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Sample records for 5-methyl uracil

  1. Immunization with Surface Antigen Vaccine Alone and after Treatment with 1-(2-Fluoro-5-Methyl-β-l-Arabinofuranosyl)-Uracil (l-FMAU) Breaks Humoral and Cell-Mediated Immune Tolerance in Chronic Woodchuck Hepatitis Virus Infection

    Menne, Stephan; Roneker, Carol A.; Korba, Brent E.; Gerin, John L.; Tennant, Bud C.; Cote, Paul J

    2002-01-01

    Woodchucks chronically infected with the woodchuck hepatitis virus (WHV) were treated with the antiviral drug 1-(2-fluoro-5-methyl-β-l-arabinofuranosyl)-uracil (l-FMAU) or placebo for 32 weeks. Half the woodchucks in each group then received four injections of surface antigen vaccine during the next 16 weeks. Vaccination alone elicited a low-level antibody response to surface antigen in most carriers but did not affect serum WHV DNA and surface antigen. Carriers treated first with l-FMAU to r...

  2. Multiphoton ionization of Uracil

    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.

  3. Vibrational properties of uracil

    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.

  4. In search of uracil derivatives as bioactive agents. Uracils and fused uracils: Synthesis, biological activity and applications.

    Pałasz, Aleksandra; Cież, Dariusz

    2015-06-01

    This review article is an effort to summarize recent developments in researches providing uracil derivatives with promising biological potential. This article also aims to discuss potential future directions on the development of more potent and specific uracil analogues for various biological targets. Uracils are considered as privileged structures in drug discovery with a wide array of biological activities and synthetic accessibility. Antiviral and anti-tumour are the two most widely reported activities of uracil analogues however they also possess herbicidal, insecticidal and bactericidal activities. Their antiviral potential is based on the inhibition of key step in viral replication pathway resulting in potent activities against HIV, hepatitis B and C, the herpes viruses etc. Uracil derivatives such as 5-fluorouracil or 5-chlorouracil were the first pharmacological active derivatives to be generated. Poor selectivity limits its therapeutic application, resulting in high incidences of gastrointestinal tract or central nervous toxicity. Numerous modifications of uracil structure have been performed to tackle these problems resulting in the development of derivatives exhibiting better pharmacological and pharmacokinetic properties including increased bioactivity, selectivity, metabolic stability, absorption and lower toxicity. Researches of new uracils and fused uracil derivatives as bioactive agents are related with modifications of substituents at N(1), N(3), C(5) and C(6) positions of pyrimidine ring. This review is an endeavour to highlight the progress in the chemistry and biological activity of the uracils, predominately after the year 2000. In particular are presented synthetic methods and biological study for such analogues as: 5-fluorouracil or 5-chlorouracil derivatives, tegafur analogues, arabinopyranonucleosides of uracil, glucopyranonucleosides of uracil, liposidomycins, caprazamycins or tunicamycins, tritylated uridine analogues, nitro or cyano

  5. Genomic uracil and human disease

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

    2006-01-01

    Uracil is present in small amounts in DNA due to spontaneous deamination of cytosine and incorporation of dUMP during replication. While deamination generates mutagenic U:G mismatches, incorporated dUMP results in U:A pairs that are not directly mutagenic, but may be cytotoxic. In most cells, mut...

  6. Influence of the products of radiolysis of uracil and thymidine on the biosynthesis of DNA of Ehrlich's ascites cells

    Polverelli, M.; Teoule, R.

    1972-09-01

    From ninth annual meeting of the European society for Radiation Biology; Rome, Italy (26 8ep 1972). The effect of gamma radiolysis products in aqueous solution of uracil and thymidine on the normal replicative biosynthesis of DNA of Ehrlich's ascites cells incubated in vitro in the presence of radioactive precursors of DNA (/sup 14/C-methyl thymidine or (/sup 14/C/sub 2/-d esoxyrytidine) was studied. The inhibiting effect of the thymidine radiolysis products, desoxy-2' - BETA -D-ribofuranosyl-1-hydroxy-5methyl-5-barbituric acid and hydroxy-6-dihydro-5, 6-thymidine, and the uracil radiolysis products, alloxanne and parabanic acid, was shown. (JSR)

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

    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...

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

    Pena Diaz, Javier; Akbari, Mansour; Sundheim, Ottar; Farez-Vidal, M Esther; Andersen, Sonja; Sneve, Ragnhild; Gonzalez-Pacanowska, Dolores; Krokan, Hans E; Slupphaug, Geir

    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 (d......UTPase) and a uracil-DNA glycosylase belonging to the highly conserved UNG-family. Uracil-DNA glycosylase activities excise uracil from DNA and initiate a multistep base-excision repair (BER) pathway to restore the correct nucleotide sequence. Here we report the biochemical characterisation of T.cruzi UNG (Tc......UNG) and its contribution to the total uracil repair activity in T.cruzi. TcUNG is shown to be the major uracil-DNA glycosylase in T.cruzi. The purified recombinant TcUNG exhibits substrate preference for removal of uracil in the order ssU>U:G>U:A, and has no associated thymine-DNA glycosylase activity. T.cruzi...

  9. Study of proton radiolysis of solid uracil film

    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.

  10. UFT (tegafur-uracil) in rectal cancer

    Casado, E; Pfeiffer, P; Feliu, J; González-Barón, M; Vestermark, L; Jensen, Helle Anita

    2008-01-01

    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 in the......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...

  11. Refining the Neuberger Model: uracil processing by activated B cells

    Maul, Robert W.; Gearhart, Patricia J.

    2014-01-01

    During the immune response, B cells undergo a programmed mutagenic cascade to promote increased affinity and expanded antibody function. The two processes, somatic hypermutation (SHM) and class switch recombination (CSR), are initiated by the protein activation-induced deaminase (AID), which converts cytosine to uracil in the immunoglobulin loci. The presence of uracil in DNA promotes DNA mutagenesis though a subset of DNA repair proteins. Two distinct mechanisms have been proposed to control...

  12. Structures in dissociative electron attachment cross-sections in thymine, uracil and halo-uracils

    The low energy parts (0 - 3 eV) of the dissociative electron attachment (DEA) cross-sections in uracil, thymine, and the halo-uracils 5-BrU, 5-ClU, 6-ClU, 5-FU, have been revisited with an improved energy resolution, focussing onto the puzzling structures observed on most cross-sections of the various anions fragments versus electron energy. The elastic electron scattering cross-sections near zero energy have also been recorded. In most cases they present a few features (cusps) related to the low energy peaks found in DEA cross-sections. Substantial differences are found in the detailed spectra of the fragments produced in 5-ClU and 6-ClU. Several interpretations already proposed to explain the previous observations, in terms of different thresholds and/or contributions of vibrational Feshbach resonances, and their limits, are discussed in the light of our new results. We expect that our more detailed results will stimulate theoretical work for a better understanding of the features observed. (authors)

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

    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......-negative bacterial strains. The phenotype of the uracil phosphoribosyltransferase-deficient strain was established. Surprisingly, the upp strain is resistant only to very low concentrations of 5-fluorouracil. Secondary mutants in thymidine phosphorylase and thymidine kinase were isolated by selection for resistance...

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

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

    2016-01-01

    , repetitive sequences flanking the CHloci, 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...

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

    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

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

    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...

  17. Biochemical Characterization of Uracil Phosphoribosyltransferase from Mycobacterium tuberculosis

    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

  18. Biosynthesis of the human DNA repair enzyme uracil DNA glycosylase

    Anti-human uracil DNA glycosylase monoclonal antibodies have been used to study the in vitro and in vivo biosynthesis of this human base excision repair enzyme. The in vitro translation of poly(A+)uracil DNA glycosylase mRNA was examined by immunoprecipitation of the [35S]methionine-labeled translation products. As identified by sucrose density analysis, immunoreactive in vitro products of 37,000 daltons and 24,000 daltons were translated from 16S poly(A+)RNA and from 11S poly (A+)RNA, respectively. However, only the 37,000 Mr polypeptide could be detected by immunoblot analysis of crude human placental and fibroblast extracts or by immunoprecipitation of [35S] labeled normal human cell extracts. This relative molecular weight correspond to the molecular weight observed for homogeneous human placental uracil DNA glycosylase. A placental mRNA preparation was used to construct a cDNA library in pUC8. Immunological screening identified two recombinant DNA plasmids each containing a 340 base pair insert. Northern blot analysis demonstrated that the insert hybridized to a 16S poly (A+)mRNA. These results suggest that immunoreactive uracil DNA glycosylase protein was synthesized at its enzymatically active molecular weight as the primary translation product of a 16S poly (A+)mRNA

  19. Biochemical characterization of uracil phosphoribosyltransferase from Mycobacterium tuberculosis.

    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.

  20. Defective repair of uracil causes telomere defects in mouse hematopoietic cells.

    Vallabhaneni, Haritha; Zhou, Fang; Maul, Robert W; Sarkar, Jaya; Yin, Jinhu; Lei, Ming; Harrington, Lea; Gearhart, Patricia J; Liu, Yie

    2015-02-27

    Uracil in the genome can result from misincorporation of dUTP instead of dTTP during DNA synthesis, and is primarily removed by uracil DNA glycosylase (UNG) during base excision repair. Telomeres contain long arrays of TTAGGG repeats and may be susceptible to uracil misincorporation. Using model telomeric DNA substrates, we showed that the position and number of uracil substitutions of thymine in telomeric DNA decreased recognition by the telomere single-strand binding protein, POT1. In primary mouse hematopoietic cells, uracil was detectable at telomeres, and UNG deficiency further increased uracil loads and led to abnormal telomere lengthening. In UNG-deficient cells, the frequencies of sister chromatid exchange and fragility in telomeres also significantly increased in the absence of telomerase. Thus, accumulation of uracil and/or UNG deficiency interferes with telomere maintenance, thereby underscoring the necessity of UNG-initiated base excision repair for the preservation of telomere integrity. PMID:25572391

  1. Time-resolved radiation chemistry: Dynamics of electron attachment to uracil following UV excitation of iodide-uracil complexes

    Electron attachment to uracil was investigated by applying time-resolved photoelectron imaging to iodide-uracil (I–U) complexes. In these studies, an ultraviolet pump pulse initiated charge transfer from the iodide to the uracil, and the resulting dynamics of the uracil temporary negative ion were probed. Five different excitation energies were used, 4.00 eV, 4.07 eV, 4.14 eV, 4.21 eV, and 4.66 eV. At the four lowest excitation energies, which lie near the vertical detachment energy of the I–U complex (4.11 eV), signatures of both the dipole bound (DB) as well as the valence bound (VB) anion of uracil were observed. In contrast, only the VB anion was observed at 4.66 eV, in agreement with previous experiments in this higher energy range. The early-time dynamics of both states were highly excitation energy dependent. The rise time of the DB anion signal was ∼250 fs at 4.00 eV and 4.07 eV, ∼120 fs at 4.14 eV and cross-correlation limited at 4.21 eV. The VB anion rise time also changed with excitation energy, ranging from 200 to 300 fs for excitation energies 4.00–4.21 eV, to a cross-correlation limited time at 4.66 eV. The results suggest that the DB state acts as a “doorway” state to the VB anion at 4.00–4.21 eV, while direct attachment to the VB anion occurs at 4.66 eV

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

    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.

  3. Targeting tumors with nonreplicating Toxoplasma gondii uracil auxotroph vaccines.

    Fox, Barbara A; Sanders, Kiah L; Chen, Shan; Bzik, David J

    2013-09-01

    Toxoplasma gondii is an intracellular parasite that has evolved to actively control its invaded host cells. Toxoplasma triggers then actively regulates host innate interleukin-12 (IL-12) and interferon-γ (IFN-γ) responses that elicit T cell control of infection. A live, nonreplicating avirulent uracil auxotroph vaccine strain (cps) of Toxoplasma triggers novel innate immune responses that stimulate amplified CD8(+) T cell responses and life-long immunity in vaccinated mice. Here, we review recent reports showing that intratumoral treatment with cps activated immune-mediated regression of established solid tumors in mice. We speculate that a better understanding of host-parasite interaction at the molecular level and applying improved genetic models based on Δku80 Toxoplasma strains will stimulate development of highly effective immunotherapeutic cancer vaccine strategies using engineered uracil auxotrophs. PMID:23928100

  4. Targeting tumors with nonreplicating Toxoplasma gondii uracil auxotroph vaccines

    Fox, Barbara A.; Sanders, Kiah L; Chen, Shan; Bzik, David J.

    2013-01-01

    Toxoplasma gondii is an intracellular parasite that has evolved to actively control its invaded host cells. Toxoplasma triggers then actively regulates host innate IL-12 and interferon-γ responses that elicit T cell control of infection. A live, nonreplicating avirulent uracil auxotroph vaccine strain (cps) of Toxoplasma triggers novel innate immune responses that stimulate amplified CD8+ T cell responses and life-long immunity in vaccinated mice. Here, we review recent reports showing that i...

  5. Perturbations of enzymic uracil excision due to purine damage in DNA.

    Duker, N J; Jensen, D E; Hart, D M; Fishbein, D E

    1982-01-01

    Phage PBS-2 DNA, which contains uracil in place of thymine, was selectively damaged and then used as substrate for purified Bacillus subtilis uracil-DNA glycosylase. This enzyme releases uracil from DNA in a limited processive manner. Irradiation by ultraviolet light (greater than 305 nm) in the presence of isopropanol and a free radical photoinitiator introduced covalently bound 8-(2-hydroxy-2-propyl)purines into DNA. Methylation by dimethylsulfate yielded 7-methylguanine. Apurinic sites wer...

  6. Molecular cloning of human uracil-DNA glycosylase, a highly conserved DNA repair enzyme.

    Olsen, L C; Aasland, R; Wittwer, C U; Krokan, H E; Helland, D E

    1989-01-01

    Uracil-DNA glycosylase is the DNA repair enzyme responsible for the removal of uracil from DNA, and it is present in all organisms investigated. Here we report on the cloning and sequencing of a cDNA encoding the human uracil-DNA glycosylase. The sequences of uracil-DNA glycosylases from yeast, Escherichia coli, herpes simplex virus type 1 and 2, and homologous genes from varicella-zoster and Epstein-Barr viruses are known. It is shown in this report that the predicted amino acid sequence of ...

  7. Synthesis and triplex formation of oligonucleotides containing 8-thioxodeoxyadenosine and 5-methyl-2-thiodeoxycytosine.

    Ohkubo, Akihiro; Miyata, Kenichi; Tsunoda, Hirosuke; Seio, Kohji; Sekine, Mitsuo

    2009-01-01

    For more effective DNA triplex formation under neutral conditions, we synthesized triplex-forming oligonucleotides (TFO) containing 8-thioxodeoxyadenine (s(8)A) residues in place of the protonated cytosines (Cs) required for the third base pairing with DNA duplexes. Consequently, it was found that s(8)A exhibited much stronger hybridization ability than C under neutral conditions when four s(8)A bases were arranged in a consecutive sequence. Moreover, we also synthesized TFOs containing 5-methyl-2-thiocytosines and examined their ability of triplex formation. PMID:19749240

  8. H. atom and OH. radical reactions with 5-methyl-cytosine

    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. atom and OH. radical addition to positions C5 and C6 of 5-MeCyt, or OH. 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. atom additions and 1 kCal/mol for the reactions involving the OH. radical. Thermodynamically, the two C6 radical adducts and the H.- 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)

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

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

    2015-01-01

    produces β-carotene to optimize assembly junctions and the uracil excision protocol. By combining uracil excision cloning with a genomic integration technology, we demonstrate that up to six DNA fragments can be assembled in a one-tube reaction for direct genome integration with high accuracy, greatly...

  10. G-quadruplex DNA structures can interfere with uracil glycosylase activity in vitro.

    Holton, Nate W; Larson, Erik D

    2016-07-01

    Genome sequences that contain tandem repeats of guanine can form stable four-stranded structures known as G-quadruplex, or G4 DNA. While the molecular mechanisms are not fully defined, such guanine-rich loci are prone to mutagenesis and recombination. Various repair pathways function to reduce the potential for genome instability by correcting base damage and replication errors; however, it is not yet fully defined how well these processes function at G4 DNA. One frequent form of base damage occurs from cytidine deamination, resulting in deoxyuracil and UG mismatches. In duplex and single-stranded DNA, uracil bases are recognised and excised by uracil glycosylases. Here, we tested the efficiency of uracil glycosylase activity in vitro on uracil bases located directly adjacent to guanine repeats and G4 DNA. We show that uracil excision by bacterial UDG and human hUNG2 is reduced at uracils positioned directly 5' or 3' of a guanine tetrad. Control reactions using oligonucleotides disrupted for G4 formation or reaction conditions that do not favour G4 formation resulted in full uracil excision activity. Based on these in vitro results, we suggest that folding of guanine-rich DNA into G4 DNA results in a DNA conformation that is resistant to uracil glycosylase-initiated repair and this has the potential to increase the risk of instability at guanine repeats in the genome. PMID:26671821

  11. The application of molecular dynamics in the uracil

    Under the (N, V, T) system, the position, speed, strength and direction of under stress and the changes of bond distance and bond angle of the evolution of each atom in uracil molecule are calculated by using the semiempirical molecular dynamics. The calculations come to the conclusions which are difficult or failed to be obtained on the microcosmic information of particles during the experiment be- cause of the limit of today's technology. It is to provide the theoretical basis that will go a step further to know molecular inner dynamics. (authors)

  12. 2-Amino-5-methyl­pyridinium 2-hy­droxy­benzoate

    Quah, Ching Kheng; Hemamalini, Madhukar; Fun, Hoong-Kun

    2010-01-01

    In the title compound, C6H9N2 +·C7H5O3 −, the protonated 2-amino-5-methyl­pyridinium cation and the 2-hy­droxy­benzoate anion are both essentially planar, with maximum deviations of 0.026 (2) and 0.034 (1) Å, respectively. The anion is stabilized by an intra­molecular O—H⋯O hydrogen bond, which forms an S(6) ring motif. In the solid state, the anions are linked to the cations via pairs of inter­molecular N—H⋯O hydrogen bonds forming R 2 2(8) ring motifs. The crystal structure is further stabi...

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

    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.

  14. Density Functional Theory for the Photoionization Dynamics of Uracil

    Toffoli, D; Gianturco, F A; Lucchese, R R

    2007-01-01

    Photoionization dynamics of the RNA base Uracil is studied in the framework of Density Functional Theory (DFT). The photoionization calculations take advantage of a newly developed parallel version of a multicentric approach to the calculation of the electronic continuum spectrum which uses a set of B-spline radial basis functions and a Kohn-Sham density functional hamiltonian. Both valence and core ionizations are considered. Scattering resonances in selected single-particle ionization channels are classified by the symmetry of the resonant state and the peak energy position in the photoelectron kinetic energy scale; the present results highlight once more the site specificity of core ionization processes. We further suggest that the resonant structures previously characterized in low-energy electron collision experiments are partly shifted below threshold by the photoionization processes. A critical evaluation of the theoretical results providing a guide for future experimental work on similar biosystems.

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

    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.

  16. The role of the environment in the ion induced fragmentation of uracil.

    Markush, Pal; Bolognesi, Paola; Cartoni, Antonella; Rousseau, Patrick; Maclot, Sylvain; Delaunay, Rudy; Domaracka, Alicja; Kocisek, Jaroslav; Castrovilli, Mattea C; Huber, Bernd A; Avaldi, Lorenzo

    2016-06-22

    The fragmentation of uracil molecules and pure and nano-hydrated uracil clusters by (12)C(4+) ion impact is investigated. This work focuses on the fragmentation behavior of complex systems and the effect of the environment. On the one hand, it is found that the environment in the form of surrounding uracil or water molecules has a significant influence on the fragmentation dynamics, providing an overall 'protective' effect, while on the other hand we observe the opening of specific fragmentation channels. In particular, we report on the first observation of a series of hydrated fragments. This indicates a strong interaction between uracil and water molecules, holding the water clusters bound to the observed molecular fragments. PMID:27271080

  17. Synthesis, structure and biological activity of nickel(II) complexes of 5-methyl 2-furfural thiosemicarbazone.

    Jouad, E M; Larcher, G; Allain, M; Riou, A; Bouet, G M; Khan, M A; Thanh, X D

    2001-09-01

    5-Methyl 2-furfuraldehyde thiosemicarbazone (M5HFTSC) with nickel(II) leads to three types of complexes: [Ni(M5HFTSC)(2)X(2)], [Ni(M5FTSC)(2)] and [Ni(M5FTSC)(2)] x 2DMF. In the first type the ligand remains in thione form, while in the two other, the anionic thiolato form is involved. The species [Ni(M5HFTSC)(2)X(2)] has been characterized spectroscopically. The structures of [Ni(M5FTSC)(2)] x 2DMF and [Ni(M5FTSC)(2)] have been solved using X-ray diffraction. Biological studies of [Ni(M5HFTSC)(2)Cl(2)] have been carried out in vitro for antifungal activity on human pathogenic fungi, Aspergillus fumigatus and Candida albicans, and in vivo for toxicity on mice. The results are compared to those of the ligand, the metal salt and a similar copper complex [Cu(M5HFTSC)Cl(2)]. PMID:11566328

  18. Molecular characterization of methanogenic N(5)-methyl-tetrahydromethanopterin: Coenzyme M methyltransferase.

    Upadhyay, Vikrant; Ceh, Katharina; Tumulka, Franz; Abele, Rupert; Hoffmann, Jan; Langer, Julian; Shima, Seigo; Ermler, Ulrich

    2016-09-01

    Methanogenic archaea share one ion gradient forming reaction in their energy metabolism catalyzed by the membrane-spanning multisubunit complex N(5)-methyl-tetrahydromethanopterin: coenzyme M methyltransferase (MtrABCDEFGH or simply Mtr). In this reaction the methyl group transfer from methyl-tetrahydromethanopterin to coenzyme M mediated by cobalamin is coupled with the vectorial translocation of Na(+) across the cytoplasmic membrane. No detailed structural and mechanistic data are reported about this process. In the present work we describe a procedure to provide a highly pure and homogenous Mtr complex on the basis of a selective removal of the only soluble subunit MtrH with the membrane perturbing agent dimethyl maleic anhydride and a subsequent two-step chromatographic purification. A molecular mass determination of the Mtr complex by laser induced liquid bead ion desorption mass spectrometry (LILBID-MS) and size exclusion chromatography coupled with multi-angle light scattering (SEC-MALS) resulted in a (MtrABCDEFG)3 heterotrimeric complex of ca. 430kDa with both techniques. Taking into account that the membrane protein complex contains various firmly bound small molecules, predominantly detergent molecules, the stoichiometry of the subunits is most likely 1:1. A schematic model for the subunit arrangement within the MtrABCDEFG protomer was deduced from the mass of Mtr subcomplexes obtained by harsh IR-laser LILBID-MS. PMID:27342374

  19. Simultaneous determination of 2-furfural and 5-methyl-2-furfural using corona discharge ion mobility spectrometry.

    Jafari, M T; Khayamian, T

    2009-06-01

    A novel technique, corona discharge ion mobility spectrometry (CD-IMS), was developed for the qualitative and quantitative determination of 2-furfural (F) and 5-methyl-2-furfural (MF) in aqueous solutions. The limits of detection (LODs) were 5.3 x 10(-3) microg/mL for F and 6.7 x 10(-3) microg/mL for MF. The linear dynamic ranges of 1.16 x 10(-2) to 1.04 microg/mL and 2.20 x 10(-2) to 1.10 microg/mL were obtained for F and MF, respectively. The relative standard deviation was below 12% for both compounds. In addition to analysis of the individual compound, simultaneous determination of F and MF was also investigated. It was realized that F imposes a matrix effect on the MF signal and vice versa. The standard addition method was used to deal with the matrix effect. The recovery of the compounds in the synthetic samples validates the capability of the method. PMID:19531891

  20. Syntheses of [5-2H]-uracil, [5-2H]-cytosine, [6-2H]-uracil and [6-2H]-cytosine

    Syntheses of [5-2H]-, [6-2H]-uracil and [5-2H]-, [6-2H]-cytosine were investigated. The catalytic reaction of uracil or cytosine with 2H2 gas in alkaline media gave rise to [6-2H]-compounds almost exclusively. On the other hand, the reaction of 5-bromouracil or 5-bromocytosine with 2H2 gas gave rise to a mixture of [5-2H]-, [6-2H]- and [5-2H, 6-2H]-compounds depending on the experimental conditions. By controlling the temperature, the pressure of 2H2 gas and the amount of catalyst, [5-2H]-uracil and [5-2H]-cytosine were obtained. The isotopic distribution in each product was measured by 1H NMR spectroscopy combined with an HPLC method. (author)

  1. New Family of Deamination Repair Enzymes in Uracil-DNA Glycosylase Superfamily*

    Lee, Hyun-Wook; Dominy, Brian N.; Cao, Weiguo

    2011-01-01

    DNA glycosylases play a major role in the repair of deaminated DNA damage. Previous investigations identified five families within the uracil-DNA glycosylase (UDG) superfamily. All enzymes within the superfamily studied thus far exhibit uracil-DNA glycosylase activity. Here we identify a new class of DNA glycosylases in the UDG superfamily that lacks UDG activity. Instead, these enzymes act as hypoxanthine-DNA glycosylases in vitro and in vivo. Molecular modeling and structure-guided mutation...

  2. Structure of uracil-DNA glycosylase from Mycobacterium tuberculosis: insights into interactions with ligands

    The molecule of uracil-DNA glycosylase from M. tuberculosis exhibits domain motion on binding to DNA or a proteinaceous inhibitor. The highly conserved DNA-binding region interacts with a citrate ion in the structure. Uracil N-glycosylase (Ung) is the most thoroughly studied of the group of uracil DNA-glycosylase (UDG) enzymes that catalyse the first step in the uracil excision-repair pathway. The overall structure of the enzyme from Mycobacterium tuberculosis is essentially the same as that of the enzyme from other sources. However, differences exist in the N- and C-terminal stretches and some catalytic loops. Comparison with appropriate structures indicate that the two-domain enzyme closes slightly when binding to DNA, while it opens slightly when binding to the proteinaceous inhibitor Ugi. The structural changes in the catalytic loops on complexation reflect the special features of their structure in the mycobacterial protein. A comparative analysis of available sequences of the enzyme from different sources indicates high conservation of amino-acid residues in the catalytic loops. The uracil-binding pocket in the structure is occupied by a citrate ion. The interactions of the citrate ion with the protein mimic those of uracil, in addition to providing insights into other possible interactions that inhibitors could be involved in

  3. Hydrogen abstraction from deoxyribose by a neighboring 3'-uracil peroxyl radical.

    Schyman, Patric; Eriksson, Leif A; Laaksonen, Aatto

    2009-05-01

    Theoretical examination of the reactivity of the uracil-5-peroxyl radical when abstracting a hydrogen atom from a neighboring 5'-deoxyribose in 5'-ApU-5-peroxyl-3' has been performed using density functional theory with the MPWB1K functional. Halogenated uracils are often used as radiosensitizers in DNA since the reactive uracil-5-yl radical is formed upon radiation and is known to create strand break and alkali-labile sites. Under aerobic conditions, such as in the cell, it has been proposed that the uracil-5-peroxyl radical is formed and would be the damaging agent. Our results show low reactivity for the uracil-5-peroxyl radical, determined by calculating the activation and reaction energies for the plausible hydrogen abstraction sites C1', C2', and C3' of the neighboring 5'-deoxyribose. These findings support the hypothesis that hydrogen abstraction primarily occurs by the uracil-5-yl radical, also under aerobic conditions, prior to formation of the peroxyl radical. PMID:19402732

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

    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. PMID:27075054

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

    Density-functional theory calculations are used to investigate the interaction of Al12N12 and B12N12 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 Al12N12 and B12N12. It is observed that B12N12 is highly sensitive to adenine, uracil, and cytosine compared with Al12N12 to serve as a biochemical sensor.

  6. Prebiotic synthesis of 5-substituted uracils: a bridge between the RNA world and the DNA-protein world

    Robertson, M. P.; Miller, S. L.

    1995-01-01

    Under prebiotic conditions, formaldehyde adds to uracil at the C-5 position to produce 5-hydroxymethyluracil with favorable rates and equilibria. Hydroxymethyluracil adds a variety of nucleophiles, such as ammonia, glycine, guanidine, hydrogen sulfide, hydrogen cyanide, imidazole, indole, and phenol, to give 5-substituted uracils with the side chains of most of the 20 amino acids in proteins. These reactions are sufficiently robust that, if uracil had been present on the primitive Earth, then these substituted uracils would also have been present. The ribozymes of the RNA world would have included many of the functional groups found in proteins today, and their catalytic activities may have been considerably greater than presently assumed.

  7. Isolation and identification of 5-hydroxyl-5-methyl-2-hexenoic acid from Actinoplanes sp. HBDN08 with antifungal activity.

    Zhang, Ji; Wang, Xiang-Jing; Yan, Yi-Jun; Jiang, Ling; Wang, Ji-Dong; Li, Bao-Ju; Xiang, Wen-Sheng

    2010-11-01

    A bioactivity-guided approach was employed to isolate and determine the chemical identity of bioactive constituents with antifungal activity from Actinoplanes sp. HBDN08. The structure of the antifungal metabolite was elucidated as 5-hydroxyl-5-methyl-2-hexenoic acid on the basis of spectral analysis. This compound showed strong in vitro antifungal activity against Botrytis cinerea, Cladosporium cucumerinum and Corynespora cassiicola, with an IC(50) of 32.45, 27.17, and 30.66 mg/L, respectively; however, it only moderately inhibited hyphal growth of Rhizoctonia solani with an IC(50) of 61.64 mg/L. The in vivo antifungal activity under greenhouse conditions demonstrated that 5-hydroxyl-5-methyl-2-hexenoic acid could effectively control the diseases caused by B. cinerea, C. cucumerinum and C. cassiicola with 71.42%, 78.63% and 65.13% control values at 350 mg/L, respectively. This strong antifungal activity suggests that 5-hydroxyl-5-methyl-2-hexenoic acid might be a promising candidate for new antifungal agents. PMID:20584599

  8. Synthesis of labeled 5-hydroxy-6-methyl(4,6-14C)uracil

    β-Uramino(1,3-14C)crotonic ester is prepared for the first time by condensation of urea with labeled (2,4-14C)acetoacetic ester in the presence of ethanol and concentrated HCl. Treatment of β-uramino(1,3-14C)crotonic ester with base gives the Na salt of β-uramino(1,3-14C)crotonic acid. Hydrolysis of the above acid by HCl at 65 degrees gives 6-methyl(4,6-14C)uracil. The oxidation of 6-methyl(4,6-14C)uracil by solid ammonium persulfate in basic solution at 40-70 degrees C gives the intermediate 6-methyl(4,6-14C)uracil-5-ammonium sulfate in 35% yield with 99-100% purity. Hydrolysis of pure 6-methyl(4,6-14C)uracil-5-ammonium sulfate by H2SO4 at 85-95 degrees C gives 5-hydroxy-6-methyl(4,6-14C)uracil in 95-100% yield with 99-100% purity. The product purity is proved by TLC, melting point, elemental analysis, and IR, UV, and PMR spectra

  9. Nanohydration of uracil: emergence of three-dimensional structures and proton-induced charge transfer.

    Bacchus-Montabonel, Marie-Christine; Calvo, Florent

    2015-04-21

    Stepwise hydration of uracil has been theoretically revisited using different methods ranging from classical force fields to quantum chemical approaches. Hydration initially begins within the uracil plane but proceeds at four molecules into three-dimensional configurations or even water clusters next to the nucleobase. The relative stability between the various structures is significantly affected by zero-point energy and finite temperature (entropy) effects and also gives rise to markedly different responses to an excitation by an impinging high-energy proton. In particular, charge transfer to the molecular complex is dramatically altered in collisions toward the coating cluster but barely modified for peripheral hydration patterns. PMID:25793649

  10. Uracil-DNA glycosylase-deficient yeast exhibit a mitochondrial mutator phenotype

    Chatterjee, Aditi; Keshav K Singh

    2001-01-01

    Mutations in mitochondrial DNA (mtDNA) have been reported in cancer and are involved in the pathogenesis of many mitochondrial diseases. Uracil-DNA glycosylase, encoded by the UNG1 gene in Saccharomyces cerevisiae, repairs uracil in DNA formed due to deamination of cytosine. Our study demonstrates that inactivation of the UNG1 gene leads to at least a 3-fold increased frequency of mutations in mtDNA compared with the wild-type. Using a Ung1p–green fluorescent protein (GFP) fusion construct, w...

  11. Review of photodynamic therapy with 5-methyl aminolevulinate in actinic keratosis, epidermoid carcinoma and basal cell carcinoma

    A bibliographic review was conduced on the use of 5-methyl aminolevulinate in dermatology, specifically in the treatment of actinic keratosis, epidermoid carcinoma and basal cell carcinoma. The basic fundamentals of photodynamic therapy are described. The preparation and method of use of photodynamic therapy with 5-methyl aminolevulinate (MAL-PDT) are detailed. The clinical studies that were realized with photodynamic therapy for the treatment of actinic keratosis, epidermoid carcinoma and basal cell carcinoma are mentioned. Different photo-inducible agents and other current therapeutic options of first-line are compared. The MAL-PDT has have the advantage of to present less side effects and the same have been more tolerable than liquid nitrogen and 5 fluorouracil. The MAL-PDT has been considered as an effective option for the treatment of Bowen's disease. Invasive epidermoid carcinoma has existed without evidence to support the routine use of this therapeutic. For superficial basal cell carcinoma, the MAL-PDT has presented a high cure rate and transient and manageable side effects in extensive and multiple lesions. The MAL-PDT has been an effective and safe treatment in patients with basal cell carcinoma, for those with less depth of 2mm. The MAL-PDT could play an important role in the field of prevention with immunosuppressed patients, particularly, those that have required transplant and its immunosuppression has been pharmacological. The use or not of the MAL-PDT, should be evaluated individually for each patient and to have suitable characteristics for each disease that was cited in this review. The photodynamic therapy with 5-methyl aminolevulinate has been a therapeutic modality of considerable economy, however, it should be evaluated in the context of number of inquiries and side effects that have offered other therapeutic modalities

  12. A convenient, high-yield synthesis of 1-substituted uracil and thymine derivatives

    Rejman, Dominik; Kovačková, Soňa; Pohl, Radek; Rosenberg, Ivan

    Manchester : University of Manchester, 2009. s. 70-70. [Nucleic Acids at the Chemistry - Biology Interface. 07.09.2009-08.09.2009, Manchester] R&D Projects: GA MZd NR9138; GA MŠk 2B06065 Institutional research plan: CEZ:AV0Z40550506 Keywords : uracil * thymin Subject RIV: CC - Organic Chemistry

  13. Tautomerism and polarizability in uracil: coupled cluster and density-functional theory study

    Millefiori, S.; Alparone, A

    2004-08-02

    Geometries, relative stabilities, static, dynamic and vibrational polarizabilities of the six uracil tautomers were calculated by coupled cluster (CCSD, CCSD(T)) and DFT B97-1 and PBE1PBE functionals in vacuo and in solution. The dioxo structure is invariably the neutral ground state of uracil, with the lowest energy keto-enol form about 11 kcal/mol less stable. The polarizability behaviour of the uracil tautomers has been characterized by computing static and dynamic values, vibrational contributions and solvent effects. Our best static gas-phase electronic CCSD(T)/aug-cc-pVDZ dipole polarizability of uracil is reported to be 70.22 a.u. Dynamic ({omega}=0.10 a.u.) and vibrational contributions are significant, amounting to ca. 10% and 20%, respectively, of the static <{alpha}{sup e}> value. Solvent effects, investigated with the polarizable continuum model, show that both the static electronic and vibrational polarizabilities increase noticeably on passing from gas phase to solution, the {alpha}{sup v}/{alpha}{sup e} ratio being higher in solution than in vacuo. The throughout excellent agreement between CC and DFT results is worth noting.

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

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

    2009-01-01

    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...

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

    Linde, Lise; Jensen, Kaj Frank

    1996-01-01

    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......-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...

  16. Thermodynamic Potential for the Abiotic Synthesis of Adenine, Cytosine, Guanine, Thymine, Uracil, Ribose, and Deoxyribose in Hydrothermal Systems

    LaRowe, D.E.; Regnier, P.

    2008-01-01

    The thermodynamic potential for the abiotic synthesis of the five common nucleobases (adenine, cytosine, guanine, thymine, and uracil) and two monosaccharides (ribose and deoxyribose) from formaldehyde and hydrogen cyanide has been quantified under temperature, pressure, and bulk composition conditi

  17. Synthesis, potential anticonvulsant and antidepressant effects of 2-(5-methyl-2,3-dioxoindolin-1-ylacetamide derivatives

    Xinghua Zhen

    2015-07-01

    Full Text Available A new series of 2-(5-methyl-2,3-dioxoindolin-1-ylacetamide derivatives were synthesized and evaluated for their anticonvulsive activity in a pentylenetetrazole (PTZ-evoked convulsion model and antidepressant activity in the forced swimming test (FST model. Eleven synthesized compounds were found to be protective against PTZ-induced seizure and showed the anticonvulsant activity. In addition, four of the synthesized compounds (4l, 4m, 4p and 4q showed potent antidepressant-like activity. Among these compounds, compound 4l was found to have the most potent antidepressant-like activity, and significantly reduced the duration of immobility time at 100 mg/kg dose level when compared to the vehicle control, which is similar to the reference drug fluoxetine.

  18. Synthesis, potential anticonvulsant and antidepressant effects of 2-(5-methyl-2,3-dioxoindolin-1-yl)acetamide derivatives.

    Zhen, Xinghua; Peng, Zhou; Zhao, Shuilian; Han, Yan; Jin, Qinghao; Guan, Liping

    2015-07-01

    A new series of 2-(5-methyl-2,3-dioxoindolin-1-yl)acetamide derivatives were synthesized and evaluated for their anticonvulsive activity in a pentylenetetrazole (PTZ)-evoked convulsion model and antidepressant activity in the forced swimming test (FST) model. Eleven synthesized compounds were found to be protective against PTZ-induced seizure and showed the anticonvulsant activity. In addition, four of the synthesized compounds (4l, 4m, 4p and 4q) showed potent antidepressant-like activity. Among these compounds, compound 4l was found to have the most potent antidepressant-like activity, and significantly reduced the duration of immobility time at 100 mg/kg dose level when compared to the vehicle control, which is similar to the reference drug fluoxetine. PMID:26579465

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

    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.

  20. The study of interaction between PFOA/PFOS and uracil by topology quality and spectroscopic analysis

    Xu, Hui-Ying; Zhu, Jian-Qing; Wang, Wei; Xu, Xiao-Lu; Lu, Yin

    2014-02-01

    It has been established that perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) can be considered as emerging persistent organic pollutants. In recent years, there was increasing distribution of PFOA/PFOS in environmental systems, and accumulation and toxic effects of PFOA/PFOS in human body. In this paper, quantum chemistry methods were employed to study the interaction between perfluorinated organic pollutants and base (uracil). The results showed that there were four stable binding modes between the two perfluorinated compounds with uracil, especially the second mode which caused the most detrimental physiological functional response. NBO analysis showed that reactive hydrogen in the two perfluorinated compounds had the greatest effect on the hydrogen bond. The nature of the hydrogen bond formed between the two perfluorinated compounds and base was investigated using the AIM theory. The changes of spectroscopic properties in complexes were analyzed by IR and NMR spectra.

  1. Direct Observation of Triplet-State Population Dynamics in the RNA Uracil Derivative 1-Cyclohexyluracil.

    Brister, Matthew M; Crespo-Hernández, Carlos E

    2015-11-01

    Investigation of the excited-state dynamics in nucleic acid monomers is an area of active research due to the crucial role these early events play in DNA and RNA photodamage. The dynamics and rate at which the triplet state is populated are key mechanistic pathways yet to be fully elucidated. Direct spectroscopic evidence is presented in this contribution for intersystem crossing dynamics in a uracil derivative, 1-cyclohexyluracil. It is shown that intersystem crossing to the triplet manifold occurs in one picosecond or less in acetonitrile solution-at least an order of magnitude faster than previously estimated experimentally. Broadband transient absorption measurements also reveal the primary electronic relaxation pathways of the uracil chromophore, including the absorption spectra of the (1)ππ*, (1)nπ*, and (3)ππ* states and the rates of vibrational cooling in the ground and (3)ππ* states. The experimental results are supported by density functional calculations. PMID:26538051

  2. Uracil incorporation in the forespore and the mother cell during spore development in Bacillus subtilis

    The transcriptional activity of the two genomes of the sporangium during spore formation was determined by pulse-labeling bacteria with 3H-uracil at different times of sporulation and preparing them for high resolution autoradiography. The quantitative analysis of autoradiographs shows that uracile incorporation in the whole sporangium decreases considerably between stages II and IV. However, the variations of the transpcriptional activity are not identical in the mother cell and in the forespore. The one of the mother cell decreases rapidly between stages II and III and then remains stable until the end of stage IV, whereas that of the forespore which is low at stage II increases as the forespore grows ovoid and then quickly diminishes. It is very weak at the beginning of stage IV and negligible at the end of this stage. (orig.)

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

    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.

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

    Lohse, Brian; Vestberg, Robert; Ivanov, Mario Tonev; Hvilsted, Søren; Berg, Rolf Henrik; Ramanujam, P.S.; Hawker, Craig J.

    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...... generation were synthesized and investigated as potential materials for high capacity optical data storage with their dimerization efficiency compared to uracil as a reference compound. This allows the impact of increasing the generation number of the dendrimers, both the number of chromophores, as well as...... irradiated at 257 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....

  5. Characterization of laser-induced plasmas of nucleobases: Uracil and thymine

    In this work, nanosecond laser ablation plasmas generated at 266 and 1064 nm of the two pyrimidine nucleobases uracil and thymine were characterized using time-of-flight mass spectrometry, optical emission spectroscopy and temporally resolved third harmonic generation of a probe laser. This multiple technique approach provides insight into the role played by the irradiation wavelength on the composition and dynamics of plasma species and on the differences between the laser plasmas of the two nucleobases.

  6. Design and synthesis of 5,6-disubstituted uracil derivatives as potent inhibitors of thymidine phosphorylase

    Nencka, Radim; Votruba, Ivan; Hřebabecký, Hubert; Tloušťová, Eva; Horská, Květoslava; Masojídková, Milena; Holý, Antonín

    Praha : ÚOCHB AV ČR, 2005 - (Hocek, M.), s. 441-442 ISBN 80-86241-25-4. - (Collection Symposium Series. 7). [Chemistry of Nucleic Acid Components /13./. Špindlerův Mlýn (CZ), 03.09.2005-09.09.2005] R&D Projects: GA ČR(CZ) GA203/03/0089 Institutional research plan: CEZ:AV0Z40550506 Keywords : thymidine phosphorylase inhibitor * uracil * angiogenesis Subject RIV: CC - Organic Chemistry

  7. A convenient, high-yield synthesis of 1-substituted uracil and thymine derivatives

    Rejman, Dominik; Kovačková, Soňa; Pohl, Radek; Dračínský, Martin; Fiedler, Pavel; Rosenberg, Ivan

    2009-01-01

    Roč. 65, č. 41 (2009), s. 8513-8523. ISSN 0040-4020 R&D Projects: GA MŠk(CZ) LC06077; GA MŠk(CZ) LC06061; GA AV ČR KAN200520801; GA ČR GA203/09/0820; GA MZd NR9138 Institutional research plan: CEZ:AV0Z40550506 Keywords : uracil * thymine Subject RIV: CC - Organic Chemistry Impact factor: 3.219, year: 2009

  8. Dichotomy in regioselectivity of Pd-catalyzed direct C-H arylation of protected uracils

    Čerňová, Miroslava; Hocek, Michal

    Praha : Institute of Organic Chemistry and Biochemistry AS CR, v. v. i., 2011 - (Hocek, M.), s. 314-316 ISBN 978-80-86241-37-1. - (Collection Symposium Series. 12). [ Chemistry of Nucleic Acid Components /15./. Český Krumlov (CZ), 05.06.2011-10.06.2011] R&D Projects: GA MŠk(CZ) LC06077 Institutional research plan: CEZ:AV0Z40550506 Keywords : direct C-H arylation * uracils * pyrimidines * palladium Subject RIV: CC - Organic Chemistry

  9. Ion-forming processes on 248 nm laser excitation of uracil and methyl-monosubstituted uracils: a time-resolved transient conductivity study in aqueous solution

    Uracil, thymine and 1-, 3-, and 6-methyluracil were studied by time-resolved optical and conductometric methods after 248 nm excitation with 20 ns laser pulses. The transient conductivity in argon-saturated aqueous solution, showing a maximum increase (ΔKmax) during the pulse, is ascribed to the generation of hydrated electrons (eaq-) and protons. Biphotonic photoionization as the primary process is inferred from the almost linear dependence of ΔKmax on the square of the laser intensity (IL2). The quantum yield varies by a factor of about two for the five pyrimidines. The neutralization kinetics depends strongly on pH and the concentrations of laser-induced eaq- and H+, i.e. on IL. At pH 6-7 the ΔK signal decays by second-order kinetics. Under argon the electron adds to the (methyl)uracil and neutralization occurs by reaction of the radical anion with a proton, which originates from a fast decay of the radical cation. (author)

  10. 1-(4-Chloro­phen­yl)-3-(5-methyl-2-fur­yl)prop-2-en-1-one

    Guo, Huan-Mei

    2009-01-01

    The title compound, C14H11ClO2, was prepared from 4-chloro­hypnone and 5-methyl­furfural by an aldol condensation reaction. The dihedral angle formed between the two benzene rings is 7.71 (2)°. The crystal structure is stabilized by C—H⋯O inter­actions.

  11. 21 CFR 73.3122 - 4-[(2,4-dimethylphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one.

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false 4- -2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one. 73.3122 Section 73.3122 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION Medical Devices § 73.3122 4-...

  12. 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

    Akbari, M; Otterlei, M; Pena Diaz, Javier; Krokan, H E

    2007-01-01

    proteins also remove the oxidized cytosine derivatives isodialuric acid, alloxan and 5-hydroxyuracil. UNG1 and UNG2 have identical catalytic domain, but different N-terminal regions required for subcellular sorting. We demonstrate that mRNA for UNG1, but not UNG2, is increased after hydrogen peroxide......, 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...... BER processes are differently organized. Furthermore, the upregulation of mRNA for mitochondrial UNG1 after oxidative stress indicates that it may have an important role in repair of oxidized pyrimidines....

  13. Crystal Structure of the Vaccinia Virus Uracil-DNA Glycosylase in Complex with DNA.

    Burmeister, Wim P; Tarbouriech, Nicolas; Fender, Pascal; Contesto-Richefeu, Céline; Peyrefitte, Christophe N; Iseni, Frédéric

    2015-07-17

    Vaccinia virus polymerase holoenzyme is composed of the DNA polymerase catalytic subunit E9 associated with its heterodimeric co-factor A20·D4 required for processive genome synthesis. Although A20 has no known enzymatic activity, D4 is an active uracil-DNA glycosylase (UNG). The presence of a repair enzyme as a component of the viral replication machinery suggests that, for poxviruses, DNA synthesis and base excision repair is coupled. We present the 2.7 Å crystal structure of the complex formed by D4 and the first 50 amino acids of A20 (D4·A201-50) bound to a 10-mer DNA duplex containing an abasic site resulting from the cleavage of a uracil base. Comparison of the viral complex with its human counterpart revealed major divergences in the contacts between protein and DNA and in the enzyme orientation on the DNA. However, the conformation of the dsDNA within both structures is very similar, suggesting a dominant role of the DNA conformation for UNG function. In contrast to human UNG, D4 appears rigid, and we do not observe a conformational change upon DNA binding. We also studied the interaction of D4·A201-50 with different DNA oligomers by surface plasmon resonance. D4 binds weakly to nonspecific DNA and to uracil-containing substrates but binds abasic sites with a Kd of gives new insight into the role of D4 as a co-factor of vaccinia virus DNA polymerase and allows a better understanding of the structural determinants required for UNG action. PMID:26045555

  14. Functionalization of single-walled carbon nanotubes with uracil, guanine, thymine and L-alanine

    Silambarasan, D.; Iyakutti, K.; Vasu, V.

    2014-06-01

    Experimental investigation of functionalization of oxidized single-walled carbon nanotubes (OSWCNTs) with three nucleic acid bases such as uracil, guanine, thymine and one amino acid, L-alanine is carried out. Initially, the SWCNTs are oxidized by acid treatment. Further, the oxidized SWCNTs are effectively functionalized with aforementioned biological compounds by ultrasonication. The diameter of OSWCNTs has increased after the adsorption of biological compounds. The cumulative Π-Π stacking, hydrogen bond and polar interaction are the key factors to realize the adsorption. The amount of adsorption of each biological compound is estimated. The adsorption of guanine is more among all the four biological compounds.

  15. 5-(Pyren-1-yl)uracil UNA monomers: Synthesis, hybridization studies and i-motif stability

    Perlíková, Pavla; Pedersen, E. B.; Wengel, J.

    Praha: Institute of Organic Chemistry and Biochemistry AS CR, v. v. i, 2014 - (Hocek, M.), s. 346-347. (Collection Symposium Series. 14). ISBN 978-80-86241-50-0. [Symposium on Chemistry of Nucleic Acid Components /16./. Český Krumlov (CZ), 08.06.2014-13.06.2014] Grant ostatní: European Research Council(XE) FP7-268776 Institutional support: RVO:61388963 Keywords : 5-(pyren-1-yl)uracil UNA monomers * DNA * unlocked nucleic acids Subject RIV: CC - Organic Chemistry

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

    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.

  17. Escherichia coli-Derived Uracil Increases the Antibacterial Activity and Growth Rate of Lactobacillus plantarum.

    Ha, Eun-Mi

    2016-05-28

    Lactobacillus plantarum (L. plantarum) is a representative probiotic. In particular, L. plantarum is the first commensal bacterium to colonize the intestine of infants. For this reason, the initial settlement of L. plantarum can play an important role in determining an infant's health as well as their eventual health status as an adult. In addition, L. plantarum combats pathogenic infections (such as Escherichia coli (E. coli), one of the early pathogenic colonizers in an unhealthy infant gut) by secreting antimicrobial substances. The aim of this research was to determine how L. plantarum combats E. coli infection and why it is a representative probiotic in the intestine. Consequently, this research observed that E. coli releases uracil. L. plantarum specifically recognizes E. coli-derived uracil, which increases the growth rate and production of antimicrobial substance of L. plantarum. In addition, through the inhibitory activity test, this study postulates that the antimicrobial substance is a protein and can be considered a bacteriocin-like substance. Therefore, this research assumes that L. plantarum exerts its antibacterial ability by recognizing E. coli and increasing its growth rate as a result, and this phenomenon could be one of the reasons for L. plantarum settling in the intestine of infants as a beneficial bacterium. PMID:27012237

  18. Radiation damage to uracil and water by proton and electron impact

    Full text: The inelastic interaction of protons (in the energy range from 20 keV to 150 keV) and electrons (from thermal energies up to 20 eV) with water and uracil, the latter a building block of the RNA has been studied in two laboratories with specially designed experimental setups. These measurements are motivated from a present lack of understanding how on a molecular level damage to living cells and organisms is caused. A unique way of simultaneous detection of the product ions after swift proton (or hydrogen) impact and the analysis of the charge state of the projectile after the collision allows to distinguish between direct ionization (e.g., projectile remains a proton) and electron capture events (e.g., proton becomes neutralized). The latter process turns out to be more destructive, i.e. leads to a higher yield of fragmentation. For electrons both the formation of positively and negatively charged ions has been investigated. We discovered that already thermal electrons lead with a rather large cross section to a dissociation of the uracil molecule producing an anion and a fast hydrogen radical. (author)

  19. Experimental study on the thermochemistry of some amino derivatives of uracil

    Ribeiro da Silva, Manuel A.V., E-mail: risilva@fc.up.pt [Centro de Investigacao em Quimica, Department of Chemistry and Biochemistry, Faculty of Science, University of Porto, Rua do Campo Alegre, 687, P-4169-007 Porto (Portugal); Amaral, Luisa M.P.F.; Szterner, Piotr [Centro de Investigacao em Quimica, Department of Chemistry and Biochemistry, Faculty of Science, University of Porto, Rua do Campo Alegre, 687, P-4169-007 Porto (Portugal)

    2011-11-15

    Highlights: > Combustion calorimetry was used to determine {Delta}{sub f}H{sub m}{sup 0}(cr) of amino derivatives of uracil. > Gas-phase {Delta}{sub f}H{sub m}{sup 0} of amino derivatives of uracil have been derived. > The relative enthalpic stability of the title compounds is discussed in structural terms. - Abstract: Values of the standard (p{sup 0} = 0.1 MPa) molar enthalpy of combustion, {Delta}{sub c}H{sub m}{sup 0}, of four crystalline compounds: 5-aminouracil, 6-aminouracil, 6-amino-1-methyluracil, and 6-amino-1,3-dimethyluracil, were determined, at T = 298.15 K, using a static bomb combustion calorimeter. The values obtained of standard molar enthalpy of combustion were used to derive the standard molar enthalpy of formation of the compounds investigated in their condensed phase and together with literature values of the standard molar enthalpy of sublimation, yielded the standard molar enthalpies of formation in the gaseous phase. These are discussed in terms of the effects of the molecular structure on the relative enthalpic stability.

  20. Hydrogen-Bonding Complexes of 5-Azauracil and Uracil Derivatives in Organic Medium.

    Diez-Martinez, Alba; Kim, Eun-Kyong; Krishnamurthy, Ramanarayanan

    2015-07-17

    Uracil derivatives form strong complexes with complementary 2,4-diaminotriazine and adenine compounds, whereas derivatives of 5-azauracil (2,4-dioxotriazine) are known to form weak complexes in aqueous medium. However, herein we report that in organic medium (CDCl3), the 5-azauracil moiety forms hydrogen-bond-mediated complexes with complementary 2,4-diaminotriazine and adenine compounds, with strengths comparable to those formed by uracil compounds. Such dichotomous base-pairing behavior of the 5-azauracil moiety, in organic versus aqueous media, is found to be consistent with the ionization of the 5-azauracil moiety in aqueous medium leading to competitive interference from water molecules (via solvation), which is absent (lack of such ionization and solvent interference) in organic medium. This discriminating role of solvent (e.g., water) could have been an important factor in the selection of molecules, based on their physicochemical properties, and subsequently in the emergence of potential primordial informational oligomers that would have played a role in the origins of life. PMID:26098835

  1. Solvent Extraction of Platinum (IV) with 4-(4-Ethoxybenzylideneamino)-5-methyl-4H-1,2,4-triazole-3-thiol (EBIMTT) from Hydrochloric Acid Media

    The solvent extraction of platinum (IV) metal from hydrochloric acid media using 4-(4-ethoxybenzylide-neamino)-5-methyl-4H-1,2,4-triazole-3-thiol (EBIMTT) in chloroform was studied as a function of several variables, such as reagent, acid and metal ion concentration, effect of various diluents, and diverse ions. The proposed method was further applied for the separation of platinum (IV) from binary mixtures, synthetic mixtures, alloys and commercially available samples

  2. QSAR study of some 5-methyl/trifluoromethoxy- 1H-indole-2,3-dione-3-thiosemicarbazone derivatives as anti-tubercular agents

    Shahlaei, M.; Fassihi, A.; Nezami, A.

    2009-01-01

    In the present study, quantitative relationships between molecular structure and anti-tubercular activity of some 5-methyl/trifluoromethoxy-1H-indole-2,3-dione-3-thiosemicarbazone derivatives were discovered. The detailed application of an efficient linear method and principal component regression (PCR) for the evaluation of quantitative structure activity relationships of the studied compounds is demonstrated. Components produced by principal component analysis were used as the input for a l...

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

    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...

  4. Design and synthesis of novel 5,6-disubstituted uracil derivatives as potent inhibitors of thymidine phosphorylase

    Nencka, Radim; Votruba, Ivan; Hřebabecký, Hubert; Tloušťová, Eva; Horská, Květoslava; Masojídková, Milena; Holý, Antonín

    2006-01-01

    Roč. 16, č. 5 (2006), s. 1335-1337. ISSN 0960-894X R&D Projects: GA ČR(CZ) GA203/03/0089 Institutional research plan: CEZ:AV0Z40550506 Keywords : thymidine phosphorylase inhibitor * disubstituted uracils * angiogenesis Subject RIV: CC - Organic Chemistry Impact factor: 2.538, year: 2006

  5. Photoinduced electron transfer in a Watson-Crick base-paired, 2-aminopurine:uracil-C60 hydrogen bonding conjugate.

    D'Souza, Francis; Gadde, Suresh; Islam, D-M Shafiqul; Pang, Siew-Cheng; Schumacher, Amy Lea; Zandler, Melvin E; Horie, Rumiko; Araki, Yasuyaki; Ito, Osamu

    2007-02-01

    A fluorescent reporter molecule, 2-aminopurine was self-assembled via Watson-Crick base-pairing to a uracil appended fullerene to form a donor-acceptor conjugate; efficient photoinduced charge separation was confirmed by time-resolved emission and transient absorption spectral studies. PMID:17252101

  6. Differentiation of Neisseria gonorrhoeae isolates requiring proline, citrulline, and uracil by plasmid content, serotyping, and pulsed-field gel electrophoresis.

    Ng, L K; Carballo, M.; Dillon, J A

    1995-01-01

    A combination of DNA macrorestriction analysis using pulsed-field gel electrophoresis and a serotyping method using three panels of monoclonal antibody was used to discriminate 43 epidemiologically unrelated Neisseria gonorrhoeae isolates requiring proline, citrulline, and uracil (PCU-) into 35 groups. This indicates that PCU- isolates of N. gonorrhoeae are not clonal.

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

    An assay has been developed using parasite-specific incorporation of 3H-uracil to assess the intracellular growth of Eimeria tenella in vitro. As shown by both scintillation counts and autoradiography, 3H-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 3H-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 3H-uridine have been introduced as a method of determining whether antiparasitic activity is direct or indirect in relation to effects on the host cell

  8. Thermodynamic potential for the abiotic synthesis of Adenine, Cytosine, Guanine, Thymine, Uracil, Ribose, and Deoxyribose in hydrothermal systems

    Larowe, D. E.; Regnier, P.

    2008-01-01

    The thermodynamic potential for the abiotic synthesis of the five common nucleobases (adenine, cytosine, guanine, thymine, and uracil) and two monosaccharides (ribose and deoxyribose) from formaldehyde and hydrogen cyanide has been quantified under temperature, pressure, and bulk composition conditions that are representative of hydrothermal systems. The activities of the precursor molecules (formaldehyde and hydrogen cyanide) required to evaluate the thermodynamics of biomolecule synthesis w...

  9. Overexpression, purification, crystallization and preliminary X-ray analysis of uracil N-glycosylase from Mycobacterium tuberculosis in complex with a proteinaceous inhibitor

    Uracil N-glycosylase from M. tuberculosis has been crystallized in complex with a proteinaceous inhibitor (Ugi) and X-ray diffraction data have been collected. Uracil N-glycosylase is an enzyme which initiates the pathway of uracil-excision repair of DNA. The enzyme from Mycobacterium tuberculosis was co-expressed with a proteinaceous inhibitor from Bacillus subtilis phage and was crystallized in monoclinic space group C2, with unit-cell parameters a = 201.14, b = 64.27, c = 203.68 Å, β = 109.7°. X-ray data from the crystal have been collected for structure analysis

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

    Toru Ishikawa

    2008-05-01

    Full Text Available 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.

  11. Evaluation of preoperative simultaneous radiochemotherapy combined with carboplatin and tegafur{center_dot}uracil

    Katayama, Akihiro; Nonaka, Satoshi; Bandoh, Nobuyuki; Imada, Masanobu; Hayashi, Tatsuya; Harabuchi, Yasuaki [Asahikawa Medical Coll., Hokkaido (Japan)

    2002-06-01

    We performed preoperative radiochemotherapy including local irradiation with total dose of 40 Gy along with concomitant combination chemotherapy with carboplatin and tegafur(center dot)uracil for 11 head and neck squamous cell carcinomas and evaluated the clinical and histopathological effects as well as the side effects. Seventy-three percent of patients accomplished significant clinical effects equal to or more than PR and significant histopathological effects in surgically resected tissues. Side effects were seen in only one patient with severe hypoleukocytemia, no patients with renal dysfunction, and 34% of patients with severe oral mucositis. These results suggest that our radiochemotherapy may be useful for preoperative treatment for patients with locally advanced head and neck squamous cell carcinomas. (author)

  12. Ultrafast dynamics of uracil and thymine studied using a sub-10 fs deep ultraviolet laser.

    Xue, Bing; Yabushita, Atsushi; Kobayashi, Takayoshi

    2016-06-22

    Single 9.6 fs deep ultraviolet pulses with a spectral range of 255-290 nm are generated by a chirped-pulse four-wave mixing technique for use as pump and probe pulses. The electronic excited state and vibrational dynamics are simultaneously observed for an aqueous solution of uracil and thymine over the full spectral range using a 128-channel lock-in amplifier detector. Two probe photon energy-dependent lifetimes gradually increasing with the probe photon energy are obtained from the decay dynamics data. Ultrafast decay dynamics through the conical intersection is assigned from the first excited ππ* to the final ground state involving the nπ* states. Vibrational modes of the electronic ground state and excited states can be observed, which are strongly coupled to the decay dynamics of the electronic excited state. PMID:27299165

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

    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.

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

    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.

  15. Enantioselective route to 5-methyl- and 5,7-dimethyl-6,7-dihydro-5H-dibenz[c,e]azepine: secondary amines with switchable axial chirality.

    Pira, Silvain L; Wallace, Timothy W; Graham, Jonathan P

    2009-04-01

    (-)-5-Methyl-6,7-dihydro-5H-dibenz[c,e]azepine 4, a new secondary amine featuring an axis-center stereochemical relay, was prepared enantioselectively from 2'-acetylbiphenyl-2-carboxylic acid, using (R)-2-phenylglycinol as an auxiliary for the control of both elements of chirality. The biaryl axis in 4 preferentially adopts the aS-configuration, with the methyl substituent pseudoequatorial, but conversion into the corresponding N-Boc derivative locks the axis into the aR-configuration, as predicted on the basis of molecular mechanics calculations. PMID:19275220

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

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

    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, 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 (B...

  17. γ-Radiolysis of poly(U) in aqueous solution. The role of primary sugar and base radicals in the release of undamaged uracil

    The release of undamaged uracil has been measured after γ-irradiation of aqueous solutions of poly(U). By varying experimental conditions, the respective efficiencies with which OH, H and esub(aq) release uracil were found to be 51, 28 and about 3%. From the determination of G(H2) in acid solutions it is concluded that >= 95% of the H atoms add to the base moiety. It is proposed that the H-adduct radicals (and similarly the OH-adduct radicals) react with the sugar moiety of a different nucleotide. Subsequent reactions of the sugar radicals so formed lead to the release of undamaged uracil. In N2O-saturated solutions the addition of tetranitromethane (TNM) causes a sharp drop in released uracil from G = 2.9 to G = 0.19. The strong suppression of uracil release by TNM is presumably due to its scavenging of the major base radical with the remaining G(uracil release) from 5'-UMP γ-irradiated under N2O is only 0.39, dropping to 0.31 in the presence of TNM. These results on base release are compared with reported data on strand breakage. (author)

  18. Insertional mutagenesis and marker rescue in a protozoan parasite: cloning of the uracil phosphoribosyltransferase locus from Toxoplasma gondii.

    Donald, R G; Roos, D. S.

    1995-01-01

    Nonhomologous integration vectors have been used to demonstrate the feasibility of insertional mutagenesis in haploid tachyzoites of the protozoan parasite Toxoplasma gondii. Mutant clones resistant to 5-fluorouracil were identified at a frequency of approximately 10(-6) (approximately 2 x 10(-5) of the stable transformants). Four independent mutants were isolated, all of which were shown to lack uracil phosphoribosyl-transferase (UPRT) activity and harbor transgenes integrated at closely lin...

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

    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 (function of the photon energy.

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

    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...

  1. Sensitive and selective detection of uracil-DNA glycosylase activity with a new pyridinium luminescent switch-on molecular probe.

    Lu, Yu-Jing; Hu, Dong-Ping; Deng, Qiang; Wang, Zheng-Ya; Huang, Bao-Hua; Fang, Yan-Xiong; Zhang, Kun; Wong, Wing-Leung

    2015-09-01

    Uracil-deoxyribonucleic acid glycosylase (UDG) is known to function as an important base-excision repair enzyme and eliminate uracil from DNA molecules to maintain genomic integrity. A new small organic molecule (DID-VP) with interesting structural properties was synthesized as a G-quadruplex selective ligand and was demonstrated to be a sensitive luminescent switch-on probe in a convenient luminescent assay specifically for UDG detection in fetal bovine serum samples under rapid and simple conditions. This newly developed analytical method is based on the UDG enzymatic activity to unwind a duplex DNA substrate, and comprises a G-quadruplex-forming sequence (ON1) and uracil-containing DNA strand (ON2) to generate a remarkable fluorescence signal through the specific interaction of DID-VP with ON1. This luminescent switch-on assay is able to achieve high sensitivity and specificity for UDG over other enzymes. The application range of the present analytical system is found to be 0.05 to 1.00 U mL(-1) UDG with a very low detection limit of 0.005 U mL(-1). The recovery study of UDG in real samples gave a very good performance with 75.05%-102.7% recovery. In addition, an extended application of the assay in screening of UDG inhibitors is demonstrated. A good dose-dependence of the luminescence response with respect to the concentration of UDG inhibitors in samples was observed. PMID:26185800

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

    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.

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

    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

  4. Interactions of Some Divalent Metal Ions with Thymine and Uracil Thiosemicarbazide Derivatives.

    Hammud, Hassan H; El-Dakdouki, Mohammad H; Sonji, Nada; Sonji, Ghassan; Bouhadir, Kamal H

    2016-05-01

    The study of interactions between metal ions and nucleobases, nucleosides, nucleotides, or nucleic acids has become an active research area in chemical, biological, and therapeutic fields. In this respect, the coordination behavior of nucleobase derivatives to transition metals was studied in order to get a better understanding about DNA-metal interactions in in vitro and in vivo systems. Two nucleobase derivatives, 3-benzoyl-1-[3-(thymine-1-yl)propamido]thiourea and 3-benzoyl-1-[3-(uracil-1-yl)propamido]thiourea, were synthesized and their dissociation constants were determined at different temperatures and 0.3 ionic strength. Potentiometric studies were carried out on the interaction of the derivatives towards some divalent metals in 50% v/v ethanol-water containing 0.3 mol.dm(-3) KCl, at five different temperatures. The formation constants of the metal complexes for both ligands follow the order: Cu(2+) > Ni(2+) > Co(2+) > Zn(2+) > Pb(2+) > Cd(2+) > Mn(2+). The thermodynamic parameters were estimated; the complexation process has been found to be spontaneous, exothermic, and entropically favorable. PMID:27049340

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

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

    2016-01-01

    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. PMID:27063406

  6. Valence and diffuse-bound anions of noble-gas complexes with uracil

    Streit, Lívia; Dolgounitcheva, O.; Zakrzewski, V. G.; Ortiz, J. V.

    2012-11-01

    Valence-bound (VB) and diffuse-bound (DB) anions of noble-gas (Ar, Kr, and Xe) complexes with uracil have been studied with ab initio methods. MP2 optimizations revealed minima corresponding to anions of both kinds in each case. Coupled-cluster singles and doubles with perturbative triples, CCSD(T), and electron propagator single-point calculations were performed in order to assess vertical and adiabatic electron detachment energies of these complexes. Ab initio electron propagator calculations employed the outer valence Green's function and partial third-order approximations, and the algebraic diagrammatic construction in third order. Basis set effects have been systematically examined. DB anions of all three complexes were adiabatically bound, with calculated adiabatic electron attachment energies below 0.06 eV. Corresponding vertical electron detachment energies were below 0.1 eV. As to VB anions, only the Xe complex had a positive adiabatic electron detachment energy, of 0.01 eV, with a corresponding vertical electron detachment energy of 0.6 eV. These computational findings are consistent with the interpretation of results previously obtained experimentally by Hendricks et al.

  7. Bis[bis(2-ethyl-5-methyl-1H-imidazol-4-yl-κN3methane](nitrato-κ2O,O′nickel(II nitrate

    Ge Gao

    2011-02-01

    Full Text Available In the title compound, [Ni(NO3(C13H20N42]NO3, the NiII ion shows a distorted octahedral geometry formed by four N atoms from two bis(2-ethyl-5-methyl-1H-imidazol-4-ylmethane ligands and two O atoms from a chelating nitrate anion. Three ethyl groups in the complex cation and the O atoms of the uncoordinated nitrate anion are disordered over two sets of positions [occupancy ratios of 0.52 (3:0.48 (3 and 0.63 (3:0.37 (3, respectively]. In the crystal, intermolecular N—H...O hydrogen bonds connect the complex cations into a zigzag chain along [010] and further N—H...O hydrogen bonds between the chains and the uncoordinated nitrate anions lead to layers parallel to (100.

  8. QSAR study of some 5-methyl/trifluoromethoxy- 1H-indole-2,3-dione-3-thiosemicarbazone derivatives as anti-tubercular agents

    Shahlaei, M.; Fassihi, A.; Nezami, A.

    2009-01-01

    In the present study, quantitative relationships between molecular structure and anti-tubercular activity of some 5-methyl/trifluoromethoxy-1H-indole-2,3-dione-3-thiosemicarbazone derivatives were discovered. The detailed application of an efficient linear method and principal component regression (PCR) for the evaluation of quantitative structure activity relationships of the studied compounds is demonstrated. Components produced by principal component analysis were used as the input for a linear model development. Results indicate a linear relationship between the principal components obtained from molecular descriptors and the inhibitory activity of this set of molecules. The maximum variance in the activity of the molecules in PCR method was 73%. The performance of the developed model was tested by several validation methods. PMID:21589807

  9. Synthesis and herbicidal activity evaluation of novel α-amino phosphonate derivatives containing a uracil moiety.

    Che, Jian-yi; Xu, Xiao-yun; Tang, Zi-long; Gu, Yu-cheng; Shi, De-qing

    2016-02-15

    A series of novel α-amino phosphonate derivatives containing a uracil moiety 3a-3l were designed and synthesized by a Lewis acid (magnesium perchlorate) catalyzed the Kabachnik-Fields reaction. The bioassays {in vitro, in vivo [Glass House 1 (GH1) and Glass House 2 (GH2)]} showed that most of compounds 3 exhibited excellent and selective herbicidal activities; for example, in GH1 test, compounds 3b, 3d, 3f, 3h and 3j showed excellent and wide spectrum herbicidal activities at the dose of 1000 g/ha, and compounds 3b and 3j exhibited 100% inhibition activities against the four plants in both post- and pre-emergence treatments. Moreover, most of compounds 3 showed higher inhibition against Amaranthus retroflexus and Digitaria sanguinalis than Glyphosate did in pre-emergence treatment. In GH2 test, the four compounds (3b, 3d, 3h and 3j) exhibited 100% inhibition against Solanum nigrum, Amaranthus retroflexus and Ipomoea hederacea in post-emergence treatment and displayed 100% inhibition against Solanum nigrum, Amaranthus retroflexus in pre-emergence treatment at the rate of 250 g/ha, and compound 3b showed the best and broad spectrum herbicidal activities against the six test plants. However, the four compounds displayed weaker herbicidal activities against Lolium perenne and Echinochloa crus-galli than the other four plants at the rate of 250 g/ha in both pre- and post-emergence treatments. So, compounds 3 can be used as a lead compound for further structure optimization for developing potential selective herbicidal agent. Their preliminary structure-activity relationships were also investigated. PMID:26786699

  10. [A CASE OF ADVANCED BLADDER NEUROENDOCRINE CARCINOMA (SMALL CELL CARCINOMA) SIGNIFICANTLY IMPROVED BY LOW DOSE OF ORAL TEGAFUR-URACIL].

    Nomi, Hayahito; Takahara, Kiyoshi; Minami, Koichiro; Maenosono, Ryoichi; Matsunaga, Tomohisa; Yoshikawa, Yuki; Tsujino, Takuya; Hirano, Hajime; Inamoto, Teruo; Yamamoto, Ikuhisa; Tsuji, Motomu; Kiyama, Satoshi; Azuma, Haruhito

    2015-10-01

    A 81-old-woman underwent a transurethral resection of bladder tumor (TURBT) at a nearby hospital in April 2011. The diagnosis was invasive urothelial carcinoma, G3 with a component of bladder small cell carcinoma, T1 or more. She was recommended to visit our hospital for combined modality therapy of bladder cancer, but she refused the treatment for over one year. In May 2012, she came to our hospital with the chief complaint of pain at urination. Cystoscopy revealed non-papillary sessile tumor in the top of the bladder, and CT scan demonstrated the presence of the right obturator lymph nodes swollen up to 1.2 cm in size. The second TURBT was performed and the diagnosis was bladder small cell carcinoma (pT3N2M0) according to urothelial cancer guidelines of the Japanese Urological Association (JUA). Because she strongly refused hospitalization anymore, we started daily oral intake of low dose Tegafur-Uracil (100 mg) for the treatment. After one month, the serum Neuron-Specific Enolase (NSE; tumor maker of small cell cancer) level was elevated to 27.6 ng/ml and the right obturator lymph node was enlarged up to 1.9 cm. Therefore, the Trgafur-Uracil dose was increased to 200 mg daily. After then, the serum NSE level was decreased to 15.5 ng/ml following reduction in size of the obturator lymph nodes with partial response in December 2013. After two years of follow-up period, her regular urine test showed normal findings, and no apparent recurrence was detected on urinary bladder with MRI and Cystoscopy. This is a case of advanced bladder small cell carcinoma significantly improved by oral administration of Tegafur-Uracil 200 mg/day for over 2 years. PMID:26717786

  11. Molecular characterization of the argJ mutation in Neisseria gonorrhoeae strains with requirements for arginine, hypoxanthine, and uracil.

    Martin, P R; Mulks, M H

    1992-01-01

    Arginine auxotrophs are commonly encountered among clinical isolates of Neisseria gonorrhoeae. Arginine auxotrophs which also require hypoxanthine and uracil (AHU strains) compose a unique set of strains that are highly homogeneous and are believed to be clonally derived. The Arg- phenotype of these strains is due to a lesion in the argJ gene encoding ornithine acetyltransferase. We have cloned the mutant argJ gene from an AHU strain and compared the sequence of this gene to the wild-type arg...

  12. Interfacial molecular recognition of adenine, adenosine and ATP by a C60-uracil adduct via complementary base pairing

    Marczak, Renata; Hoang, Vu T.; Noworyta, Krzysztof; Zandler, Melvin E.; Kutner, Wlodzimierz; D'Souza, Francis

    2002-10-01

    A new C60-uracil adduct was demonstrated to recognize adenine, adenosine, or adenosine 5'-triphosphate (ATP) via complementary base pairing which led to complex formation. The base-pairing mechanism was modeled by ab initio B3LYP/3-21G(*) calculations which revealed the Watson-Crick (A-T) interactions. Stable "expanded liquid" Langmuir films of the complexes were prepared with the limiting area per molecule increasing for different subphase composition in the order: water < adenine < adenosine < ATP solution. Comparison of experimental and calculated areas per molecule and dipole moments suggest both prevailing horizontal orientation of the complexes in films.

  13. Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase

    Yousif, Ashraf S.; Stanlie, Andre; Mondal, Samiran; Honjo, Tasuku; Begum, Nasim A.

    2014-01-01

    Uracil DNA glycosylase (UNG) has been known as a critical base excision repair protein required for class switch recombination (CSR) and somatic hypermutation (SHM). On the other hand, its precise function in both CSR and SHM is extremely debatable and elusive. Here, we showed that UNG suppresses S region SHM (s-SHM) by recruiting the faithful DNA repair complex and, in the absence of UNG, the error-prone repair complex that induces s-SHM overrides. Moreover, UNG promotes activation-induced c...

  14. Multicomponent Synthesis of Uracil Analogues Promoted by Pd-Catalyzed Carbonylation of α-Chloroketones in the Presence of Isocyanates and Amines.

    Perrone, Serena; Capua, Martina; Salomone, Antonio; Troisi, Luigino

    2015-08-21

    A short and efficient one-pot synthesis of uracil derivatives with a high structural variability is described. The process is a multicomponent reaction based on a palladium-catalyzed carbonylation of α-chloroketones in the presence of primary amines and isocyanates. In most cases, when the formation of unsymmetrical N,N'-disubstituted uracil derivatives can occur, the methodology demonstrates to be highly regioselective. A mechanistic hypothesis involving β-dicarbonyl palladium intermediates and urea derivatives, generated in situ, has been discussed. PMID:26172334

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

    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...... assayed at 60 °C. Enzyme activity was strongly stimulated by GTP and inhibited by CTP. GTP caused an approximately 20-fold increase in the turnover number kcat and raised the Km values for 5-phosphoribosyl-1-diphosphate (PRPP) and uracil by two- and >10-fold, respectively. The inhibition by CTP was...

  16. 2-Methyl-6-(6-methyl-1H-benzimidazol-2-ylphenol–2-methyl-6-(5-methyl-1H-benzimidazol-2-ylphenol (3/1

    Suchada Chantrapromma

    2009-12-01

    Full Text Available The title compound, 0.75C15H14N2O·0.25C15H14N2O, is a co-crystal of 2-methyl-6-(6-methyl-1H-benzimidazol-2-ylphenol as the major component and 2-methyl-6-(5-methyl-1H-benzimidazol-2-ylphenol as the minor component. The refined site-occupancy ratio is 0.746 (4/0.254 (4. The conformations of both components are identical except for that of the methyl substituent on the benzene ring of the benzimidazole unit which is positionally disordered over two positions. The molecule is essentially planar, the dihedral angle between the benzimidazole plane and the benzene ring being 3.49 (4°. An intramolecular O—H...N hydrogen bond generates an S(6 ring motif. In the crystal packing, molecules are linked through N—H...O hydrogen bonds into chains along [201]. These chains are stacked approximately along the a-axis direction. The crystal packing is further stabilized by weak N—H...O and O...H...N hydrogen bonds, together with weak intermolecular C—H...π interactions. A π–π interaction with a centroid–centroid distance of 3.6241 (6 Å is also observed between the substituted phenyl ring and that of the benzimidazole system.

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

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

    1998-01-01

    , 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......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...

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

    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.

  19. A DFT analysis of the molecular structure, vibrational spectra and other molecular properties of 5-nitrouracil and comparison with uracil

    Kattan, D.; Alcolea Palafox, M.; Rathor, S. K.; Rastogi, V. K.

    2016-02-01

    The four unit cells found in the crystals of the biomolecule 5-Nitrouracil were simulated as tetramer forms by density functional calculations. Four tetramer forms were fully optimized. Specific scale factors and scaling equations deduced from uracil molecule were employed in the predicted wavenumbers of 5-nitrouracil. The experimental FT-Raman and FT-IR spectra were recorded in the solid state. Comprehensive interpretation of the experimental FT-IR and FT-Raman spectra of the compound under study in the solid state is based on potential energy distribution. A good reproduction of the experimental wavenumbers is obtained and the % error is very small in the majority of cases. A complete vibrational assignment in the isolated state was also carried out aided by the theoretical harmonic frequency analysis and the results compared with those reported in Ar matrix. The scaled wavenumbers were used in the reassignment of several experimental bands. A comparison between the molecular structure and charge distribution of 5-Nitrouracil with related 5-uracil derivatives was presented. The effect of the nitro substitution in the 5th position of the pyrimidine ring was evaluated.

  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

    Clausen, Rasmus P; Hansen, Kasper B; Calí, Patrizia; Nielsen, Birgitte; Greenwood, Jeremy R; Begtrup, Mikael; Egebjerg, Jan; Bräuner-Osborne, Hans

    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 pharmacologic...

  1. 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

    Wang, Shuang-Yan; Larsen, Younes; Navarrete, Cristina V.; Jensen, Anders A.; Nielsen, Birgitte; Al-Musaed, Ali; Frydenvang, Karla; Kastrup, Jette Sandholm; Pickering, Darryl S; Clausen, Rasmus Prætorius

    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...

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

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

    2010-01-01

    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...

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

    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. PMID:26743004

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

    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...

  5. Investigation of the fluorescence quenching of 2,3-diazabicyclo[2.2.2]oct-2-ene (DBO) by certain substituted uracils

    Anbazhagan, V. [School of Chemistry, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu (India); Renganathan, R. [School of Chemistry, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu (India)], E-mail: rrengas@yahoo.com

    2009-04-15

    The fluorescence quenching of 2,3-diazabicyclo[2.2.2]oct-2-ene (DBO) by a series of uracils has been studied in water and acetonitrile solvents using steady-state and time-resolved fluorescence techniques. The steady-state fluorescence quenching technique has been performed in three different pHs (i.e. 4, 8 and 12). The bimolecular quenching rate constant (k{sub q}) increases with increase in pH of uracils. In acidic pH, a pure hydrogen atom abstraction is proposed as the quenching mechanism. This is supported by a pronounced solvent deuterium isotope effect. Electron transfer from the anionic form of uracil to the excited state of DBO is proposed as a mechanism for quenching in basic pH on the basis of highly exergonic thermodynamics obtained from the Rehm-Weller equation. The variation of k{sub q} is explained on the basis of the electronic effect of substitution in uracils as well.

  6. Generation of AcGFP fusion with single-chain Fv selected from a phage display library constructed from mice hyperimmunized against 5-methyl 2'-deoxycytidine.

    Ohshima, Motohiro; Inoue, Kazuyuki; Hayashi, Hideki; Tsuji, Daiki; Mizugaki, Michinao; Itoh, Kunihiko

    2010-11-01

    DNA methylation is involved in many diseases such as cancer and autoimmunity. We generated recombinant single-chain Fv (scFv) antibodies against 5-methyl-2'-deoxycytidine (m(5)dCyd) using phage display technology and a hyperimmunized mouse, and the scFv of most interest were constructed as fusion proteins with green fluorescent protein obtained from Aequorea coerulescens GFP (AcGFP). Using RNA isolated from mouse spleens, we constructed a scFv library consisting of λ light chains. The scFv library was selected against m(5)Cyd-BSA and enriched through four rounds of panning. The scFv library was concentrated about 390-fold and an individual clone was reacted with m(5)Cyd-BSA. Two scFvs with high reactivity for m(5)Cyd-BSA termed 1-2 and 1-12 were produced. Furthermore, methylated DNA-binding activities of the scFvs were confirmed using an indirect immunofluorescence assay. Additionally, N- and C-terminal scFv 1-2 fusion with AcGFP were constructed, and we observed the N-terminal AcGFP exhibited much higher fluorescence intensity than the C-terminal fusions. The AcGFP-scFv 1-2 modified N-terminus of scFv with AcGFP had high fluorescence intensity, but the scFv 1-2-AcGFP modified C-terminus of scFv with AcGFP had low fluorescence intensity. The cross-reactivity of AcGFP-scFv 1-2 was similar to scFv 1-2, and thus, AcGFP-scFv 1-2 could be used in a direct immunofluorescence assay. The scFv fusion proteins may be useful for the detection and quantification of cellular methylated DNA in various specimens. PMID:20876190

  7. A novel diterpene skeleton: identification of a highly aromatic, cytotoxic and antioxidant 5-methyl-10-demethyl-abietane-type diterpene from Premna serratifolia.

    Habtemariam, Solomon; Varghese, George K

    2015-01-01

    Premna serratifolia Linn. (syn: . P. corymbosa (Burm. f.) Merr., P. integrifolia L. and P. obtusifolia R. Br.) is a member of the Verbenaceae family that is extensively used in the Ayurvedic system of medicine in India. As part of our continuous pharmacological and phytochemical studies on medicinal plants, we have screened the methanolic extracts of leaves, root bark (RB) and root wood of P. serratifolia for cytotoxic activity against two cancer cell lines: SHSY-5Y neuroblastoma and B16 melanoma cells. The RB extract that showed promising activity was fractionated using solvents of increasing polarity followed by a combination of Sephadex LH-20 column and Combiflash chromatography as well as HPLC to afford the active principle. Comprehensive spectroscopic analysis including 1D and 2D NMR (COSY, HMQC, HMBC, NOESY) and MS analysis revealed the identity of the isolated compound as 11,12,16-trihydroxy-2-oxo-5-methyl-10-demethyl-abieta-1[10],6,8,11,13-pentene that appears to be a novel compound based on a new diterpene skeleton. The cytotoxic activity of the isolated compound was 21 and 23 times higher than the crude extract against the SHSY-5Y and B16 cells, respectively. The novel compound also possesses in vitro antioxidant effects as evidenced by the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging effect where an IC50 value of 20.4 ± 1.3 μM was obtained. In comparison, the positive control, caffeic acid, showed an IC50 value of 14.4 ± 1.6 μM. PMID:25250850

  8. A preliminary experimental study on the cardiac toxicity of glutamate and the role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor in rats

    LIU Yan; ZHOU Lan; XU Hai-fei; YAN Li; DING Fan; HAO Wei; CAO Ji-min

    2013-01-01

    Background Monosodium L-glutamate (MSG) is a food flavour enhancer and its potential harmfulness to the heart remains controversial.We investigated whether MSG could induce cardiac arrhythmias and apoptosis via the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.Methods Myocardial infarction (MI) was created by ligating the coronary artery and ventricular arrhythmias were monitored by electrocardiogram in the rat in vivo.Neonatal rat cardiomyocytes were isolated and cultured.Cell viability was estimated by 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide (MTT) assay.Calcium mobilization was monitored by confocal microscopy.Cardiomyocyte apoptosis was evaluated by acridine orange staining,flow cytometry,DNA laddering,reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting.Results MSG (i.v.) decreased the heart rate at 0.5 g/kg and serious bradycardia at 1.5 g/kg,but could not induce ventricular tachyarrhythmias in normal rats in vivo.In rats with acute MI in vivo,however,MSG (1.5 g/kg,i.v.) induced ventricular tachyarrhythmias and these arrhythmias could be prevented by blocking the AMPA and N-methyl-d-aspartate (NMDA) receptors.Selectively activating the AMPA or NMDA receptor induced ventricular tachyarrhythmias in MI rats.At the cellular level,AMPA induced calcium mobilization,oxidative stress,mitochondrial dysfunction and apoptosis in cultured cardiomyocytes,especially when the AMPA receptor desensitization were blocked by cyclothiazide.The above toxic cellular effects of AMPA were abolished by AMPA receptor blockade or by H2O2 scavengers.Conclusions MSG induces bradycardia in normal rats,but triggers lethal tachyarrhythmias in myocardial infarcted rats probably by hindering AMPA receptors.AMPA receptor overstimulation also induces cardiomyocyte apoptosis,which may facilitate arrhythmia.

  9. Preventive action of ATP on biosynthesis of uridylic nucleotides of uracil in rat tissues after prolonged γ-irradiation

    Action of a single intramuscular injection of ATP (350 mg/kg) prior to the whole-body prolonged γ-irradiation of rats with a minimum lethal dose (1100 R; dose of 0.8 R/min) on the uracil phosphoribosyltransferase (UPRTF) and uridine-5'-phosphate-kinase (UMP-kinase) activity of extracts from thymus, spleen and liver has been investigated. It has been found that exogenous ATP has no protective action on postirradiation changes in the UTRTF activity of haemopoietic tissues, and have a small favourable action on the activity of this enzyme in the liver and the activity of UMP-kinase in the thymus and spleen. A single injection of ATP (the same dose) to non-irradiated animals causes a transient inhibition of UPRTF, but it has no effect on the UMP-kinase activity. Causes of inefficacy of exogenous ATP administered to rats prior to prolonged irradiation are discussed

  10. The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating hydantoin or uracil rings.

    Procopiou, Panayiotis A; Barrett, Victoria J; Bevan, Nicola J; Butchers, Peter R; Conroy, Richard; Emmons, Amanda; Ford, Alison J; Jeulin, Séverine; Looker, Brian E; Lunniss, Gillian E; Morrison, Valerie S; Mutch, Peter J; Perciaccante, Rossana; Ruston, Mark; Smith, Claire E; Somers, Graham

    2011-07-15

    A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 μM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m. PMID:21696967

  11. Opinion: uracil DNA glycosylase (UNG) plays distinct and non-canonical roles in somatic hypermutation and class switch recombination.

    Yousif, Ashraf S; Stanlie, Andre; Begum, Nasim A; Honjo, Tasuku

    2014-10-01

    Activation-induced cytidine deaminase (AID) is essential to class switch recombination (CSR) and somatic hypermutation (SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair complex, is required for CSR. The role of UNG in CSR and SHM is extremely controversial. AID deficiency in mice abolishes both CSR and SHM, while UNG-deficient mice have drastically reduced CSR but augmented SHM raising a possibility of differential functions of UNG in CSR and SHM. Interestingly, UNG has been associated with a CSR-specific repair adapter protein Brd4, which interacts with acetyl histone 4, γH2AX and 53BP1 to promote non-homologous end joining during CSR. A non-canonical scaffold function of UNG, but not the catalytic activity, can be attributed to the recruitment of essential repair proteins associated with the error-free repair during SHM, and the end joining during CSR. PMID:24994819

  12. Ion complex membranes of acrylonitrile copolymers having methacrylic acid and amphiphilic quaternized ammonium groups for uracil molecular imprinting

    Copolymers having methacrylic acid and amphiphilic quaternized ammonium groups were used for preparation of molecular imprinting membrane of uracil (URA) template. The imprinted polymeric membranes were prepared by phase inversion molecular imprinting by using poly(acrylonitrile-co-methylacrylic acid) [P(AN-co-MAA)] and poly(acrylonitrile-co-vinylbenzyl-stearyldimethylamine chloride) [P(AN-co-SMA)]. Evidence confirmed that both copolymers were mixed to form ion complex by electrostatic interaction between the methacrylic acid and the quaternized ammonium groups. The electrostatic networks of the resultant membranes made the membrane dense and useful for molecule recognition of the template. The imprinted membranes made of different mole ratio of their copolymer segments were examined in binding of URA and other analog molecules

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

    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. PMID:27113273

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

    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.

  15. Secretion of Rhoptry and Dense Granule Effector Proteins by Nonreplicating Toxoplasma gondii Uracil Auxotrophs Controls the Development of Antitumor Immunity.

    Fox, Barbara A; Sanders, Kiah L; Rommereim, Leah M; Guevara, Rebekah B; Bzik, David J

    2016-07-01

    Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α+ dendritic cells, the IL-12/interferon-gamma (IFN-γ) TH1 axis, as well as CD4+ and CD8+ T cells. Deletion of parasitophorous vacuole membrane (PVM) associated proteins ROP5, ROP17, ROP18, ROP35 or ROP38, intravacuolar network associated dense granule proteins GRA2 or GRA12, and GRA24 which traffics past the PVM to the host cell nucleus severely abrogated the antitumor response. In contrast, deletion of other secreted effector molecules such as GRA15, GRA16, or ROP16 that manipulate host cell signaling and transcriptional pathways, or deletion of PVM associated ROP21 or GRA3 molecules did not affect the antitumor activity. Association of ROP18 with the PVM was found to be essential for the development of the antitumor responses. Surprisingly, the ROP18 kinase activity required for resistance to IFN-γ activated host innate immunity related GTPases and virulence was not essential for the antitumor response. These data show that PVM functions of parasite secreted effector molecules, including ROP18, manipulate host cell responses through ROP18 kinase virulence independent mechanisms to activate potent antitumor responses. Our results demonstrate that PVM associated rhoptry effector proteins secreted prior to host cell invasion and dense granule effector proteins localized to the intravacuolar network and host nucleus that are secreted after host cell invasion coordinately control the

  16. Anion exchange chromatography for the determination of 5-methyl-2'-deoxycytidine: application to cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines.

    Iglesias, Tamara; Espina, Marta; Montes-Bayón, María; Sierra, Luisa María; Blanco-González, Elisa

    2015-03-01

    Epigenetic alterations are increasingly implicated in the initiation and progression of cancer. Genome-wide (global) hypomethylation seems to occur in early neoplasia and is a feature of genomic DNA derived from solid tumour tissues like ovarian cancer. Thus, analytical methods that provide sensitive and quantitative information about cytosine methylation in DNA are currently required. In this work, we compare two different anion-exchange columns for the separation of methylated cytosine from the other DNA nucleotides: a silica-based (Tracer Extrasil SAX) column and a polystyrene/divinyl benzene-based (Mono-Q™) column. Under the optimised conditions, linearity range, precision and detection limits of the developed high-performance liquid chromatography (HPLC) method were evaluated and compared using conventional ultraviolet (UV) absorbance detection at 270 nm. Good separation of the five target nucleotides, including 5-methyl-2'-deoxycytidine monophosphate (5mdCMP) and 2'-deoxycytidine monophosphate (dCMP) was achieved on the Mono-Q™ column with a gradient elution of ammonium acetate buffer (1 M, pH 6.9) at a flow rate of 1 mL min(-1). The coupling of this column to inductively coupled plasma mass spectrometry (ICP-MS) permitted also phosphorous ((31)P) specific detection of the nucleotides. Both detection systems offered adequate analytical performance characteristics, with detection limits of 30 and 40 μg L(-1) for 5mdCMP by HPLC-UV and HPLC-ICP-MS, respectively. However, the latter method allowed the determination of the global DNA methylation level (%) without the need for external calibration. Different genomic DNA samples were analysed including calf thymus DNA and DNA from two human cancer cell lines (adenocarcinoma epithelial A549 and ovarian carcinoma A2780) using the proposed strategy. In the line A2780, the cisplatin-sensitive and cisplatin-resistant variants were analysed, finding no significant differences in the methylation percentage after

  17. pH-Metric study of 2-amino-, 2-amino-5-methyl-and 2-amino-5-isopropyl-1,3,4-thiadiazoledipropionic acid complexing with zinc and cadmium

    Acid-base properties of 2-amino-(H2QI), 2-amino-5-methyl-(H2Q2) and 2-amino-5-isopropyl-1,3,4-thiadiazoledipropionic (H2Q3) acids and stability of their complexes with zinc and cadmium of the MQ1-3 type in aqueous medium at t=25 deg C and μ=0.15 M KNO3 have been studied by pH-metric method

  18. 1,6-Bis[(benzyloxy)methyl]uracil derivatives-Novel antivirals with activity against HIV-1 and influenza H1N1 virus.

    Geisman, Alexander N; Valuev-Elliston, Vladimir T; Ozerov, Alexander A; Khandazhinskaya, Anastasia L; Chizhov, Alexander O; Kochetkov, Sergey N; Pannecouque, Christophe; Naesens, Lieve; Seley-Radtke, Katherine L; Novikov, Mikhail S

    2016-06-01

    A series of 1,6-bis[(benzyloxy)methyl]uracil derivatives combining structural features of both diphenyl ether and pyridone types of NNRTIs were synthesized. Target compounds were found to inhibit HIV-1 reverse transcriptase at micro- and submicromolar levels of concentrations and exhibited anti-HIV-1 activity in MT-4 cell culture, demonstrating resistance profile similar to first generation NNRTIs. The synthesized compounds also showed profound activity against influenza virus (H1N1) in MDCK cell culture without detectable cytotoxicity. The lead compound of this assay appeared to exceed rimantadine, amantadine, ribavirin and oseltamivir carboxylate in activity. The mechanism of action of 1,6-bis[(benzyloxy)methyl]uracils against influenza virus is currently under investigation. PMID:27112451

  19. Switching between reaction pathways by an alcohol cosolvent effect: SmI2-ethylene glycol vs SmI2-H2O mediated synthesis of uracils.

    Szostak, Michal; Spain, Malcolm; Sautier, Brice; Procter, David J

    2014-11-01

    A chemoselective switch between reaction pathways by an alcohol cosolvent effect in a general SmI2-mediated synthesis of uracil derivatives is described. The method relies on the use of coordinating solvents to increase the redox potential of Sm(II) and results in a chemoselective 1,2-reduction (SmI2-H2O) or 1,2-migration via in situ generated N-acyliminium ions (SmI2-ethylene glycol, EG). This work exploits the mild conditions of the SmI2-mediated monoreduction of barbituric acids and offers an attractive protocol for the synthesis of uracil derivatives with biological activity from readily accessible building blocks. PMID:25343692

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

    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.

  1. Synthesis of 5-[3-(2-aminopyrimidin-4-yl)aminopropyn-1-yl]uracil derivative that recognizes Ade-Thy base pairs in double-stranded DNA.

    Ito, Yu; Masaki, Yoshiaki; Kanamori, Takashi; Ohkubo, Akihiro; Seio, Kohji; Sekine, Mitsuo

    2016-01-01

    5-[3-(2-Aminopyrimidin-4-yl)aminopropyn-1-yl]uracil (Ura(Pyr)) was designed as a new nucleobase to recognize Ade-Thy base pair in double-stranded DNA. We successfully synthesized the dexoynucleoside phosphoramidite having Ura(Pyr) and incorporated it into triplex forming oligonucleotides (TFOs). Melting temperature analysis revealed that introduction of Ura(Pyr) into TFOs could effectively stabilize their triplex structures without loss of base recognition capabilities. PMID:26602276

  2. A unique dual recognition hairpin probe mediated fluorescence amplification method for sensitive detection of uracil-DNA glycosylase and endonuclease IV activities.

    Wu, Yushu; Yan, Ping; Xu, Xiaowen; Jiang, Wei

    2016-03-01

    Uracil-DNA glycosylase (UDG) and endonuclease IV (Endo IV) play cooperative roles in uracil base-excision repair (UBER) and inactivity of either will interrupt the UBER to cause disease. Detection of UDG and Endo IV activities is crucial to evaluate the UBER process in fundamental research and diagnostic application. Here, a unique dual recognition hairpin probe mediated fluorescence amplification method was developed for sensitively and selectively detecting UDG and Endo IV activities. For detecting UDG activity, the uracil base in the probe was excised by the target enzyme to generate an apurinic/apyrimidinic (AP) site, achieving the UDG recognition. Then, the AP site was cleaved by a tool enzyme Endo IV, releasing a primer to trigger rolling circle amplification (RCA) reaction. Finally, the RCA reaction produced numerous repeated G-quadruplex sequences, which interacted with N-methyl-mesoporphyrin IX to generate an enhanced fluorescence signal. Alternatively, for detecting Endo IV activity, the uracil base in the probe was first converted into an AP site by a tool enzyme UDG. Next, the AP site was cleaved by the target enzyme, achieving the Endo IV recognition. The signal was then generated and amplified in the same way as those in the UDG activity assay. The detection limits were as low as 0.00017 U mL(-1) for UDG and 0.11 U mL(-1) for Endo IV, respectively. Moreover, UDG and Endo IV can be well distinguished from their analogs. This method is beneficial for properly evaluating the UBER process in function studies and disease prognoses. PMID:26899234

  3. Typing by serovar, antibiogram, plasmid content, riboprobing, and isoenzyme typing to determine whether Neisseria gonorrhoeae isolates requiring proline, citrulline, and uracil for growth are clonal.

    Ng, L K; Dillon, J R

    1993-01-01

    Neisseria gonorrhoeae isolates requiring proline, citrulline, and uracil for growth (PCU-) have homogeneous phenotypes; most are plasmid-free, belong to few serovars, and are significantly associated with intermediate levels of susceptibility to penicillin, tetracycline, erythromycin, and cefoxitin. Because of their lack of variation by these criteria, molecular typing methods, ribotyping (restriction fragment length polymorphism [RFLP] of rRNA genes), and multilocus enzyme electrophoresis we...

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

    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.

  5. Exploring the role of the 5-substituent for the intrinsic fluorescence of 5-aryl and 5-heteroaryl uracil nucleotides: a systematic study.

    Pesnot, Thomas; Tedaldi, Lauren M; Jambrina, Pablo G; Rosta, Edina; Wagner, Gerd K

    2013-10-01

    Derivatives of UMP (uridine monophosphate) with a fluorogenic substituent in position 5 represent a small but unique class of fluorophores, which has found important applications in chemical biology and biomolecular chemistry. In this study, we have synthesised a series of derivatives of the uracil nucleotides UMP, UDP and UTP with different aromatic and heteroaromatic substituents in position 5, in order to systematically investigate the influence of the 5-substituent on fluorescence emission. We have determined relevant photophysical parameters for all derivatives in this series, including quantum yields for the best fluorophores. The strongest fluorescence emission was observed with a 5-formylthien-2-yl substituent in position 5 of the uracil base, while the corresponding 3-formylthien-2-yl-substituted regioisomer was significantly less fluorescent. The 5-(5-formylthien-2-yl) uracil fluorophore was studied further in solvents of different polarity and proticity. In conjunction with results from a conformational analysis based on NMR data and computational experiments, these findings provide insights into the steric and electronic factors that govern fluorescence emission in this class of fluorophores. In particular, they highlight the interplay between fluorescence emission and conformation in this series. Finally, we carried out ligand-binding experiments with the 5-(5-formylthien-2-yl) uracil fluorophore and a UDP-sugar-dependent glycosyltransferase, demonstrating its utility for biological applications. The results from our photophysical and biological studies suggest, for the first time, a structural explanation for the fluorescence quenching effect that is observed upon binding of these fluorophores to a target protein. PMID:23945704

  6. Differential modes of DNA binding by mismatch uracil DNA glycosylase from Escherichia coli: implications for abasic lesion processing and enzyme communication in the base excision repair pathway

    Grippon, Seden; Zhao, Qiyuan; Robinson, Tom; Marshall, Jacqueline J. T.; O’Neill, Rory J.; Manning, Hugh; Kennedy, Gordon; Dunsby, Christopher; Neil, Mark; Halford, Stephen E.; French, Paul M. W.; Baldwin, Geoff S.

    2010-01-01

    Mismatch uracil DNA glycosylase (Mug) from Escherichia coli is an initiating enzyme in the base-excision repair pathway. As with other DNA glycosylases, the abasic product is potentially more harmful than the initial lesion. Since Mug is known to bind its product tightly, inhibiting enzyme turnover, understanding how Mug binds DNA is of significance when considering how Mug interacts with downstream enzymes in the base-excision repair pathway. We have demonstrated differential binding modes o...

  7. Mechanism for the abiotic synthesis of uracil via UV-induced oxidation of pyrimidine in pure H2O ices under astrophysical conditions

    The UV photoirradiation of pyrimidine in pure H2O ices has been explored using second-order Moeller-Plesset perturbation theory and density functional theory methods, and compared with experimental results. Mechanisms studied include those starting with neutral pyrimidine or cationic pyrimidine radicals, and reacting with OH radical. The ab initio calculations reveal that the formation of some key species, including the nucleobase uracil, is energetically favored over others. The presence of one or several water molecules is necessary in order to abstract a proton which leads to the final products. Formation of many of the photoproducts in UV-irradiated H2O:pyrimidine=20:1 ice mixtures was established in a previous experimental study. Among all the products, uracil is predicted by quantum chemical calculations to be the most favored, and has been identified in experimental samples by two independent chromatography techniques. The results of the present study strongly support the scenario in which prebiotic molecules, such as the nucleobase uracil, can be formed under abiotic processes in astrophysically relevant environments, namely in condensed phase on the surface of icy, cold grains before being delivered to the telluric planets, like Earth.

  8. Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach

    Weiss, Jason T.; Dawson, John C.; MacLeod, Kenneth G.; Rybski, Witold; Fraser, Craig; Torres-Sánchez, Carmen; Patton, E. Elizabeth; Bradley, Mark; Carragher, Neil O.; Unciti-Broceta, Asier

    2014-02-01

    A bioorthogonal organometallic reaction is a biocompatible transformation undergone by a synthetic material exclusively through the mediation of a non-biotic metal source; a selective process used to label biomolecules and activate probes in biological environs. Here we report the in vitro bioorthogonal generation of 5-fluorouracil from a biologically inert precursor by heterogeneous Pd0 catalysis. Although independently harmless, combined treatment of 5-fluoro-1-propargyl-uracil and Pd0-functionalized resins exhibits comparable antiproliferative properties to the unmodified drug in colorectal and pancreatic cancer cells. Live-cell imaging and immunoassay studies demonstrate that the cytotoxic activity of the prodrug/Pd0-resin combination is due to the in situ generation of 5-fluorouracil. Pd0-resins can be carefully implanted in the yolk sac of zebrafish embryos and display excellent biocompatibility and local catalytic activity. The in vitro efficacy shown by this masking/activation strategy underlines its potential to develop a bioorthogonally activated prodrug approach and supports further in vivo investigations.

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

    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.

  10. Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase

    Yousif, Ashraf S.; Stanlie, Andre; Mondal, Samiran; Honjo, Tasuku; Begum, Nasim A.

    2014-01-01

    Activation-induced cytidine deaminase (AID) is essential to class-switch recombination (CSR) and somatic hypermutation (SHM) in both V region SHM and S region SHM (s-SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair (BER) complex, is required for CSR. Strikingly, however, UNG deficiency causes augmentation of SHM, suggesting involvement of distinct functions of UNG in SHM and CSR. Here, we show that noncanonical scaffold functions of UNG regulate s-SHM negatively and CSR positively. The s-SHM suppressive function of UNG is attributed to the recruitment of faithful BER components at the cleaved DNA locus, with competition against error-prone polymerases. By contrast, the CSR-promoting function of UNG enhances AID-dependent S-S synapse formation by recruiting p53-binding protein 1 and DNA-dependent protein kinase, catalytic subunit. Several loss-of-catalysis mutants of UNG discriminated CSR-promoting activity from s-SHM suppressive activity. Taken together, the noncanonical function of UNG regulates the steps after AID-induced DNA cleavage: error-prone repair suppression in s-SHM and end-joining promotion in CSR. PMID:24591630

  11. Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase.

    Yousif, Ashraf S; Stanlie, Andre; Mondal, Samiran; Honjo, Tasuku; Begum, Nasim A

    2014-03-18

    Activation-induced cytidine deaminase (AID) is essential to class-switch recombination (CSR) and somatic hypermutation (SHM) in both V region SHM and S region SHM (s-SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair (BER) complex, is required for CSR. Strikingly, however, UNG deficiency causes augmentation of SHM, suggesting involvement of distinct functions of UNG in SHM and CSR. Here, we show that noncanonical scaffold functions of UNG regulate s-SHM negatively and CSR positively. The s-SHM suppressive function of UNG is attributed to the recruitment of faithful BER components at the cleaved DNA locus, with competition against error-prone polymerases. By contrast, the CSR-promoting function of UNG enhances AID-dependent S-S synapse formation by recruiting p53-binding protein 1 and DNA-dependent protein kinase, catalytic subunit. Several loss-of-catalysis mutants of UNG discriminated CSR-promoting activity from s-SHM suppressive activity. Taken together, the noncanonical function of UNG regulates the steps after AID-induced DNA cleavage: error-prone repair suppression in s-SHM and end-joining promotion in CSR. PMID:24591630

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

    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.

  13. 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

    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.

  14. Avirulent uracil auxotrophs based on disruption of orotidine-5'-monophosphate decarboxylase elicit protective immunity to Toxoplasma gondii.

    Fox, Barbara A; Bzik, David J

    2010-09-01

    The orotidine-5'-monophosphate decarboxylase (OMPDC) gene, encoding the final enzyme of the de novo pyrimidine biosynthesis pathway, was deleted using Toxoplasma gondii KU80 knockouts to develop an avirulent nonreverting pyrimidine auxotroph strain. Additionally, to functionally address the role of the pyrimidine salvage pathway, the uridine phosphorylase (UP) salvage activity was knocked out and a double knockout of UP and OMPDC was also constructed. The nonreverting DeltaOMPDC, DeltaUP, and DeltaOMPDC DeltaUP knockout strains were evaluated for pyrimidine auxotrophy, for attenuation of virulence, and for their ability to elicit potent immunity to reinfection. The DeltaUP knockout strain was replication competent and virulent. In contrast, the DeltaOMPDC and DeltaOMPDC DeltaUP strains were uracil auxotrophs that rapidly lost their viability during pyrimidine starvation. Replication of the DeltaOMPDC strain but not the DeltaOMPDC DeltaUP strain was also partially rescued in vitro with uridine or cytidine supplementation. Compared to their hypervirulent parental type I strain, the DeltaOMPDC and DeltaOMPDC DeltaUP knockout strains exhibited extreme attenuation in murine virulence (approximately 8 logs). Genetic complementation of the DeltaOMPDC strain using a functional OMPDC allele restored normal replication and type I parental strain virulence phenotypes. A single immunization of mice with either the live critically attenuated DeltaOMPDC strain or the DeltaOMPDC DeltaUP knockout strain effectively induced potent protective immunity to lethal challenge infection. The avirulent nonreverting DeltaOMPDC and DeltaOMPDC DeltaUP strains provide new tools for the dissection of the host response to infection and are promising candidates for safe and effective Th1 vaccine platforms that can be easily genetically engineered. PMID:20605980

  15. 1-calcium phosphate-uracil, a synthesized pyrimidine derivative agent, has anti-proliferative, pro-apoptotic and anti-invasion effects on multiple tumor cell lines

    Peng, Jing; Chen, Xinlian; Hu, Qian; Yang, Mei; Liu, Hongqian; Wei, Wei; Liu, Shanling; Wang, HE

    2014-01-01

    1-calcium phosphate-uracil (1-CP-U), a synthetic pyrimidine derivative, has been documented to demonstrate a variety of different biological activities. However, the potency and mechanisms of this agent’s anti-cancer activity have not been elucidated to date. In the present study, the anti-cancer effects of 1-CP-U were examined in a range of in vitro assays. Different cell lines were treated with 1-CP-U at varied concentrations (0.7, 1.0, 1.4 μmol/l) for indicated durations. The cell prolifer...

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

    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...

  17. Stereoselective capture of N-acyliminium ions generated from α-hydroxy-N-acylcarbamides: direct synthesis of uracils from barbituric acids enabled by SmI2 reduction.

    Szostak, Michal; Sautier, Brice; Procter, David J

    2014-01-17

    Lewis acid promoted cleavage of α-amino alcohols derived from barbituric acids via chemoselective Sm(II)-mediated electron transfer affords a wide range of C6-substituted 5,6-dihydrouracils. The reaction involves the first generation of N-acyliminium ions directly from the versatile barbituric acids and proceeds with excellent stereoselectivity. The products are shown to be active in generic transition metal catalyzed reactions, thus providing a modular and highly practical sequence to the biologically significant uracil derivatives. PMID:24359321

  18. Highly Accurate CCSD(T) and DFT–SAPT Stabilization Energies of H-Bonded and Stacked Structures of the Uracil Dimer

    Pitonak, Michal; Riley, Kevin E.; Neogrady, Pavel; Hobza, Pavel

    2008-06-23

    The CCSD(T) interaction energies for the H-bonded and stacked structures of the uracil dimer are determined at the aug-cc-pVDZ and aug-cc-pVTZ levels. On the basis of these calculations we can construct the CCSD(T) interaction energies at the complete basis set (CBS) limit. The most accurate energies, based either on direct extrapolation of the CCSD(T) correlation energies obtained with the aug-cc-pVDZ and aug-cc-pVTZ basis sets or on the sum of extrapolated MP2 interaction energies (from aug-cc-pVTZ and aug-cc-pVQZ basis sets) and extrapolated ΔCCSD(T) correction terms [difference between CCSD(T) and MP2 interaction energies] differ only slightly, which demonstrates the reliability and robustness of both techniques. The latter values, which represent new standards for the H-bonding and stacking structures of the uracil dimer, differ from the previously published data for the S22 set by a small amount. This suggests that interaction energies of the S22 set are generated with chemical accuracy. The most accurate CCSD(T)/CBS interaction energies are compared with interaction energies obtained from various computational procedures, namely the SCS–MP2 (SCS: spin-component-scaled), SCS(MI)–MP2 (MI: molecular interaction), MP3, dispersion-augmented DFT (DFT–D), M06–2X, and DFT–SAPT (SAPT: symmetry-adapted perturbation theory) methods. Among these techniques, the best results are obtained with the SCS(MI)–MP2 method. Remarkably good binding energies are also obtained with the DFT–SAPT method. Both DFT techniques tested yield similarly good interaction energies. The large magnitude of the stacking energy for the uracil dimer, compared to that of the benzene dimer, is explained by attractive electrostatic interactions present in the stacked uracil dimer. These interactions force both subsystems to approach each other and the dispersion energy benefits from a shorter intersystem separation.

  19. Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase

    TSUJIMOTO, HIROAKI; TSUKIOKA, SAYAKA; ONO, Satoru; Sakamoto, Etsuko; Sakamoto, Kazuki; TSUTA, KOHJI; Nakagawa, Fumio; Saito, Hitoshi; Uchida, Junji; Kiniwa, Mamoru; Fukushima, Masakazu

    2010-01-01

    The combination of oral tegafur-uracil (UFT) with leucovorin (LV) is used to treat patients with stage II to III colon cancer based on the results of postoperative randomized studies in which UFT/LV treatment showed an equivalent efficacy to intravenous 5-FU plus LV therapy. However, whether the addition of LV to UFT can elevate the antitumor activity of UFT in colorectal tumors with high expression levels of thymidylate synthase (TS), which affects 5-FU efficacy, remains to be clarified. Thi...

  20. Synergistic extraction of U(VI) and Th(IV) from nitric acid with 4-benzoyl-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-thione (HBMPPT) and tri-n-octylphosphine oxide (TOPO) in toluene

    The extractant HBMPPT (4-benzoyl-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-thione) was synthesized from HBMPP. Its m.p. was 106-108 deg C. The synergistic extraction of U(VI) and Th(IV) from nitric acid solution by HBMPPT and TOPO in toluene was studied. The extraction ability of HBMPPT was not so high as that of its parent (HBMPP), but when a little tri-n-octylphophine oxide (TOPO) was added the ability to extract U(VI) and Th(IV) was seriously improved. The synergistic extracted complexes may be presented as UO2NO3 x BMPPT x TOPO and UO2(BMPPT)2 x TOPO for U(VI), and Th(NO3)3 x BMPPT x TOPO and Th(NO3)2(BMPPT)2 x TOPO for Th(IV) respectively. (author)

  1. Alkali-labile lesion and uracil-DNA-glycosylase-sensitive site removal after BrdUrd and UVB treatment of Chinese hamster cells

    A marked cell-cycle dependency for the recovery of cells after BrdUrd UVB treatment has led us to look for similar characteristics in the molecular events associated with DNA repair. Such characteristics are reported for the repair of alkali-labile lesions. When asynchronously growing cells were uniformly substituted with BrdUrd (a condition that results in the greatest cell killing), the repair kinetics followed a simple exponential response with a half-time of approximately 17 min. However, when lesions were restricted to 3-5% of the genome and the repair observed in the mid-S phase (a condition associated with sublethal damage repair), the DNA repair kinetics were complex. The rejoining of the DNA was biphasic with greater than 90% of the lesion with a half-time of less than 6-7 min. Uracil removal followed similar kinetics. Caffeine, a potent inhibitor of cell survival after BrdUrd/UVB treatment, had no measurable effect on either uracil removal or alkali-labile lesion repair. (author)

  2. 5-methyl-tetrahydrofolate and the S-adenosylmethionine cycle in C57BL/6J mouse tissues: gender differences and effects of arylamine N-acetyltransferase-1 deletion.

    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.

  3. First chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil (T.P.F.) followed by concomitant chemoradiotherapy in the treatment of cavum locally evolved undifferentiated carcinomas without metastases; Chimiotherapie premiere par docetaxel, cisplatine et 5-fluoro-uracile (TPF) suivie de chimioradiotherapie concomitante dans le traitement des carcinomes indifferencies localement evolues non metastatiques du cavum

    Sahli, B.; Bali, M.S.; Miles, I.; Djemaa, A. [CHU Benbadis, Constantine (Algeria)

    2009-10-15

    It is a prospective study in order to evaluate the feasibility and the toxicity of a chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil followed by a concomitant chemoradiotherapy in the treatment of non metastatic locally evolved undifferentiated carcinomas of the cavum. The conclusion was despite the low number of patients in our series, the observed results show that this neoadjuvant chemotherapy followed by a concomitant chemoradiotherapy in the locally evolved undifferentiated carcinomas of the cavum is feasible. however, the high acute toxicity needs the use of conformal irradiation techniques. Besides, a longer follow up is necessary to evaluate the therapy efficiency and the delayed toxicity of this protocol. (N.C.)

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

    The effect of the fluorinated memantine derivative and NMDA receptor antagonist, 1-amino-3-fluoromethyl-5-methyl-adamantane (19F-MEM), at the NMDA receptor ion channel was studied by patch clamp recording. The results showed that 19F-MEM is a moderate NMDA receptor channel blocker. A procedure for the routine preparation of the 18F-labelled analog 18F-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 18F-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 18F-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 18F-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 antagonist, decreased the binding of 18F-MEM from the

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

    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. PMID:26634967

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

    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.

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

    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.

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

    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.

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

    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.

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

    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 (Kb) 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

  11. Bis{3-amino-1-carbamothioyl-5-[(2-{[(5-methyl-1H-imidazol-3-ium-4-ylmethyl]sulfanyl}ethylamino]-1H-1,2,4-triazol-4-ium} hexachloridobismuthate(III nitrate dihydrate

    G. M. Golzar Hossain

    2013-07-01

    Full Text Available The asymmetric unit of the title hydrated salt, (C10H18N8S22[BiCl6]NO3·2H2O, contains two independent 3-amino-1-carbamothioyl-5-[(2-{[(5-methyl-1H-imidazol-3-ium-4-ylmethyl]sulfanyl}ethylamino]-1H-1,2,4-triazol-4-ium cations, one hexachloridobismuthate anion, one nitrate anion and two solvent water molecules. The dihedral angles between the imidazole and triazole rings in the cations are 44.7 (3 and 89.4 (3°. The BiIII ion is coordinated by six chloride ligands in a slightly distorted octahedral geometry. In each cation, an intramolecular N—H...S hydrogen bond is observed. In the crystal, N—H...Cl, N—H...S, N—H...O, O—H...Cl, O—H...S and O—H...O hydrogen bonds connect the components into a three-dimensional network. In addtion, π–π stacking interactions between inversion-related triazole rings are observed, with a centroid–centroid distance of 3.322 (3 Å

  12. 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

    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.

  13. Design, Synthesis, and Preclinical Evaluation of 4-Substituted-5-methyl-furo[2,3-d]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells.

    Devambatla, Ravi Kumar Vyas; Namjoshi, Ojas A; Choudhary, Shruti; Hamel, Ernest; Shaffer, Corena V; Rohena, Cristina C; Mooberry, Susan L; Gangjee, Aleem

    2016-06-23

    The design, synthesis, and biological evaluations of eight 4-substituted 5-methyl-furo[2,3-d]pyrimidines are reported. Synthesis involved N(4)-alkylation of N-aryl-5-methylfuro[2,3-d]pyrimidin-4-amines, obtained from Ullmann coupling of 4-amino-5-methylfuro[2,3-d]pyrimidine and appropriate aryl iodides. Compounds 3, 4, and 9 showed potent microtubule depolymerizing activities, while compounds 6-8 had slightly lower potency. Compounds 4, 6, 7, and 9 inhibited tubulin assembly with IC50 values comparable to that of combretastatin A-4 (CA-4). Compounds 3, 4, and 6-9 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that can limit the efficacy of paclitaxel, docetaxel, and the vinca alkaloids. In the NCI 60-cell line panel, compound 3 exhibited GI50 values less than 10 nM in 47 of the cell lines. In an MDA-MB-435 xenograft model, compound 3 had statistically significant antitumor effects. The biological effects of 3 identify it as a novel, potent microtubule depolymerizing agent with antitumor activity. PMID:27213719

  14. 2-(3-Methoxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (HKL-1) induces G2/M arrest and mitotic catastrophe in human leukemia HL-60 cells

    2-(3-Methoxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (HKL-1), a 2-phenyl-1,8-naphthyridin-4-one (2-PN) derivative, was synthesized and evaluated as an effective antimitotic agent in our laboratory. However, the molecular mechanisms are uncertain. In this study, HKL-1 was demonstrated to induce multipolar spindles, sustain mitotic arrest and generate multinucleated cells, all of which indicate mitotic catastrophe, in human leukemia HL-60 cells. Western blotting showed that HKL-1 induces mitotic catastrophe in HL-60 cells through regulating mitotic phase-specific kinases (down-regulating CDK1, cyclin B1, CENP-E, and aurora B) and regulating the expression of Bcl-2 family proteins (down-regulating Bcl-2 and up-regulating Bax and Bak), followed by caspase-9/-3 cleavage. These findings suggest that HKL-1 appears to exert its cytotoxicity toward HL-60 cells in culture by inducing mitotic catastrophe. Highlights: ► HKL-1 is a potential antimitotic agent against HL-60 cells. ► HKL-1 induces spindle disruption and sustained resulted in mitotic catastrophe. ► CENP-E and aurora B protein expressions significantly reduced. ► Bcl-2 family protein expressions altered and caspase-9/-3 activation. ► HKL-1 is an attractive candidate for possible use as a novel antimitotic agent.

  15. Inhibition of Anchorage-Independent Proliferation and G0/G1 Cell-Cycle Regulation in Human Colorectal Carcinoma Cells by 4,7-Dimethoxy-5-Methyl-l,3-Benzodioxole Isolated from the Fruiting Body of Antrodia camphorate

    Hsiu-Man Lien

    2011-01-01

    Full Text Available In this study, 4,7-dimethoxy-5-methyl-l,3-benzodioxole (SY-1 was isolated from three different sources of dried fruiting bodies of Antrodia camphorate (AC. AC is a medicinal mushroom that grows on the inner heartwood wall of Cinnamomum kanehirai Hay (Lauraceae, an endemic species that is used in Chinese medicine for its anti-tumor and immunomodulatory properties. In this study, we demonstrated that SY-1 profoundly decreased the proliferation of human colon cancer cells (COLO 205 through G0/G1 cell-cycle arrest (50–150 μM and induction of apoptosis (>150 μM. Cell-cycle arrest induced by SY-1 was associated with a significant increase in levels of p53, p21/Cip1 and p27/Kip1, and a decrease in cyclins D1, D3 and A. In contrast, SY-1 treatment did not induce significant changes in G0/G1 phase cell-cycle regulatory proteins in normal human colonic epithelial cells (FHC. The cells were cultured in soft agar to evaluate anchorage-independent colony formation, and we found that the number of transformed colonies was significantly reduced in the SY-1-treated COLO 205 cells. These findings demonstrate for the first time that SY-1 inhibits human colon cancer cell proliferation through inhibition of cell growth and anchorage-independent colony formation in soft agar. However, the detailed mechanisms of these processes remain unclear and will require further investigation.

  16. Influence of substituents on chemical shift of {delta}({sup 13}C) in the series of 5-methyl-5H-indole [2,3-b]quinoline derivatives; Wplyw podstawnikow na przesuniecie chemiczne {sigma}({sup 13}C) w serii pochodnych 5-metylo-5H-indolo-[2,3-b]chinoliny

    Kamienska-Trela, K.; Kania, L.; Kaczmarek, L. [Inst. Chemii Organicznej, Polska Akademia Nauk, Warsaw (Poland)

    1994-12-31

    {sup 13}C NMR spectra of series of 5-methyl-5H-indole quinoline substituted with different groups and their number have been measured. The influence of steric and electronic properties of substituents on observed chemical shifts of {sup 13}C nuclei have been discussed. 1 fig., 1 tab.

  17. 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

    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.

  18. Use of sequence microdivergence in mycobacterial ortholog to analyze contributions of the water-activating loop histidine of Escherichia coli uracil-DNA glycosylase in reactant binding and catalysis

    Uracil-DNA glycosylase (Ung), a DNA repair enzyme, pioneers uracil excision repair pathway. Structural determinations and mutational analyses of the Ung class of proteins have greatly facilitated our understanding of the mechanism of uracil excision from DNA. More recently, a hybrid quantum-mechanical/molecular mechanical analysis revealed that while the histidine (H67 in EcoUng) of the GQDPYH motif (ω loop) in the active site pocket is important in positioning the reactants, it makes an unfavorable energetic contribution (penalty) in achieving the transition state intermediate. Mutational analysis of this histidine is unavailable from any of the Ung class of proteins. A complication in demonstrating negative role of a residue, especially when located within the active site pocket, is that the mutants with enhanced activity are rarely obtained. Interestingly, unlike the most Ung proteins, the H67 equivalent in the ω loop in mycobacterial Ung is represented by P67. Exploiting this natural diversity to maintain structural integrity of the active site, we transplanted an H67P mutation in EcoUng. Uracil inhibition assays and binding of a proteinaceous inhibitor, Ugi (a transition state substrate mimic), with the mutant (H67P) revealed that its active site pocket was not perturbed. The catalytic efficiency (Vmax/Km) of the mutant was similar to that of the wild type Ung. However, the mutant showed increased Km and Vmax. Together with the data from a double mutation H67P/G68T, these observations provide the first biochemical evidence for the proposed diverse roles of H67 in catalysis by Ung

  19. Electron spin resonance and intermediate neglect of differential overlap molecular orbital study of the π cations of (hydroxymethyl)uracil and (hydroxymethyl)cytosine. Evidence for internal hydrogen bonding

    The π-cation radicals of 5-(hydroxymethyl)uracil (HOMeU) and 5-(hydroxymethyl)cytosine (HOMeC) have been produced by Cl2- attack in γ-irradiated basic 12 M LiCl and photoionization in basic 8 M NaClO4 glasses at low temperatures. Analysis of the ESR spectra found for these radicals shows that each of the π-cation radicals converts to another species probably by a change in a nitrogen protonation state as the temperature is raised. For example, 5-(hydroxymethyl)uracil cation shows a 28.5-G average splitting for the two hydroxymethyl-group β protons which convert upon annealing to a 36-G splitting. The splittings and the narrowness of the line widths found after annealing are suggestive of a configuration which is intramolecularly rigid and stabilized by a intramolecular hydrogen bond from the hydroxyl proton to the 4-position oxygen. The π cation of 5-(hydroxymethyl)cytosine converts to a radical with substantial spin density on the exocyclic nitrogen which again shows strong evidence for intramolecular hydrogen bonding. Final radicals are found to be produced from the π-cation radicals of (hydroxymethyl)uracil and (hydroxymethyl)cytosine by deprotonation of a methylene proton. INDO calculations for the π cation of (hydroxymethyl)uracil as a function of orientation of the hydroxyl group show that the hydrogen bond to the 4-position oxygen increases in strength by a factor of 3 upon deprotonation at the 3-position nitrogen. The hydrogen bond is therefore predicted to substantially stabilize the π-cation radical

  20. Molecular mechanisms induced by the effects of ionizing radiation on nucleic acids: Free radicals in 5-halogenated uracil derivatives after reaction of radiolysis products of water in low-temperature glass

    This thesis deals with the molecular mechanisms induced by the effects of ionizing radiation on the DNA. The study has been made for the main purpose of clarifying the possible role of the indirect effect, namely the attack of diffusible water radicals, in the process of radiosensitivity enhancement due to the incorporation of bromouracil instead of thymine into the DNA. The results of the experiments can be summarized by the statement that among the reactions studied in the low-temperature glasses, none revealed such a clear difference between uracil and thymine on the one hand, and the halogenated uracils on the other, that this difference could suffice to explain in terms of quality and quantity the observed in-vivo enhancement of radiosensitivity by halogenated uracils. This conclusion is in agreement with the results of radiobiological measurements on phagae and bacteria which in all cases revealed no or only very slight enhancement of the radiosensitivity in the indirect effect subsequent to bromouracil incorporation. (orig./AJ)

  1. Magnetic behavior of MnPS3 phases intercalated by [Zn2L]2+ (LH2: macrocyclic ligand obtained by condensation of 2-hydroxy-5-methyl-1,3-benzenedicarbaldehyde and 1,2-diaminobenzene)

    The intercalation of the cationic binuclear macrocyclic complex [Zn2L]2+ (LH2: macrocyclic ligand obtained by the template condensation of 2-hydroxy-5-methyl-1,3-benzenedicarbaldehyde and 1,2-diaminobenzene) was achieved by a cationic exchange process, using K0.4Mn0.8PS3 as a precursor. Three intercalated materials were obtained and characterized: (Zn2L)0.05K0.3Mn0.8PS3(1), (Zn2L)0.1K0.2Mn0.8PS3(2) and (Zn2L)0.05K0.3Mn0.8PS3(3), the latter phase being obtained by an assisted microwave radiation process. The magnetic data permit to estimate the Weiss temperature θ of ∼-130 K for (1); ∼-155 K for (2) and ∼-130 K for (3). The spin canting present in the potassium precursor remains unperturbed in composite (3), and spontaneous magnetization is observed under 50 K in both materials. However composites (1) and (2) do not present this spontaneous magnetization at low temperatures. The electronic properties of the intercalates do not appear to be significantly altered. The reflectance spectra of the intercalated phases (1), (2) and (3) show a gap value between 1.90 and 1.80 eV, lower than the value observed for the K0.4Mn0.8PS3 precursor of 2.8 eV. -- Graphical Abstract: Microwave assisted synthesis was used to obtain an intercalated MnPS3 phase with a binuclear Zn(II) macrocyclic complex. A comparative magnetic study of the composites obtained by assisted microwave and traditional synthetic methods is reported. Display Omitted Highlights: → A rapid and efficient preparation of intercalated MnPS3 composites by assisted microwave synthesis is described. → The exchange of potassium ions of the precursor by the macrocyclic Zn(II) complex is partial. → The composite obtained by assisted microwave synthesis retains the spontaneous magnetization, observed in the low temperature range of the magnetic susceptibility of the potassium precursor. → The materials obtained by the conventional method loose the spontaneous magnetization in the low temperature range, which

  2. Positive allosteric modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors differentially modulates the behavioural effects of citalopram in mouse models of antidepressant and anxiolytic action.

    Fitzpatrick, Ciarán M; Larsen, Maria; Madsen, Louise H; Caballero-Puntiverio, Maitane; Pickering, Darryl S; Clausen, Rasmus P; Andreasen, Jesper T

    2016-09-01

    Drugs that increase monoamine neurotransmission are effective in both anxiety and depression. The therapeutic effects of monoamine-based antidepressant drugs may involve indirect effects on neurotransmission through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR). Thus, chronic antidepressant treatment increases AMPAR-mediated neurotransmission and AMPAR-positive allosteric modulators have shown antidepressant-like efficacy in rodents. Here, the effect of enhanced AMPAR neurotransmission on the antidepressant-like and anxiolytic-like actions of the selective serotonin reuptake inhibitor citalopram (0-10 mg/kg) was investigated in mice using the AMPAR-positive allosteric modulator LY451646 (0-3 mg/kg). Antidepressant-like effects were assessed using the forced-swim test (FST), whereas anxiolytic-like effects were tested using the elevated zero maze (EZM) and the marble burying test. LY451646 (3 mg/kg) increased swim distance in the FST and a subactive dose of LY451646 (1 mg/kg) enhanced the effect of citalopram in the FST. In the EZM, LY451646 (3 mg/kg) did not show anxiogenic effects alone, but blocked the anxiolytic-like action of citalopram in the EZM, as reflected by an increase in the latency to enter the open areas and a decrease in the number of entries and time spent in the open areas in citalopram-treated mice. In the marble burying test, LY451646 (3 mg/kg) showed no effect alone, but significantly attenuated the anxiolytic-like effect of citalopram (1.25-2.5 mg/kg) by increasing the number of marbles buried in citalopram-treated mice. These results suggest that AMPAR neurotransmission plays opposite roles in anxiety and depression as AMPAR potentiation facilitated the antidepressant-like effects of citalopram while attenuating its anxiolytic-like effect. These findings have ramifications in the search for AMPAR-based novel anxiolytic and antidepressant treatments. PMID:27341500

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

    Teimoory, Faranak; Loppnow, Glen R

    2016-05-01

    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. PMID:26717253

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

    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.

  5. 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

    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.

  6. 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

    Jensen, Anders A.; Christesen, Thomas; Bølcho, Ulrik; Greenwood, Jeremy R; Postorino, Giovanna; Vogensen, Stine B; Johansen, Tommy N; Egebjerg, Jan; Bräuner-Osborne, Hans; Clausen, Rasmus P

    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...

  7. The in vivo antitumor effects on human COLO 205 cancer cells of the 4,7-dimethoxy-5-(2-propen-1-yl)-1,3-benzodioxole (apiole) derivative of 5-substituted 4,7-dimethoxy-5-methyl-l,3-benzodioxole (SY-1) isolated from the fruiting body of Antrodia camphorate

    Po-Li Wei; Shih-Hsin Tu; Hsiu-Man Lien; Li-Ching Chen; Ching-Shyang Chen; Chih-Hsiung Wu; Ching-Shui Huang; Hui-Wen Chang; Chien-Hsi Chang; How Tseng; Yuan-Soon Ho

    2012-01-01

    Context: The compound 4,7-dimethoxy-5-(2-propen-1-yl)-1,3-benzodioxole (apiole) has been isolated from several different plant species, including Petroselinum sativum. Our recent study found that apiole is a chemical derivative of 4,7-dimethoxy-5-methyl-l,3-benzodioxole (SY-1), which has been isolated from dried Antrodia camphorata (AC ) fruiting bodies, a traditional Chinese medicine with antitumor properties. Aims: Our previous in vitro study demonstrated that apiole inhibits the growth ...

  8. Preoperative Chemoradiotherapy for Rectal Cancer: Randomized Trial Comparing Oral Uracil and Tegafur and Oral Leucovorin Vs. Intravenous 5-Fluorouracil and Leucovorin

    Purpose: To compare, in a randomized trial, 5-fluorouracil (FU) plus leucovorin (LV) (FU+LV) vs. oral uracil and tegafur (UFT) plus LV (UFT+LV) given concomitantly with preoperative irradiation in patients with cT3-4 or N+ rectal cancer. Methods and Materials: A total of 155 patients were entered onto the trial. Patients received pelvic radiotherapy (4500-5,040 cGy in 5 to 6 weeks) and chemotherapy consisting of two 5-day courses of 20 mg/m2/d LV and 350 mg/m2/d FU in the first and fifth weeks of radiotherapy (77 patients) or one course of 25 mg/d oral LV and 300 mg/m2/d UFT for 4 weeks beginning in the second week of radiotherapy (78 patients). The primary endpoints were pathologic complete response (pCR) and resectability rate. Secondary endpoints included downstaging rate, toxicity, and survival. Results: Grade 3-5 acute hematologic toxicity occurred only with FU+LV (leukopenia 9%; p = 0.02). There were no differences in resectability rates (92.1% vs. 93.4%; p = 0.82). The pCR rate was 13.2% in both arms. Tumor downstaging was more frequent with UFT+LV (59.2% vs. 43.3%; p = 0.04). Three-year overall survival was 87% with FU+LV and 74% with UFT+LV (p = 0.37). The 3-year cumulative incidences of local recurrence were 7.5% and 8.9%, respectively (p = 0.619; relative risk, 1.46; 95% confidence interval 0.32-6.55). Conclusion: Although this study lacked statistical power to exclude clinically significant differences between both groups, the outcome of patients treated with UFT+LV did not differ significantly from that of patients treated with FU+LV, and hematologic toxicity was significantly lower in the experimental arm

  9. Avirulent Uracil Auxotrophs Based on Disruption of Orotidine-5′-Monophosphate Decarboxylase Elicit Protective Immunity to Toxoplasma gondii ▿ †

    Fox, Barbara A.; Bzik, David J.

    2010-01-01

    The orotidine-5′-monophosphate decarboxylase (OMPDC) gene, encoding the final enzyme of the de novo pyrimidine biosynthesis pathway, was deleted using Toxoplasma gondii KU80 knockouts to develop an avirulent nonreverting pyrimidine auxotroph strain. Additionally, to functionally address the role of the pyrimidine salvage pathway, the uridine phosphorylase (UP) salvage activity was knocked out and a double knockout of UP and OMPDC was also constructed. The nonreverting ΔOMPDC, ΔUP, and ΔOMPDC ΔUP knockout strains were evaluated for pyrimidine auxotrophy, for attenuation of virulence, and for their ability to elicit potent immunity to reinfection. The ΔUP knockout strain was replication competent and virulent. In contrast, the ΔOMPDC and ΔOMPDC ΔUP strains were uracil auxotrophs that rapidly lost their viability during pyrimidine starvation. Replication of the ΔOMPDC strain but not the ΔOMPDC ΔUP strain was also partially rescued in vitro with uridine or cytidine supplementation. Compared to their hypervirulent parental type I strain, the ΔOMPDC and ΔOMPDC ΔUP knockout strains exhibited extreme attenuation in murine virulence (∼8 logs). Genetic complementation of the ΔOMPDC strain using a functional OMPDC allele restored normal replication and type I parental strain virulence phenotypes. A single immunization of mice with either the live critically attenuated ΔOMPDC strain or the ΔOMPDC ΔUP knockout strain effectively induced potent protective immunity to lethal challenge infection. The avirulent nonreverting ΔOMPDC and ΔOMPDC ΔUP strains provide new tools for the dissection of the host response to infection and are promising candidates for safe and effective Th1 vaccine platforms that can be easily genetically engineered. PMID:20605980

  10. Development and validation of a rapid and sensitive UPLC-MS/MS method for determination of uracil and dihydrouracil in human plasma.

    Jacobs, Bart A W; Rosing, Hilde; de Vries, Niels; Meulendijks, Didier; Henricks, Linda M; Schellens, Jan H M; Beijnen, Jos H

    2016-07-15

    Quantification of the endogenous dihydropyrimidine dehydrogenase (DPD) substrate uracil (U) and the reaction product dihydrouracil (UH2) in plasma might be suitable for identification of patients at risk of fluoropyrimidine-induced toxicity as a result of DPD deficiency. In this paper, we describe the development and validation of a rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay for quantification of U and UH2 in human plasma. Analytes were extracted by protein precipitation, chromatographically separated on an Acquity UPLC(®) HSS T3 column with gradient elution and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. U was quantified in the negative ion mode and UH2 in the positive ion mode. Stable isotopes for U and UH2 were used as internal standards. Total chromatographic run time was 5min. Validated concentration ranges for U and UH2 were from 1 to 100ng/mL and 10 to 1000ng/mL, respectively. Inter-assay bias and inter-assay precision for U were within ±2.8% and ≤12.4%. For UH2, inter-assay bias and inter-assay precision were within ±2.9% and ≤7.2%. Adequate stability of U and UH2 in dry extract, final extract, stock solution and plasma was demonstrated. Stability of U and UH2 in whole blood was only satisfactory when stored up to 4hours at 2-8°C, but not at ambient temperatures. An accurate, precise and sensitive UPLC-MS/MS assay for quantification of U and UH2 in plasma was developed. This assay is now applied to support clinical studies with fluoropyrimidine drugs. PMID:27179185

  11. {sup 1}H and {sup 13}C NMR spectroscopy of 5-methyl-5H-indole-[2,3-b]quinoline; Spektroskopia {sup 1}H i {sup 13}C NMR 5-metylo-5H-indole-[2,3-b]chinoliny

    Kamienska-Trela, K.; Kania, L.; Kaczmarek, L. [Inst. Chemii Organicznej, Polska Akademia Nauk, Warsaw (Poland)

    1994-12-31

    {sup 1}H and {sup 13}C NMR spectra of 5-methyl-5H-indole quinoline have been measured in CDCl{sub 3} solution. The full assignation of resonant signals observed for this compound has been done. Also the chemical shifts {delta}({sup 1}H) and {delta}({sup 13}C) have been determined. That parameters as being tightly dependent on electronic density in molecule are very important also from the view point of biological activity of investigated compound. 3 refs, 1 fig., 1 tab.

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

    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.

  13. Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase

    TSUJIMOTO, HIROAKI; TSUKIOKA, SAYAKA; ONO, SATORU; SAKAMOTO, ETSUKO; SAKAMOTO, KAZUKI; TSUTA, KOHJI; NAKAGAWA, FUMIO; SAITO, HITOSHI; UCHIDA, JUNJI; KINIWA, MAMORU; FUKUSHIMA, MASAKAZU

    2010-01-01

    The combination of oral tegafur-uracil (UFT) with leucovorin (LV) is used to treat patients with stage II to III colon cancer based on the results of postoperative randomized studies in which UFT/LV treatment showed an equivalent efficacy to intravenous 5-FU plus LV therapy. However, whether the addition of LV to UFT can elevate the antitumor activity of UFT in colorectal tumors with high expression levels of thymidylate synthase (TS), which affects 5-FU efficacy, remains to be clarified. This study investigated the effect of LV on the antitumor activity of UFT and/or 5-FU prodrugs in low folate diet-fed nude mice using human colorectal cancer xenografts with various expression levels of TS. The addition of LV to UFT resulted in a 55–79% inhibition of tumor growth among 11 types of colorectal tumor xenograft, whereas UFT alone showed 23–67% antitumor activity. Although there was an inverse relationship between the antitumor effect of UFT alone and UFT plus LV and tumoral TS activity, UFT plus LV appeared to have a more potent antitumor effect than UFT alone on colorectal tumors such as Co-3 and KM12C/5-FU with high expression levels of TS. This finding was confirmed by the significant positive correlation between the relative inhibition ratio of UFT/LV to UFT alone and TS levels in tumors. To investigate the reason for the higher efficacy of UFT/LV on colorectal cancer xenografts with high TS activity, intratumoral levels of reduced folates and a ternary complex of TS after oral UFT with or without LV were measured using Co-3 xenografts. Elevated levels of reduced folates and an increased ternary complex of TS in LV-treated tumors were noted. Our results indicate that a combined therapy of UFT with LV may contribute to the treatment of colorectal cancer patients with low and high expression levels of tumoral TS by increased formation of the ternary complex of TS leading to potentiated antitumor efficacy of UFT. PMID:22870097

  14. Imaging herpes viral thymidine kinase-1 reporter gene expression with a new 18F-labeled probe: 2'-fluoro-2'-deoxy-5-[18F]fluoroethyl-1-β-D-arabinofuranosyl uracil

    The preparation and radiolabeling of 2'-fluoro-2'-deoxy-1-β-D-arabinofuranosyl-5-(2-fluoroethyl)-uracil (FFEAU) with 18F and its evaluation as a probe for imaging herpes simplex virus 1 thymidine kinase (HSV1-tk) gene expression are described. 2'-Fluoro-2'-deoxy-3',5'-di-O-benzoyl-1-β-D-arabinofuranosyl-3-N-benzoyl-5- (2-[18F]fluoroethyl)-uracil 12 was prepared by nucleophilic substitution of the corresponding tosyl 8 or trifluoroethanesulfonyl 9 derivative with n-Bu4N[18F]F. Base hydrolysis was used to remove the benzoyl protecting groups, followed by HPLC purification, to afford [18F]FFEAU 13. The trifluoroethanesulfonyl substrate 9 appears to be the better labeling precursor. Carrier n-Bu4NF was added to the labeling reaction, which resulted in specific activities of 40-70 Ci/mmol (estimated). Radiochemical purity averaged 94±4%. Although [18F]FFEAU was obtained in low radiochemical yield with 9 and further optimization of the radiosynthesis will be required, sufficient product was available for a series of in vitro and in vivo studies. [18F]FFEAU was directly compared with [3H]TdR in a series of in vitro accumulation studies involving a HSV1-tk stably transduced cell line, RG2TK+ and a nontransduced, wild-type RG2 cells. The initial in vitro and in vivo imaging studies are promising; FFEAU has in vitro accumulation and sensitivity characteristics similar to that previously reported for FIAU, but greater selectivity than FIAU due to lower uptake and retention in nontransduced cells and tissues. The animal imaging experiment showed low levels of radioactivity in the lungs, with little or no radioactivity seen in the heart, liver, spleen and intestines.

  15. Effects of 6-methyl-uracil upon the phagocytic activity in mice following whole-body X-irradiation or 2,4,6,-triethyleneimino-s-triazine treatment

    1. Phagocytic activity measured by means of the intravasal clearence of a soot dispersion in male NMRI-mice was increased six to ten days after whole-body X-irradiation (640 R) and decreased during the same period after i.v. administration of 2,4,6-triethyleneimino-s-triazine (TEM 2.0 mg/kg). 2. By means of 6-methyl-uracil food admixtures (200 to 400 ppm during 2 or 3 weeks) or by repeated intravenous injections of a N-methyl-D-glucosamine-6-methyluracil complex (62.5 to 250 mg/kg daily during five days), a significant augmentation of the phagocytic index being related to time and dosage was obtained in otherwise untreated mice. Comparable results were seen using cytidine and cytidine-5'-phosphate, whereas guanosine-5'-phosphate remained ineffective. 3. Whilst stimulating effects of 6-methyl-uracil or its N-methyl-D-glucosamine complex on X-irradiated mice were suspended, an increase up to supernormal values of the phagocytic index was produced by the pyrimidine base in animals treated with TEM. In accordance to this the survival rate of lethally X-irradiated mice (960 R) could not be increased; with animals given lethal TEM-doses, however, a significantly increased survival rate was obtained. 4. The present investigations as well as former biochemical analyses confirm the assumption that 6-methyluracil produces its regeneration effects, to some extent at least, by specific pathways influencing the reticuloendothelium. Different results from X-irradiated and TEM-treated mice are referring to the different points of attack of the two noxa. (orig.)

  16. Comment on "Structural and vibrational studies on 1-(5-Methyl- [1,3,4] thiadiazol-2-yl)-pyrolidin-2-ol" [Spectrochimica Acta Part A, 152 (2016) 252-261]. The importance of intramolecular OH⋯N hydrogen bonding in the conformational properties of thiadiazol-pyrrolidin-2-ol bearing species.

    Laurella, Sergio L; Erben, Mauricio F

    2016-07-01

    The title paper [1] reports a study on the spectroscopic and physicochemical properties of 1-(5-methyl- [1,3,4]thiadiazol-2-yl)-pyrrolidin-2-ol (MTPN) based on experimental and theoretical data. The latter ones are based on the computed molecular structure for a rather unusual conformer. Here, after a careful analysis of the conformational space of MTPN, the most stable conformation was determined for the molecule isolated in a vacuum, which results to be 21.9kJ/mol more stable than the conformer reported previously. Our study also includes the closely related species 1-(5-trifluoromethyl- [1,3,4]thiadiazol-2-yl)-pyrrolidin-2-ol (FMTPN). An intramolecular OH⋯N hydrogen bond determines the conformational behavior of the [1,3,4]thiadiazol-2-yl)-pyrrolidin-2-ol group as demonstrated by Natural Bond Orbital population analysis. PMID:27070529

  17. 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

    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

  18. Current progress of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptor trafficking in learning and memory%α-氨基-3羟基-5-甲基-4-异恶唑丙酸受体运输参与学习记忆机制的研究进展

    王苗苗; 王超; 杨美华; 王国林

    2014-01-01

    Background α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors mediate the overwhelming majority of excitatory synaptic transmission in the central nervous system.Postsynaptic AMPA receptor trafficking is closely related to learning and memory.Objective To review the relationship between postsynaptic AMPA receptor trafficking and learning and memory.Content This review introduces the changes of AMPA receptor trafficking and the underlying mechanisms in long-term potentiation (LTP) and long-term depression (LTD)-the two most characterized forms of synaptic plasticity.Both forms of synaptic plasticity are thought to be the cellular basis of learning and memory.The phosphorylation of multiple proteins and the modification of related signaling molecules and pathways are involved in these processes.The role of AMPA receptor trafficking in learning and memory behavior is also discussed.Trend To provide new ideas for dissecting the mechanisms of learning and memory related neurodegenerative diseases.%背景 α-氨基-3羟基-5-甲基-4-异恶唑丙酸(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptor,AMPA)受体介导中枢神经系统大多数兴奋性突触传递,其在突触后膜的运输与学习记忆密切相关. 目的 对AMPA受体在突触后膜的运输与学习记忆的关系作用进行归纳和小结. 内容 介绍AMPA受体运输在学习记忆的重要细胞学基础-突触可塑性的两种主要形式长时程增强(long-term potentiation,LTP)和长时程抑制(long-term depression,LTD)中的改变及其可能机制,涉及多个蛋白的磷酸化和参与调节其改变的信号分子及通路,并说明AMPA受体运输参与相关的学习记忆行为. 趋向 为学习记忆受损相关神经退行性疾病的发生机制的探索提供思路.

  19. 3-Ethylsulfinyl-2-(4-iodophenyl-5-methyl-1-benzofuran

    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].

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

    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.

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

    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].

  2. 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?

    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. PMID:26580317

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

    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.

  4. 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

    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.

  5. Old and new pharmacology: positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C) receptor antagonist SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']di pyrrole-1(2H)-carboxamide).

    Dunlop, John; Lock, Tim; Jow, Brian; Sitzia, Fabrizio; Grauer, Steven; Jow, Flora; Kramer, Angela; Bowlby, Mark R; Randall, Andrew; Kowal, Dianne; Gilbert, Adam; Comery, Thomas A; Larocque, James; Soloveva, Veronica; Brown, Jon; Roncarati, Renza

    2009-03-01

    The alpha7 nicotinic acetylcholine receptor (nAChR) has been implicated in Alzheimer's disease and schizophrenia, leading to efforts targeted toward discovering agonists and positive allosteric modulators (PAMs) of this receptor. In a Ca2+ flux fluorometric imaging plate reader assay, SB-206553 (3,5-dihydro-5-methyl -N-3-pyridinylbenzo [1, 2-b:4,5 -b']-di pyrrole-1(2H)-carboxamide), a compound known as a 5-hydroxytryptamine(2B/2C) receptor antagonist, produced an 8-fold potentiation of the evoked calcium signal in the presence of an EC(20) concentration of nicotine and a corresponding EC(50) of 1.5 muM for potentiation of EC(20) nicotine responses in GH4C1 cells expressing the alpha7 receptor. SB-206553 was devoid of direct alpha7 receptor agonist activity and selective against other nicotinic receptors. Confirmation of the PAM activity of SB-206553 on the alpha7 nAChR was obtained in patch-clamp electrophysiological experiments in GH4C1 cells, where it failed to evoke any detectable currents when applied alone, yet dramatically potentiated the currents evoked by an EC(20) (17 microM) and EC(100) (124 microM) of acetylcholine (ACh). Native nicotinic receptors in CA1 stratum radiatum interneurons of rat hippocampal slices could also be activated by ACh (200 microM), an effect that was entirely blocked by the alpha7-selective antagonist methyllycaconitine (MLA). These ACh currents were potentiated by SB-206553, which increased the area of the current response significantly, resulting in a 40-fold enhancement at 100 microM. In behavioral experiments in rats, SB-206553 reversed an MK-801 (dizocilpine maleate)-induced deficit in the prepulse inhibition of acoustic startle response, an effect attenuated in the presence of MLA. This latter observation provides further evidence in support of the potential therapeutic utility of alpha7 nAChR PAMs in schizophrenia. PMID:19050173

  6. 2-(2-羟基-5-甲基-3-叔丁基苯甲基)-4-甲基-6-叔丁基苯基乙酸酯的合成%SYNTHESIS OF 2-[ 1-( 2-HYD R O XY-3-tert-B UTYL-5-METHYL )-ETHYL]-4-METHYL-6-tert-BUTYLPHENYL ACETATE

    杜飞; 范延超

    2011-01-01

    By performing the thermal aging experiments of the polymeric material added antioxidant 2, 2'-methylenebis(4-methyl-6-tert-butyl phenol)(2246), it became a dimmer while showing its anti-aging performance, which caused the polymeric material changed to yellow gradually.In order to correct the defect, the study on 2246 synthesized through esterification acetyl chloride and 2-[1-(2-hydroxy-3tert-butyl-5-methyl)-ethyl]-4-methyl-6-tert-butylphenyl to replace 2246.This product can prevent from absorbing visible light which is achromatous.At the same time it can form a quinine derivative by absorbing ultraviolet radiation which could inversely transform itself by a exothermic process.Under the following optimal conditions:n(2246)∶n(acetyl chloride)∶n(triethylaamine)=1.00∶1.14∶ 1.20,73-77℃, and 4 h, the product was synthesized with the conversion of 98.5%, molar yield of 97.0%,product purity of 99.6%and melting point of 101.3-102.5℃.IR,1H NMR confirmed the structure of the product.%以抗氧剂2246和乙酰氯为原料,进行单酚羟基酯化反应,合成了2-(2-羟基-5-甲基-3-叔丁基苯甲基)-4-甲基-6-叔丁基苯基乙酸酯(简称抗氧剂2246单乙酸酯),作为传统抗氧剂2246的更新换代产品.合成抗氧剂2246单乙酸酯的最佳工艺条件是:n(抗氧剂2246)∶n(乙酰氯):n(三乙胺)=1.00∶1.15∶1.20,反应温度73~77℃、反应时间4 h,合成抗氧剂2246单乙酸酯的原料转化率99.0%,产物选择性98.5%,收率97.0%,产物质量分数99.2%,熔点101.3~102.5℃.产物结构经IR、1H NMR进行了确证.

  7. 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

    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.

  8. HIV-1逆转录酶抑制剂的合成及活性评价%Synthesis and anti-HIV-1 activity evaluation of N-1-alkyl-5-halogeno-6-alkylamino uracils as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

    闫寒; 王孝伟; 郭盈; 张志丽; 刘俊义

    2011-01-01

    N-1-alkyl-5-halogeno-6-alkylamino uracils, which are novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)analogues, were synthesized as the selective and potent non-nucleoside human immunodeficiency virus(HIV)-1 reverse transcriptase inhibitors. Some of the compounds showed potent inhibitory activity against HIV-1 reverse transcriptase. For instance, compounds ld, lm and In exhibited potent anti-HIV-1 activity with the ICso values of 13.3, 11.7 and 3.15 gM, respectively,which are comparable to that of nevirapinc(IC5O 8.38 μM).%本研究以HIV-1逆转录酶为靶点,设计了一类具有HEPT类结构的化合物:1-乙氧基甲基/苄氧基甲基-5-卤代-6-脂肪胺尿嘧啶作为抑制剂,并对合成的目标化合物进行了生物活性测定,一些化合物显示出较强的抗HIV生物活性,与对照物奈韦拉平相比(IC50 8.30μM)化合物1d,1m和1n的IC50 值分别达到了13.3,11.7和3.15 μM.

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

    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.

  10. 2-Amino-5-methyl­pyridinium 4-hydroxy­benzoate

    Hemamalini, Madhukar; Fun, Hoong-Kun

    2010-01-01

    In the title salt, C6H9N2 +·C7H5O3 −, the carboxyl­ate mean plane of the 4-hydroxy­benzoate anion is twisted by 13.07 (4)° from the attached ring. In the crystal structure, the ions are linked into a two-dimensional network by N—H⋯O, O—H⋯O and C—H⋯O hydrogen bonds. Within this network, the N—H⋯O hydrogen bonds generate R 2 2(8) ring motifs. In addition, π–π inter­actions involving the pyridinium rings, with a centroid–centroid distance of 3.7599 (4) Å, are observed....

  11. 1-(4-Chlorophenyl)-3-(5-methyl-2-furyl)prop-2-en-1-one

    Huan-Mei Guo

    2009-01-01

    The title compound, C14H11ClO2, was prepared from 4-chlorohypnone and 5-methylfurfural by an aldol condensation reaction. The dihedral angle formed between the two benzene rings is 7.71 (2)°. The crystal structure is stabilized by C—H...O interactions.

  12. 1-(4-Chlorophenyl-3-(5-methyl-2-furylprop-2-en-1-one

    Huan-Mei Guo

    2009-11-01

    Full Text Available The title compound, C14H11ClO2, was prepared from 4-chlorohypnone and 5-methylfurfural by an aldol condensation reaction. The dihedral angle formed between the two benzene rings is 7.71 (2°. The crystal structure is stabilized by C—H...O interactions.

  13. La 5-methyl-3phenyl-4isoxazolyl penicilina en infecciones producidas por estafilococo productor de penicilinasa

    Rocha Posada, Hernando

    2011-01-01

    Durante el tiempo comprendido entre 1941 y 1959, sólo fue posible obtener 7 preparados penicilínicos, debido a ciertas limitaciones y dificultades de la técnica de fermentación biosintética. Estos compuestos o derivados fueron las  penicilinas K, F, dihidro F, X, 0, V Y G, con semejanzas y diferencias antibacterianas frente a los diferentes microorganismos y por lo tanto con variada actividad terapéutica. A pesar de tratarse del más antiguo de los antibióticos y de ser el más extensamente usa...

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

    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...

  15. Pharmacokinetic studies on 5-methyl-iminodiacetic acid vanillin (MIDAV) in rabbits

    MIDAV (code 7603) is a new chelating agent which has been shown to have remarkable effect in the removal of radio thorium and radiocerium in animal experiment. The pharmacokinetics of MIDAV was studied in rabbits. The rabbits were divided into three groups, each group has five male animals. In two groups of them, 50 and 100 mg/kg of MIDAV was administered i.v., respectively and in third one, 250 mg/kg was injected (im.). The serum level of MIDAV after i.v. administration was fitted to a two-compartment open model. The pharmacokinetic equation for the group injected i.v. with 100 mg/kg was as follows: c(t) = 1174e-28.6t + 190e-0.81t. The serum level of the compound after im. injection was described by one-compartment open model. The results show that the absorption, distribution and excretion of MIDAV in rabbit body were rather fast

  16. 2-(2-Chlorophenyl-5-methyl-1,3-dioxane-5-carboxylic acid

    Guo-Kai Jia

    2012-07-01

    Full Text Available In the title compound, C12H13ClO4, the 1,3-dioxane ring adopts a chair conformation and the 2-chlorobenzene and methyl substituents occupy equatorial sites. The carboxyl group is in an axial inclination. In the crystal, carboxylic acid inversion dimers linked by pairs of O—H...O hydrogen bonds generate R22(8 loops.

  17. Oxidative damage to 5-methylcytosine in DNA.

    Zuo, S; Boorstein, R J; Teebor, G.W.

    1995-01-01

    Exposure of pyrimidines of DNA to ionizing radiation under aerobic conditions or oxidizing agents results in attack on the 5,6 double bond of the pyrimidine ring or on the exocyclic 5-methyl group. The primary product of oxidation of the 5,6 double bond of thymine is thymine glycol, while oxidation of the 5-methyl group yields 5-hydroxymethyluracil. Oxidation of the 5,6 double bond of cytosine yields cytosine glycol, which decomposes to 5-hydroxycytosine, 5-hydroxyuracil and uracil glycol, al...

  18. Cytosine deaminase and uracil phosphoribosyl transferase inhibition of transplantation tumor gene fusion%胞嘧啶脱氨酶和尿嘧啶磷酸核糖转移酶融合基因对食管癌裸鼠移植瘤的抑制作用

    潘雪; 李向楠; 王鹏; 侯晓旭

    2015-01-01

    Objective To study the multidrug resistance gene 1 (MDR1) promoter regulated cytosine deaminase and uracil phosphoribosyltransferase fusion gene (CD:UPRT) killing of esophageal cancer cells in nude mice EC9706 cells.Methods 0.2 ml EC9706 cells were inoculated subcutaneously in nude mice and esophageal cancer xenograft model to build and build pAdTrack-MDR1-CD:UPRT plasmids,were randomly divided into three groups of treated and observed 30 d,tumor volume was measured using the V =x × y2/2 (x long diameter,y for short diameter).Routine pathological examination of tumor tissue,immunohistochemical detection of CD protein.Results Successfully constructed subcutaneous xenograft model of esophageal cancer,treatment for 30 days,group B,group C rapid tumor growth,surface necrosis,tumor volume was (3.21 ±0.23) cm3,(3.15 ±0.22) cm3;A group of tumor growth restrained,the first 30 days volume (cm3),compared to the difference of (0.98 ±0.15) was statistically significant (P <0.05).A group of tumor cells arranged in a sparse,large areas of necrosis red dye,partially visible condensation nuclei,nuclear fragmentation;group B,group C tumor cells tightly packed,rich in blood vessels,cell morphology and cell nuclei were pleomorphic,and a large stained mitotic common.After immunohistochemical staining,A,group B tumor tissues were positive,indicating that the protein expression of CD,group C immunohistochemical staining of tumor tissue was negative.Conclusion MDR1 promoter regulated CD:UPRT/5-fluorocytosine (5-FC) fusion suicide gene system for esophageal carcinoma in nude mice xenograft significant cytotoxicity,gene therapy for esophageal cancer provides a possible approach.%目的 观察多药耐药基因1(MDR1)启动子调控的胞嘧啶脱氨酶和尿嘧啶磷酸核糖转移酶融合基因(CD:UPRT)在裸鼠体内对食管癌细胞EC9706细胞的杀伤作用.方法 0.2 ml EC9706细胞悬液接种裸鼠,构建食管癌皮下移植瘤模型及pAdTrack-MDR1-CD

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

    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.

  20. 4-Bromo-2-[5-methyl-2-(morpholin-4-yl-1,3-thiazol-4-yl]phenol

    Lucian G. Bahrin

    2013-07-01

    Full Text Available In the title compound, C14H15BrN2O2S, synthesized by the reaction of the corresponding phenacyl thiocyanate with morpholine, the dihedral angle between the 1,3-thiazole ring and the phenolic substituent ring is 23.46 (10° as a result of the steric influence of the ortho-methyl group on the thiazole ring. A strong intramolecular phenolic O—H...N hydrogen bond is present in the molecule. In the crystal, a weak C—H...Ophenol hydrogen bond gives rise to chains lying parallel to [20-1]. A short intermolecular Br...Omorpholine interaction is also present [3.1338 (19 Å].

  1. Design, Synthesis, and Fungicidal Activities of Novel 5-Methyl-1H-1,2,3- trizole-4-carboxyl Amide Analogues.

    Wang, Zhen-Jun; Yang, Hui-Hui; Tian, Lei; Zhao, Wei-Guang

    2016-01-01

    Succinate dehydrogenase inhibitors (SDHIs) are fungicides with an amide bond widely used to control plant diseases caused by phytopathogenic fungi. Because of broad spectrum activity of new SDHIs, they have attracted wide attention from the research community. A series of structurally novel SDHIs with a bioactive 1,2,3-triazole moiety were designed and synthesized. Bioactivity screening showed that some of designed N-phenethyl-1,2,3-trizole-4-carboxyl amide analogues exhibited good fungicidal activities toward Sclerotinia sclerotiorum and Botrytis cinerea, while some of Nbenzyl- 1,2,3-trizole-4-carboxyl amide analogues exhibited good fungicidal activities toward Phytophthora capsici and Cercospora arachidicola. EC50 value of compound 5d against Cercospora arachidicola (6.6 µg/mL) was lower than that of chlorothalonil (12.3 µg/mL). PMID:26558376

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

    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. PMID:26776225

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

    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.

  4. QM/MM Lineshape Simulation of the Hydrogen-bonded Uracil NH Stretching Vibration of the Adenine:Uracil Base Pair in CDCl$_3$

    Yan, Yun-an; Kühn, Oliver

    2008-01-01

    A hybrid Car-Parrinello QM/MM molecular dynamics simulation has been carried out for the Watson-Crick base pair of 9-ethyl-8-phenyladenine and 1-cyclohexyluracil in deuterochloroform solution at room temperature. The resulting trajectory is analyzed putting emphasis on the N-H$...$N Hydrogen bond geometry. Using an empirical correlation between the $\\NN$-distance and the fundamental NH-stretching frequency, the time-dependence of this energy gap along the trajectory is obtained. From the gap-correlation function we determine the infrared absorption spectrum using lineshape theory in combination with a multimode oscillator model. The obtained average transition frequency and the width of the spectrum is in reasonable agreement with recent experimental data.

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

    Pingaew R; Nantasenamat C; Prachayasittikul S; Ruchirawat S; Prachayasittikul V

    2014-01-01

    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; 4Laborato...

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

    Andersen, Gorm

    2006-01-01

    Det første skridt i nedbrydningen af pyrimidiner er enten en reduktiv eller en oxidativ reaktion! Er der virkelig ingen alternativer? Nedbrydningen af pyrimidiner har stor betydning i mennesket. Genetiske defekter i den tilhørende pathway medfører alvorlige symptomer og specielt i for kræftpatien...

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

    ISHIKAWA, TORU

    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 u...

  8. N-{(2S-3-Hydroxy-4-[(5-methyl-1,3,4-thiadiazol-2-ylsulfanyl]-1-phenyl-2-butyl}-4-methylbenzenesulfonamide

    Claudia R. B. Gomes

    2011-09-01

    Full Text Available The thiadiazoyl and sulfonyl-benzene rings in the title compound, C20H23N3O3S3, are aligned to the same side of the molecule, forming a twisted `U' shape [dihedral angle = 77.6 (5°]. The benzyl-benzene ring is orientated in the opposite direction from the molecule but projects approximately along the same axis as the other rings [dihedral angle between benzene rings = 28.2 (5°] so that, overall, the molecule has a flattened shape. The hydroxy and amine groups are almost syn which enables the formation of intermolecular hydroxy-OH...N(thiadiazoyl and amine-H...O(sulfonyl hydrogen bonds leading to a supramolecular chain aligned along the a axis.

  9. Crystal structure of 5-{3-[2,6-dimethyl-4-(5-methyl-1,2,4-oxadiazol-3-ylphenoxy]propyl}-N-(11-hydroxyundecylisoxazole-3-carboxamide hemihydrate

    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.

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

    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.

  11. trans-Di-μ-carbonyl-bis{carbonyl[η5-2,3,4,5-tetramethyl-1-(5-methyl-2-furylcyclopentadienyl]ruthenium(I}(Ru—Ru

    Jin Lin

    2009-08-01

    Full Text Available In the crystal structure of the title compound, [Ru2(C14H17O2(CO4], each RuI atom is connected to one end-on and two bridging carbonyl groups and one cyclopentadienyl ring. The two Ru atoms are connected into binuclear complexes via two bridging carbonyl groups, forming four-membered rings which are located on centres of inversion. The Ru—Ru distance of 2.7483 (11 Å corresponds to a single bond. The two carbonyl groups in these binuclear complexes are trans-oriented.

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

    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.

  13. Preparation of [11C]-thymidine and [11C]-2'-arabino-2'-fluoro-β-5-methyl-uridine (FMAU) using a hollow fiber membrane bioreactor system

    A series of hollow fiber membranes containing immobilized enzymes were prepared and used in the synthesis of 11C-labelled nucleosides. 11C-Formaldehyde was produced in an alcohol oxidase/catalase bioreactor and circulated through a thymidylate synthase bioreactor with an appropriate substrate to produce the corresponding 11C-nucleotide. These labellled nucleotides were subsequently dephosphorylated in an alkaline phosphatase bioreactor. The bioreactor approach was amenable to hot-cell conditions and yielded 11C-products in higher yield and shorter synthesis times than conventional chemical approaches. (author)

  14. 7-(4-Methoxyphenyl-5-methyl-9-phenyl-7H-pyrrolo[2′,3′:4,5]pyrimido[1,6-d]tetrazole

    Mukesh M. Jotani

    2010-01-01

    Full Text Available The title compound, C20H16N6O, is composed of a tetrazolo ring and a 4-methoxyphenyl and a benzene-substituted pyrrole ring at the 7 and 9 positions fused to a pyrimidine ring in a nearly planar fashion [maximum deviation of 0.018 (1 Å for the fused ring system]. A methyl group at the 5 position is also in the plane of the hetero cyclic system. The dihedral angle between the mean planes of the benzene and 4-methoxyphenyl rings is 40.4 (2°. The dihedral angles between the mean planes of the pyrimidine and the benzene and 4-methoxyphenyl rings are 15.6 (5° and 52.6 (7°, respectively. A weak intramolecular C—H...N hydrogen bond interaction, which forms an S(7 graph-set motif, helps to establish the relative conformations of the tetrazolo and benzene rings. In the crystal, weak intermolecular C—H...O, C—H...π and π–π stacking interactions [centroid–centroid distances = 3.5270 (16, 3.5113 (16, 3.7275 (17 and 3.7866 (17 Å] link the molecules into a two-dimensional array obliquely parallel to (101 and propagating along the b axis.

  15. Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159

    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...... neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. Employing (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over total 18 steps. Both...

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

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

    2014-08-01

    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. PMID:25050452

  17. UV-MALDI mass spectrometric quantitation of uracil based pesticides in fruit soft drinks along with matrix effects evaluation.

    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. PMID:24018142

  18. Mechanism of the Isotopic Exchange Reaction of the 5-H Hydrogen of Uracil Derivatives in Water and Nonprotic Solvents

    Dračínský, Martin; Jansa, Petr; Chocholoušová, Jana; Vacek, Jaroslav; Kovačková, Soňa; Holý, Antonín

    -, č. 4 (2011), s. 777-785. ISSN 1434-193X R&D Projects: GA MŠk 1M0508; GA AV ČR KJB400550903 Institutional research plan: CEZ:AV0Z40550506 Keywords : tautomerism * NMR spectroscopy * nucleobases Subject RIV: CC - Organic Chemistry Impact factor: 3.329, year: 2011

  19. Generation of a Uracil Auxotroph Strain of the Probiotic Yeast Saccharomyces boulardii as a Host for the Recombinant Protein Production.

    Hamedi, Hassan; Misaghi, Ali; Modarressi, Mohammad Hossein; Salehi, Taghi Zahraei; Khorasanizadeh, Dorsa; Khalaj, Vahid

    2013-01-01

    BACKGROUND: Saccharomyces boulardii (S. boulardii) is the best known probiotic yeast. The genetic engineering of this probiotic strain requires the availability of appropriate mutants to accept various gene constructs carrying different selection markers. As the auxotrophy selection markers are under focus, we have generated a ura3 auxotroph mutant of S. boulardii for use in further genetic manipulations. METHODS: Classical UV mutagenesis was used for the generation of auxotroph mutants. The ...

  20. Human adipose tissue-derived mesenchymal stem cells expressing yeast cytosinedeaminase::uracil phosphoribosyltransferase inhibit intracerebral rat glioblastoma

    Altanerova, V.; Cihova, M.; Babič, Michal; Rychly, B.; Ondicova, K.; Mravec, B.; Altaner, C.

    2012-01-01

    Roč. 130, č. 10 (2012), s. 2455-2463. ISSN 0020-7136 Institutional research plan: CEZ:AV0Z40500505 Keywords : glioblastoma * mesenchymal stem cells * suicide gene therapy Subject RIV: CD - Macromolecular Chemistry Impact factor: 6.198, year: 2012

  1. Characterization of the three-dimensional free energy manifold for the uracil ribonucleoside from asynchronous replica exchange simulations.

    Radak, Brian K; Romanus, Melissa; Lee, Tai-Sung; Chen, Haoyuan; Huang, Ming; Treikalis, Antons; Balasubramanian, Vivekanandan; Jha, Shantenu; York, Darrin M

    2015-02-10

    Replica exchange molecular dynamics has emerged as a powerful tool for efficiently sampling free energy landscapes for conformational and chemical transitions. However, daunting challenges remain in efficiently getting such simulations to scale to the very large number of replicas required to address problems in state spaces beyond two dimensions. The development of enabling technology to carry out such simulations is in its infancy, and thus it remains an open question as to which applications demand extension into higher dimensions. In the present work, we explore this problem space by applying asynchronous Hamiltonian replica exchange molecular dynamics with a combined quantum mechanical/molecular mechanical potential to explore the conformational space for a simple ribonucleoside. This is done using a newly developed software framework capable of executing >3,000 replicas with only enough resources to run 2,000 simultaneously. This may not be possible with traditional synchronous replica exchange approaches. Our results demonstrate 1.) the necessity of high dimensional sampling simulations for biological systems, even as simple as a single ribonucleoside, and 2.) the utility of asynchronous exchange protocols in managing simultaneous resource requirements expected in high dimensional sampling simulations. It is expected that more complicated systems will only increase in computational demand and complexity, and thus the reported asynchronous approach may be increasingly beneficial in order to make such applications available to a broad range of computational scientists. PMID:26580900

  2. Unlocked Nucleic Acids with a Pyrene-Modified Uracil: Synthesis, Hybridization Studies, Fluorescent Properties and i-Motif Stability

    Perlíková, Pavla; Karlsen, K. K.; Pedersen, E. B.; Wengel, J.

    2014-01-01

    Roč. 15, č. 1 (2014), s. 146-156. ISSN 1439-4227 Grant ostatní: European Research Council(XE) FP7-268776 Institutional support: RVO:61388963 Keywords : fluorescence * i-motifs * nucleic acid hybridization * oligonucleotides * unlocked nucleic acids Subject RIV: CE - Biochemistry Impact factor: 3.088, year: 2014

  3. (5R*,11R*-5-Methyl-1,2-dihydro-5,11-methano-5H,11H-1,3-thiazolo[2,3-d][1,3,5]benzoxadiazocine

    Viktor Kettmann

    2009-11-01

    Full Text Available The title compound, C13H14N2OS, crystallizes as a racemate in a non-chiral space group. It represents a conformationally restricted analogue of so-called Biginelli compounds known to exhibit multiple pharmacological activities and was selected for a single-crystal X-ray analysis in order to probe the chemical and spatial requirements of some kinds of activity. It was found that the state of hybridization of the formally aminic nitrogen of the heterocycle is between sp2 and sp3 with the lone-pair electrons partially delocalized through conjugation with the sulfur atom rather than the double bond of the pyrimidine nucleus. As a result, the thiazolo ring adopts a flat-envelope conformation and the puckering of the central pyrimidine ring is close to a half-chair. The critical phenyl ring is fixed in a pseudo-axial and perpendicular [dihedral angle 84.6 (1°] orientation with respect to the pyrimidine ring via an oxygen bridge.

  4. 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

    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.

  5. Novel Regulation of the Synthesis of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Subunit GluA1 by Carnitine Palmitoyltransferase 1C (CPT1C) in the Hippocampus.

    Fadó, Rut; Soto, David; Miñano-Molina, Alfredo J; Pozo, Macarena; Carrasco, Patricia; Yefimenko, Natalia; Rodríguez-Álvarez, José; Casals, Núria

    2015-10-16

    The regulation of AMPA-type receptor (AMPAR) abundance in the postsynaptic membrane is an important mechanism involved in learning and memory formation. Recent data suggest that one of the constituents of the AMPAR complex is carnitine palmitoyltransferase 1C (CPT1C), a brain-specific isoform located in the endoplasmic reticulum of neurons. Previous results had demonstrated that CPT1C deficiency disrupted spine maturation in hippocampal neurons and impaired spatial learning, but the role of CPT1C in AMPAR physiology had remained mostly unknown. In the present study, we show that CPT1C binds GluA1 and GluA2 and that the three proteins have the same expression profile during neuronal maturation. Moreover, in hippocampal neurons of CPT1C KO mice, AMPAR-mediated miniature excitatory postsynaptic currents and synaptic levels of AMPAR subunits GluA1 and GluA2 are significantly reduced. We show that AMPAR expression is dependent on CPT1C levels because total protein levels of GluA1 and GluA2 are decreased in CPT1C KO neurons and are increased in CPT1C-overexpressing neurons, whereas other synaptic proteins remain unaltered. Notably, mRNA levels of AMPARs remained unchanged in those cultures, indicating that CPT1C is post-transcriptionally involved. We demonstrate that CPT1C is directly involved in the de novo synthesis of GluA1 and not in protein degradation. Moreover, in CPT1C KO cultured neurons, GluA1 synthesis after chemical long term depression was clearly diminished, and brain-derived neurotrophic factor treatment was unable to phosphorylate the mammalian target of rapamycin (mTOR) and stimulate GluA1 protein synthesis. These data newly identify CPT1C as a regulator of AMPAR translation efficiency and therefore also synaptic function in the hippocampus. PMID:26338711

  6. Crystal structure of 5-[bis-(methyl-sulfon-yl)meth-yl]-1,3-dimethyl-5-(methyl-sulfon-yl)pyrimidine-2,4,6(1H,3H,5H)-trione.

    Mallah, Eyad; Al-Sheikh, Ahmed; Sweidan, Kamal; Abu Dayyih, Wael; Steimann, Manfred

    2015-01-01

    In the title compound, C10H16N2O9S3, the pyrimidine ring of the 1,3-dimethyl barbituric acid moiety has an envelope conformation with the C atom carrying the methyl-sulfonyl and bis-(methyl-sulfon-yl)methyl substituents as the flap. The dihedral angle between mean plane of the pyrimidine ring and the S/C/S plane is 72.4 (3)°. In the crystal, mol-ecules are linked via C-H⋯O hydrogen bonds, forming a three-dimensional structure. PMID:25705508

  7. Crystal structure of 5-[bis­(methyl­sulfon­yl)meth­yl]-1,3-dimethyl-5-(methyl­sulfon­yl)pyrimidine-2,4,6(1H,3H,5H)-trione

    Mallah, Eyad; Al-Sheikh, Ahmed; Sweidan, Kamal; Abu Dayyih, Wael; Steimann, Manfred

    2015-01-01

    In the title compound, C10H16N2O9S3, the pyrimidine ring of the 1,3-dimethyl barbituric acid moiety has an envelope conformation with the C atom carrying the methyl­sulfonyl and bis­(methyl­sulfon­yl)methyl substituents as the flap. The dihedral angle between mean plane of the pyrimidine ring and the S/C/S plane is 72.4 (3)°. In the crystal, mol­ecules are linked via C—H⋯O hydrogen bonds, forming a three-dimensional structure. PMID:25705508

  8. 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

    Nielsen, Trine Damgaard; Larsen, Dorrit Bjerg; Hansen, Suzanne Lisbet;

    2010-01-01

    Cognitive deficits are a major clinical unmet need in schizophrenia. The psychotomimetic drug phencyclicline (PCP) is widely applied in rodents to mimic symptoms of schizophrenia, including cognitive deficits. Precious studies have shown that sub-chronic PCP induces an enduring episodic memory de...

  9. Bis(nitrato-κObis[4,4,5,5-tetramethyl-2-(5-methyl-1H-imidazol-4-yl-κN3-2-imidazoline-1-oxyl 3-oxide-κO]nickel(II

    Jiu Li Chang

    2011-11-01

    Full Text Available In the centrosymmetric mononuclear title complex, [Ni(NO32(C11H17N4O22], the NiII atom displays a distorted octahedral coordination geometry and is six-coordinated by two N,O-bidentate nitronyl nitroxide radical ligands and two monodentate nitrate anions.

  10. Dichloridobis[4,4,5,5-tetramethyl-2-(5-methyl-1H-imidazol-4-yl-κN3-2-imidazoline-1-oxyl 3-oxide-κO]copper(II

    Zhi Yong Gao

    2011-11-01

    Full Text Available In the title complex, [CuCl2(C11H17N4O22], the CuII ion, lying on an inversion center, is six-coordinated in a distorted octahedral [Cu(N2O2Cl2] environment by two N,O-bidentate nitronyl nitroxide radical ligands and two trans-chloride anions. In the imidazoline-1-oxyl-3-oxide unit of the ligand, the four methyl groups and the C atoms to which they are bonded are disordered over two sets of sites, with a refined occupancy ratio of 0.737 (5:0.263 (5.