. Two aurone glycosides from heartwood of Pterocarpus santalinus.

    Science.gov (United States)

    Kesari, Achyut Narayan; Gupta, Rajesh Kumar; Watal, Geeta

    2004-12-01

    Two new aurone glycosides, 6 hydroxy 5 methyl 3',4',5' trimethoxy aurone 4-O-alpha-L-rhamnopyranoside and 6,4' dihydroxy aurone 4-O-rutinoside have been isolated from the ethanolic extract of the wood of Pterocarpus santalinus. Their structures were determined on the basis of chemical and spectroscopic analysis (UV, IR, EIMS, (1)H and (13)C NMR).