- The inhibitory effect of citrus flavonoids naringenin and hesperetin against purine nucleoside phosphorylase: Spectroscopic, atomic force microscopy and molecular modeling studies
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In this work, the inhibitory effect of two citrus flavonoids naringenin and hesperetin on human purine nucleoside phosphorylase (hPNP) and their binding mechanism were evaluated. Results from enzymatic kinetics revealed that naringenin and hesperetin reversibly inhibited hPNP via a mixed-type manner with IC50 values of 4.83 × 10?4 M and 5.32 × 10?4 M, respectively. Analysis of molecular modeling revealed that both naringenin and hesperetin bound directly into the active site by generating multiple forces including hydrogen bonding, π–π and π-Alkyl interactions with His64, Glu201, Ser220, His257, Phe200 and Val217 residues of hPNP, which caused the inhibition of hPNP activity. Moreover, conformational analysis by three-dimension fluorescence, circular dichroism and atomic force microscopy revealed that the binding of naringenin and hesperetin to hPNP induced changes in the microenvironment, secondary structure and morphology of hPNP. These results suggested that occupying the active site and enzymatic conformational perturbation induced by naringenin and hesperetin are the main reasons for reducing the inhibition of hPNP activity, which would be helpful in understanding the inhibitory mechanism of naringenin and hesperetin against hPNP.
- Gong, Deming,Lv, Xingang,Ren, Er-Fang,Wang, Lang-Hong,Wang, Qilei
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- Ribocation Transition State Capture and Rebound in Human Purine Nucleoside Phosphorylase
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Purine nucleoside phosphorylase (PNP) catalyzes the phosphorolysis of 6-oxy-purine nucleosides to the corresponding purine base and α-D-ribose 1-phosphate. Its genetic loss causes a lethal T cell deficiency. The highly reactive ribocation transition state
- Ghanem, Mahmoud,Murkin, Andrew S.,Schramm, Vern L.
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- Calcium-stimulated guanosine-inosine nucleosidase from yellow lupin (Lupinus luteus)
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Guanosine-inosine-preferring nucleoside N-ribohydrolase has been purified to homogeneity from yellow lupin (Lupinus luteus) seeds by ammonium sulfate fractionation, ion-exchange chromatography and gel filtration. The enzyme functions as a monomeric, 80 kDa polypeptide, most effectively between pH 4.7 and 5.5. Of various mono- and divalent cations tested, Ca2+ appeared to stimulate enzyme activity. The nucleosidase was activated 6-fold by 2 mM exogenous CaCl2 or Ca(NO3)2, with Ka = 0.5 mM (estimated for CaCl2). The Km values estimated for guanosine and inosine were 2.7 ± 0.3 μM. Guanosine was hydrolyzed 12% faster than inosine while adenosine and xanthosine were poor substrates. 2′-Deoxyguanosine, 2′-deoxyinosine, 2′-methylguanosine, pyrimidine nucleosides and 5′-GMP were not hydrolyzed. However, the enzyme efficiently liberated the corresponding bases from synthetic nucleosides, such as 1-methylguanosine, 7-methylguanosine, 1-N2-ethenoguanosine and 1-N2-isopropenoguanosine, but hydrolyzed poorly the ribosides of 6-methylaminopurine and 2,6-diaminopurine. MnCl2 or ZnCl2 inhibited the hydrolysis of guanosine with I50 ≈ 60 μM. Whereas 2′-deoxyguanosine, 2′-methylguanosine, adenosine, as well as guanine were competitive inhibitors of this reaction (Ki values were 1.5, 3.6, 21 and 9.7 μM, respectively), hypoxanthine was a weaker inhibitor (Ki = 64 μM). Adenine, ribose, 2-deoxyribose, 5′-GMP and pyrimidine nucleosides did not inhibit the enzyme. The guanosine-inosine hydrolase activity occurred in all parts of lupin seedlings and in cotyledons it increased up to 5-fold during seed germination, reaching maximum in the third/fourth day. The lupin nucleosidase has been compared with other nucleosidases.
- Szuwart, Maciej,Starzynska, Elzbieta,Pietrowska-Borek, Malgorzata,Guranowski, Andrzej
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- Enzymatic deamination of the epigenetic base N-6-methyladenine
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Two enzymes of unknown function from the amidohydrolase superfamily were discovered to catalyze the deamination of N-6-methyladenine to hypoxanthine and methyl amine. The methylation of adenine in bacterial DNA is a common modification for the protection of host DNA against restriction endonucleases. The enzyme from Bacillus halodurans, Bh0637, catalyzes the deamination of N-6-methyladenine with a kcat of 185 s-1 and a k cat/Km of 2.5 x 106 M-1 s -1. Bh0637 catalyzes the deamination of N-6-methyladenine 2 orders of magnitude faster than adenine. A comparative model of Bh0637 was computed using the three-dimensional structure of Atu4426 (PDB code: 3NQB) as a structural template and computational docking was used to rationalize the preferential utilization of N-6-methyladenine over adenine. This is the first identification of an N-6-methyladenine deaminase (6-MAD).
- Kamat, Siddhesh S.,Fan, Hao,Sauder, J. Michael,Burley, Stephen K.,Shoichet, Brian K.,Sali, Andrej,Raushel, Frank M.
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- Localization of purine metabolizing enzymes in bovine brain microvessel endothelial cells: An enzymatic blood-brain barrier for dideoxynucleosides?
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Purpose. The specific activities of the purine and pyrimidine metabolizing enzymes, purine nucleoside phosphorylase (PNP), adenosine deaminase (ADA) and cytidine deaminase (CDA) were determined in bovine brain microvessel endothelial cells, (BBMECs), whole cerebral tissue and erythrocytes. In addition, the substrate specificities (K(m) and V(max)) of purified calf spleen PNP for inosine and 2',3'-dideoxyinosine (ddI) and of purified calf intestinal ADA for 2',3'-dideoxyadenosine (ddA), 6-chloro-2',3'-dideoxypurine (6-Cl-ddP), and 2'-β-fluoro-2',3'-dideoxyadenosine (F-ddA) have been explored. Methods. BBMECs were isolated from bovine cerebral cortex by a two step enzymatic dispersion treatment followed by centrifugation over 50% Percoll density gradients. Activities of alkaline phosphatase, γ-glutamyl transpeptidase, ADA, PNP and CDA were determined in various tissue homogenates (cerebral cortex, BBMECs and erythrocytes). Enzyme kinetic studies were also conducted using commercially available enzymes and several nucleoside analogs of interest. Results. The activities of ADA and PNP were 42-fold and 247-fold higher in the cerebral microvessels than in the cerebral cortex, respectively, while there was no detectable CDA activity in the microvessel fraction and very little overall activity in the cortex. Conclusions. ADA and PNP may serve as an enzymatic blood-brain barrier for some of the anti-HIV dideoxynucleosides. Simulations of brain availability for ddI, ddA, 6-Cl-ddP, and FddA demonstrated that the quantitative significance of enzyme localization may vary dramatically, however, depending on the membrane permeability of the drug and its bioconversion rate constant within the endothelial cell.
- Johnson, Mark D.,Andersen, Bradley D.
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- Phloroglucinols Inhibit Chemical Mediators and Xanthine Oxidase, and Protect Cisplatin-Induced Cell Death by Reducing Reactive Oxygen Species in Normal Human Urothelial and Bladder Cancer Cells
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Phloroglucinols, garcinielliptones HA-HE (1-5), and C (6) were studied in vitro for their inhibitory effects on chemical mediators released from mast cells, neutrophils, and macrophages. Compound 6 revealed significant inhibitory effect on release of lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP)/cytochalasin B (CB). Compounds 3, 4, and 6 showed significant inhibitory effects on superoxide anion generation in rat neutrophils stimulated with (fMLP)/(CB), while compounds 1 and 5 revealed inhibitory effects on tumor necrosis factor-α (TNF-α) formation in macrophages stimulated with lipopolysaccharide (LPS). Compounds 1 and 3-6 showed inhibitory effects on xanthine oxidase (XO) and could inhibit the DNA breakage caused by O2-.. Treatment of NTUB1 with 2 to 60 μM compound 3 and 5 μM cisplatin and SV-HUC1 with 9 to 60 μM 3 and 5 μM cisplatin, respectively, resulted in an increase of viability of cells. These results indicated that compounds 1 and 3-6 showed anti-inflammatory effects and antioxidant activities. Compound 3 mediates through the suppression of XO activity and reduction of reactive oxygen species (ROS), and protection of subsequent cell death.
- Lin, Kai-Wei,Huang, A.-Mei,Tu, Huang-Yao,Weng, Jing-R.U.,Hour, Tzyh-Chyuan,Wei, Bai-Luh,Yang, Shyh-Chyun,Wang, Jih-Pyang,Pu, Yeong-Shiau,Lin, Chun-Nan
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- Synthetic method of nitric acid catalyzed hypoxanthine derivative
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The invention discloses a synthetic method of a nitric acid catalytic hypoxanthine derivative, and belongs to the technical field of pharmaceutical chemistry. 6 - Chloropurine derivatives were mixed with a solvent, a catalytic amount of nitric acid heating reaction was added, and acid generated in the reaction was neutralized, and the solvent was removed under reduced pressure to obtain a hypoxanthine derivative. The hypoxanthine derivative obtained by the method is low in cost, high in purity and good in substrate adaptability; various impurities in a traditional method are removed; separation and purification are convenient; and the reliability of the quality of the hypoxanthine derivative is improved.
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Paragraph 0027-0036
(2021/10/11)
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- Thermodynamic Reaction Control of Nucleoside Phosphorolysis
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Nucleoside analogs represent a class of important drugs for cancer and antiviral treatments. Nucleoside phosphorylases (NPases) catalyze the phosphorolysis of nucleosides and are widely employed for the synthesis of pentose-1-phosphates and nucleoside analogs, which are difficult to access via conventional synthetic methods. However, for the vast majority of nucleosides, it has been observed that either no or incomplete conversion of the starting materials is achieved in NPase-catalyzed reactions. For some substrates, it has been shown that these reactions are reversible equilibrium reactions that adhere to the law of mass action. In this contribution, we broadly demonstrate that nucleoside phosphorolysis is a thermodynamically controlled endothermic reaction that proceeds to a reaction equilibrium dictated by the substrate-specific equilibrium constant of phosphorolysis, irrespective of the type or amount of NPase used, as shown by several examples. Furthermore, we explored the temperature-dependency of nucleoside phosphorolysis equilibrium states and provide the apparent transformed reaction enthalpy and apparent transformed reaction entropy for 24 nucleosides, confirming that these conversions are thermodynamically controlled endothermic reactions. This data allows calculation of the Gibbs free energy and, consequently, the equilibrium constant of phosphorolysis at any given reaction temperature. Overall, our investigations revealed that pyrimidine nucleosides are generally more susceptible to phosphorolysis than purine nucleosides. The data disclosed in this work allow the accurate prediction of phosphorolysis or transglycosylation yields for a range of pyrimidine and purine nucleosides and thus serve to empower further research in the field of nucleoside biocatalysis. (Figure presented.).
- Kaspar, Felix,Giessmann, Robert T.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
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supporting information
p. 867 - 876
(2020/01/24)
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- Synthesis of Adenine Nucleosides by Transglycosylation using Two Sequential Nucleoside Phosphorylase-Based Bioreactors with On-Line Reaction Monitoring by using HPLC
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Uridine phosphorylase from Clostridium perfringens (CpUP, EC 2.4.2.3) was immobilized covalently in an aminopropylsilica monolithic column (25 mm×4.6 mm) upon functionalization with glutaraldehyde. Imino bonds that result from the reaction between the enzyme and the support were reduced chemically to afford a 66 % yield (13 mg) determined spectrophotometrically. The CpUP immobilized enzyme reactor (IMER) was connected to a silica particle-based IMER that contained a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP, EC 2.4.2.1), which was developed previously and used successfully for the fast synthesis of some purine ribonucleosides by a “one-enzyme” transglycosylation. CpUP-IMER and AhPNP-IMER were connected to a HPLC system by a six-way switching valve. In this set-up, the synthesis of 2′-deoxyadenosine (dAdo, 8), adenosine (Ado, 9), and arabinosyladenine (araA, 10) by a “two-enzyme” transglycosylation is coupled directly to on-line reaction monitoring. Under the optimized transglycosylation conditions (2:1 ratio sugar donor/base acceptor; 10 mm phosphate buffer; pH 7.25; temperature 37 °C, flow rate 0.1 mL min?1), defined by a 2(5-2) III experimental design, the conversion of dAdo and Ado was approximately 90 %, and araA was synthesized in 20 % yield.
- Cattaneo, Giulia,Rabuffetti, Marco,Speranza, Giovanna,Kupfer, Tom,Peters, Benjamin,Massolini, Gabriella,Ubiali, Daniela,Calleri, Enrica
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p. 4614 - 4620
(2017/12/13)
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- The Chemoenzymatic Synthesis of 2-Chloro- and 2-Fluorocordycepins
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Two approaches to the chemoenzymatic synthesis of 2-fluorocordycepin and 2-chlorocordycepin were studied: (i) the use of 3′-deoxyadenosine (cordycepin) and 3′-deoxyinosine (3′dIno) as donors of 3-deoxy- d -ribofuranose in the transglycosylation of 2-fluoro- (2F Ade) and 2-chloroadenine (2Cl Ade) catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP), and (ii) the use of 2-fluoroadenosine and 3′-deoxyinosine as substrates of the cross-glycosylation and PNP as a biocatalyst. An efficient method for 3′-deoxyinosine synthesis starting from inosine was developed. However, the very poor solubility of 2Cl Ade and 2F Ade is the limiting factor of the first approach. The second approach enables this problem to be overcome and it appears to be advantageous over the former approach from the viewpoint of practical synthesis of the title nucleosides. The 3-deoxy-α- d -ribofuranose-1-phosphate intermediary formed in the 3′dIno phosphorolysis by PNP was found to be the weak and marginal substrate of E. coli thymidine (TP) and uridine (UP) phosphorylases, respectively. Finally, one-pot cascade transformation of 3-deoxy- d -ribose in cordycepin in the presence of adenine and E. coli ribokinase, phosphopentomutase, and PNP was tested and cordycepin formation in ca. 3.4% yield was proved.
- Denisova, Alexandra O.,Tokunova, Yulia A.,Fateev, Ilja V.,Breslav, Alexandra A.,Leonov, Vladimir N.,Dorofeeva, Elena V.,Lutonina, Olga I.,Muzyka, Inessa S.,Esipov, Roman S.,Kayushin, Alexey L.,Konstantinova, Irina D.,Miroshnikov, Anatoly I.,Stepchenko, Vladimir A.,Mikhailopulo, Igor A.
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p. 4853 - 4860
(2017/10/06)
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- Structural and biochemical characterization of the nucleoside hydrolase from C. elegans reveals the role of two active site cysteine residues in catalysis
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Nucleoside hydrolases (NHs) catalyze the hydrolysis of the N-glycoside bond in ribonucleosides and are found in all three domains of life. Although in parasitic protozoa a role in purine salvage has been well established, their precise function in bacteria and higher eukaryotes is still largely unknown. NHs have been classified into three homology groups based on the conservation of active site residues. While many structures are available of representatives of group I and II, structural information for group III NHs is lacking. Here, we report the first crystal structure of a purine-specific nucleoside hydrolase belonging to homology group III from the nematode Caenorhabditis elegans (CeNH) to 1.65? resolution. In contrast to dimeric purine-specific NHs from group II, CeNH is a homotetramer. A cysteine residue that characterizes group III NHs (Cys253) structurally aligns with the catalytic histidine and tryptophan residues of group I and group II enzymes, respectively. Moreover, a second cysteine (Cys42) points into the active site of CeNH. Substrate docking shows that both cysteine residues are appropriately positioned to interact with the purine ring. Site-directed mutagenesis and kinetic analysis proposes a catalytic role for both cysteines residues, with Cys253 playing the most prominent role in leaving group activation.
- Singh, Ranjan Kumar,Steyaert, Jan,Versées, Wim
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p. 985 - 996
(2017/05/01)
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- METHOD FOR DIAGNOSING ACUTE CARDIAC ISCHEMIA
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Chemiluminescent detection of metabolic by-products of inosine and hypoxanthine is used to diagnose ischemic events such as early acute cardiac ischemia.
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Page/Page column 1
(2015/11/16)
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- A novel ionic liquid based on imidazolium cation as an efficient and reusable catalyst for the one-pot synthesis of benzoxazoles, benzthiazoles, benzimidazoles and 2-arylsubstituted benzimidazoles
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A novel dicationic ionic liquid based on imidazolium cation is designed, synthesized and successfully used as catalyst for the one-pot synthesis of benzoxazoles, benzthiazoles, benzimidazoles and 2-arylsubstituted benzimidazoles. The remarkable feature of this new catalyst is its ethyleneoxy bridge which participates in dissolving organic compound in ionic liquid. The application of this ionic liquid is studied in a new one-pot method for synthesis of heterocyclic compounds under solvent-free conditions. Simple and convenient procedure, high conversion, reusability of catalyst, easy purification and shorter reaction time are the advantageous features of this method.
- Hasanpour, Maede,Eshghi, Hossein,Bakavoli, Mehdi,Mirzaeia, Mahdi
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p. 412 - 419
(2015/05/27)
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- Flow-Synthesis of Nucleosides Catalyzed by an Immobilized Purine Nucleoside Phosphorylase from Aeromonas hydrophila: Integrated Systems of Reaction Control and Product Purification
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A purine nucleoside phosphorylase from Aeromonas hydrophyla (AhPNP) was covalently immobilized in a pre-packed stainless steel column containing aminopropylsilica particles via Schiff base chemistry upon glutaraldehyde activation. The resulting AhPNP-IMER (Immobilized Enzyme Reactor, immobilization yield ≈50%) was coupled on-line through a 6-way switching valve to an HPLC apparatus containing an analytical or a semi-preparative chromatographic column. The synthesis of five 6-modified purine ribonucleosides was carried out by continuously pumping the reaction mixture through the AhPNP-IMER until the highest conversion was reached, and then directing the reaction mixture to chromatographic separation. The conditions of the AhPNP-catalyzed transglycosylations (2:1 ratio sugar donor:base acceptor; 10 mM phosphate buffer; pH 7.5; temperature 37 °C, flow rate 0.5 mL min-1) were optimized by a fractional factorial experimental design. Coupling the bioconversion step with the product purification in such an integrated platform resulted in a fast and efficient synthetic process (yield=52-89%; 10 mg) where sample handling was minimized. To date, AhPNP-IMER has retained completely its activity upon 50 reactions in 10 months.
- Calleri, Enrica,Cattaneo, Giulia,Rabuffetti, Marco,Serra, Immacolata,Bavaro, Teodora,Massolini, Gabriella,Speranza, Giovanna,Ubiali, Daniela
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p. 2520 - 2528
(2015/08/18)
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- IMMUNOHISTOCHEMISTRY DETECTION METHOD
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The invention provides compositions and methods for the detection of targets in a sample; in particular, an immunohistochemistry (IHC) sample. Probes and detectable labels may be provided in multiple layers in order to increase the flexibility of a detection system, and to allow for amplification to enhance the signal from a target. The layers may be created by incorporating probes and detectable labels into larger molecular units that interact through nucleic acids base-pairing, including peptide-nucleic acid (PNA) base-pairing. Optional non-natural bases allow for degenerate base pairing schemes. The compositions and methods are compatible with immunohistochemistry (IHC), but also could be used in immunocytochemistry (ICC), in situ hybrid.
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(2015/01/16)
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- Characterization of inosine-uridine nucleoside hydrolase (RihC) from Escherichia coli
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A non-specific nucleoside hydrolase from Escherichia coli (RihC) has been cloned, overexpressed, and purified to greater than 95% homogeneity. Size exclusion chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis show that the protein exists as a homodimer. The enzyme showed significant activity against the standard ribonucleosides with uridine, xanthosine, and inosine having the greatest activity. The Michaelis constants were relatively constant for uridine, cytidine, inosine, adenosine, xanthosine, and ribothymidine at approximately 480 μM. No activity was exhibited against 2′-OH and 3′-OH deoxynucleosides. Nucleosides in which additional groups have been added to the exocyclic N6 amino group also exhibited no activity. Nucleosides lacking the 5′-OH group or with the 2′-OH group in the arabino configuration exhibited greatly reduced activity. Purine nucleosides and pyrimidine nucleosides in which the N7 or N3 nitrogens respectively were replaced with carbon also had no activity.
- Arivett, Brock,Farone, Mary,Masiragani, Ranjith,Burden, Andrew,Judge, Shelby,Osinloye, Adedoyin,Minici, Claudia,Degano, Massimo,Robinson, Matthew,Kline, Paul
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p. 656 - 662
(2014/03/21)
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- Chemoenzymatic method of 1,2,4-triazole nucleoside synthesis: Possibilities and limitations
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Possibilities and limitations of chemoenzymatic synthesis of novel structural analogues of an antiviral preparation of Ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) were established. A synthesis of various amides of 1H-1,2,4-triazole-3-carboxylic acid and its 5-substituted analogues - potential substrates of purine nucleoside phosphorylase - has been described. Comparative efficiency of preparation methods of these amides, as well as the methods of introduction of functional groups to the C5 position of heterocyclic system, were investigated. Novel analogues of Ribavirin containing various substitutes in the carboxamide group were synthesized. A biotechnological method was developed for the preparation of 1-β-D-ribofuranozyl-1,2,4-triazole-3-carbonitryl, an intermediate in the synthesis of Viramidine, the modern analogue of Ribavirin.
- Konstantinova,Chudinov,Fateev,Matveev,Zhurilo,Shvets,Miroshnikov
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- Meteorites as catalysts for prebiotic chemistry
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From outer space: Twelve meteorite specimens, representative of their major classes, catalyse the synthesis of nucleobases, carboxylic acids, aminoacids and low-molecular-weight compounds from formamide (see figure). Different chemical pathways are identified, the yields are high for a prebiotic process and the products come in rich and composite panels.
- Saladino, Raffaele,Botta, Giorgia,Delfino, Michela,Di Mauro, Ernesto
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p. 16916 - 16922
(2014/01/06)
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- Discovery of a cytokinin deaminase
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An enzyme of unknown function within the amidohydrolase superfamily was discovered to catalyze the hydrolysis of N-6-substituted adenine derivatives, several of which are cytokinins. Cytokinins are a common type of plant hormone and N-6-substituted adenines are also found as modifications to tRNA. Patl2390, from Pseudoalteromonas atlantica T6c, was shown to hydrolytically deaminate N-6-isopentenyladenine to hypoxanthine and isopentenylamine with a k cat/Km of 1.2 × 107 M-1 s -1. Additional substrates include N-6-benzyl adenine, cis- and trans-zeatin, kinetin, O-6-methylguanine, N-6-butyladenine, N-6-methyladenine, N,N-dimethyladenine, 6-methoxypurine, 6-chloropurine, and 6-thiomethylpurine. This enzyme does not catalyze the deamination of adenine or adenosine. A comparative model of Patl2390 was computed using the three-dimensional crystal structure of Pa0148 (PDB code 3PAO) as a structural template, and docking was used to refine the model to accommodate experimentally identified substrates. This is the first identification of an enzyme that will hydrolyze an N-6-substituted side chain larger than methylamine from adenine.
- Goble, Alissa M.,Fan, Hao,Sali, Andrej,Raushel, Frank M.
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experimental part
p. 1036 - 1040
(2012/05/20)
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- Determination of adenosine deaminase activity in dried blood spots by a nonradiochemical assay using reversed-phase high-performance liquid chromatography
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Adenosine deaminase (ADA) deficiency is a rare metabolic disease causing severe combined immunodeficiency (SCID). An assay to determine ADA activity in dried blood spots was developed using reversed-phase HPLC. The assay was linear with reaction times up to at least 4 hours, and protein concentrations up to at least 2.2 mg/ml. The intra-assay CV and the inter-assay CV for the complete assay was 3.5 and 8.4%, respectively. The ADA activity in a control blood spot, stored at 4°C, remained stable for at least one year. Only a slightly decreased ADA activity (35 ± 13 nmol/mg/h, n = 4) was observed in heterozygotes for a c.704G > A mutation in the ADA gene when compared to that observed in controls (41 ± 13 nmol/mg/h, n = 108). In addition, increased ADA activity as found in a rare form of congenital anemia can be assessed, as observed in a bloodspot from a patient diagnosed with Diamond Blackfan anemia (ADA activity 150 nmol/mg/h). Copyright
- Van Kuilenburg,Zoetekouw,Meijer,Kuijpers
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experimental part
p. 461 - 465
(2011/08/10)
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- Guanine, adenine, and hypoxanthine production in UV-irradiated formamide solutions: Relaxation of the requirements for prebiotic purine nucleobase formation
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Relaxed requirements: We demonstrate the formation of adenine, hypoxanthine, and guanine from heated (130 °C), UV-irradiated formamide solutions in the absence of an inorganic catalyst. Evidence is also provided that "classical" HCN pathways for purine nucleobase production are also active in heated and UV-irradiated formamide reactions. (Chemical Equation Presented)
- Barks, Hannah L.,Buckley, Ragan,Grieves, Gregory A.,Di Mauro, Ernesto,Hud, Nicholas V.,Orlando, Thomas M.
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experimental part
p. 1240-1243+1159
(2011/04/18)
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- HAIR TREATMENT PRODUCTS COMPRISING POLYMERS
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The invention relates to hair treatment products, comprising at least one copolymer made of 0.1 to 50% (in relation to the total number of monomers in the copolymer) monomers of the formula (I), wherein the unknowns are defined as in claim 1, and A2) are monomers from the group of acrylic acid, methacrylic acid and the like, and—optionally non-ionic monomers from the group of acrylamide, vinyl alcohol, and the like, wherein the monomers A2 and A3 together represent 50 to 99.9% (in relation to the total number of monomers in the copolymer) of the copolymer, at least one silicon and at least one selected care product, wherein the products result in advantageous effects for skin and hair.
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- PROCESS FOR PRODUCTION OF CRYSTAL OF PURINE NUCLEOSIDE COMPOUND
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Disclosed is a process for producing a crystal of a purine nucleoside compound, particularly a crystal of 2',3'-dideoxyinosine, which is not decomposed during storage and has excellent storage stability. Specifically disclosed is a process for producing a crystal of a purine nucleoside which has a concentration of phosphate attached to the crystal of 25 ppm or more and has excellent storage stability. The process comprises the steps of: (1) preparing an aqueous solution containing a phosphate ion (PO43-) and a purine nucleoside compound; and (2) crystallizing out the purine nucleoside compound from the aqueous solution.
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Page/Page column 3
(2009/12/07)
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- Efficient synthesis of14C-labeled 1H-pyrazolo[3,4-d]pyrimidine and related [4.3.0]-bicyclic pyrimidino systems
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In support of a research program aimed at discovering purine-related anticancer drug candidates, a method for the 14C-labeling of pyrazolopyrimidines utilizing the readily available labeled starting material, sodium [14C]formate, has been developed with a good overall yield. This new method was proven to be general in the preparation of other related [4.3.0]heterocycles containing N, O, and S atoms. A concise synthesis of a model compound, 8-aza-7-deaza-5′-[14C]noraristeromycin, was achieved utilizing this methodology as a key step.
- Ho, Jonathan Z.,Van Arsdale, Kyle R.,Braun, Matthew P.
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scheme or table
p. 958 - 963
(2009/03/11)
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- The fate of C5′ radicals of purine nucleosides under oxidative conditions
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The factors that influence the reactivity of C5′ radicals in purine moieties under aerobic conditions are unknown not only in DNA, but also in simple nucleosides. 5′,8-Cyclopurine lesions are the result of a rapid C5′ radical attack to the purine moieties before the reaction with oxygen. These well-known lesions among the DNA modifications were suppressed by the presence of molecular oxygen in solution. Here we elucidate the chemistry of three purine-substituted C5′ radicals (i.e., 2′-deoxyadenosin- 5′-yl, 2′-deoxyinosin-5′-yl, and 2′-deoxyguanosin- 5′-yl) under oxidative conditions using γ-radiolysis coupled with product studies. 2′-Deoxyadenosin-5′-yl and 2′-deoxyinosin- 5′-yl radicals were selectively generated by the reaction of hydrated electrons (eaq-) with 8-bromo-2′-deoxyadenosine and 8-bromo-2′-deoxyinosine followed by a rapid radical translocation from the C8 to the C5′ position. Trapping these two C5′ radicals with Fe(CN)63- gave corresponding hydrated 5′-aldehydes in good yields that were isolated and fully characterized. When an oxygen concentration in the range of 13-266 μM (typical oxygenated tissues) is used, the hydrated 5′-aldehyde is accompanied by the 5′,8-cyclopurine nucleoside. The formation of 5′,8-cyclopurines is relevant in all experiments, and the yields increased with decreasing O2 concentration. The reaction of HO? radicals with 2′-deoxyadenosine and 2′-deoxyguanosine under normoxic conditions was also investigated. The minor path of C5′ radicals formation was found to be ca. 10% by quantifying the hydrated 5′-aldehyde in both experiments. Rate constants for the reactions of the 2′-deoxyadenosin-5′-yl with cysteine and glutathione in water were determined by pulse radiolysis to be (2.1 ± 0.5) × 107 and (4.9 ± 0.6) × 10 7 M-1 s-1 at 22°C, respectively.
- Boussicault, Fabien,Kaloudis, Panagiotis,Caminal, Clara,Mulazzani, Quinto G.,Chatgilialoglu, Chryssostomos
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supporting information; scheme or table
p. 8377 - 8385
(2009/02/02)
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- Chemical radiation studies of 8-bromo-2′ -deoxyinosine and 8-bromoinosine in aqueous solutions
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The reactions of hydrated electrons (eaq-) with 8-bromo-2′-deoxyinosine (8) and 8-bromoinosine (12) have been investigated by radiolytic methods coupled with product studies and have been addressed computationally by means of BB1K-HMDFT calculations. Pulse radiolysis revealed that one-electron reductive cleavage of the C-Br bond gives the C8 radical 9 or 13 followed by a fast radical translocation to the sugar moiety. Selective generation of a C5′ radical occurs in the 2′-de-oxyribo derivative, whereas in the ribo analogue the reaction is partitioned between the C5′ and C2′ positions with similar rates. Both C5′ radicals undergo cyclizations, 10→11 and 14→15, with rate constants of 1.4 × 105 and of 1.3 × 104 s-1, respectively. The redox properties of radicals 10 and 11 have also been investigated. A synthetically useful photoreaction has also been developed as a one-pot procedure that allows the conversion of 8 to 5′,8-cyclo-2′- deoxyinosine in a high yield and a diastereoisomeric ratio (5′R)/ (5′S) of 4:1. The present results are compared with data previously obtained for 8-bromoadenine and 8-bromoguanine nucleosides. Theory suggests that the behavior of 8-bromopurine derivatives with respect to solvated electrons can be attributed to differences in the energy gap between the π*- and σ*-radical anions.
- Russo, Marialuisa,Jimenez, Liliana B.,Mulazzani, Quinto G.,D'Angelantonio, Mila,Guerra, Maurizio,Miranda, Miguel A.,Chatgilialoglu, Chryssostomos
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p. 7684 - 7693
(2007/10/03)
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- Kinetic properties of Cellulomonas sp. purine nucleoside phosphorylase with typical and non-typical substrates: Implications for the reaction mechanism
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Phosphorolysis catalyzed by Cellulomonas sp. PNP with typical nucleoside substrate, inosine (Ino), and non-typical 7-methylguanosine (m7Guo), with either nucleoside or phosphate (Pi) as the varied substrate, kinetics of the reverse synthetic reaction with guanine (Gua) and ribose-1-phosphate (R1P) as the varied substrates, and product inhibition patterns of synthetic and phosphorolytic reaction pathways were studied by steady-state kinetic methods. It is concluded that, like for mammalian trimeric PNP, complex kinetic characteristics observed for Cellulomonas enzyme results from simultaneous occurrence of three phenomena. These are sequential but random, not ordered binding of substrates, tight binding of me substrate purine bases, leading to the circumstances that for such substrates (products) rapid-equilibrium assumptions do not hold, and a dual role of Pi, a substrate, and also a reaction modifier that helps to release a tightly bound purine base. Copyright Taylor & Francis, Inc.
- Wielgus-Kutrowska, Beata,Bzowska, Agnieszka
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p. 471 - 476
(2008/02/01)
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- Phosphodiesterase 4 inhibitors
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PDE4 inhibition is achieved by novel compounds of the Formula I: wherein R1 and R2 are as defined herein.
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- Hypophosphorous acid-iodine: An efficient and mild reagent for cleavage of N-C bond
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A mixture of hypophosphorous acid (H3PO2) and iodine in acetic acid can selectively cleave the N-alkyl bond in a variety of substituted heterocylic compounds in good to excellent yields without any damage to amide bond present in the substrates.
- Meng, Ge,He, Yan-Ping,Chen, Fen-Er
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p. 2593 - 2598
(2007/10/03)
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- Synthesis of purine antiviral agents, hypoxanthine and 6-mercaptopurine
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Some potentially biologically active 6-substituted purine derivatives have been synthesized from simple organic reagents. The reaction of urea with ethyl cyanoacetate gave 6-aminopyrimidine-2,4-dione which was converted in two steps into purine derivative, xanthine. The latter was treated with formamide at 200°C to obtain hypoxanthine. The chlorination of hypoxanthine with POCl3 gave 6-chloropurine which was converted into 6-mercaptopurine via reaction with thiourea in acetonitrile, followed by treatment with boiling ethanol.
- Sariri,Khalili
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p. 1053 - 1055
(2007/10/03)
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- Purine derivatives having phosphodiesterase iv inhibition activity
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Disclosed are compounds of the formula: whereinR3, R6a, R6b and R8 are substituted as disclosed herein. The compounds are effective in effecting PDE IV inhibition in patients in need thereof.
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- The stability of 6-mercaptopurine riboside in neutral and basic medium
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The kinetics of hydrolysis of 6-mercaptopurine riboside (R-6-MP) was studied in aqueous solutions over the pH range of 6.11 - 12.13 at 353 K. The decomposition was investigated by HPLC method. At the pH range from 6.11 to 12.13 hydrolysis of 6-mercaptopurine riboside includes: spontaneous hydrolysis of non-protonated R-6-MP molecules mono- and di-anions R-6-MP molecules under the effect of water.
- Jelinska,Magdziarz
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p. 407 - 409
(2007/10/03)
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- Phosphazole compounds
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A class of substituted and unsubstituted nucleo-base analogs and related azoles, designated as "phosphazoles," is disclosed, certain preferred embodiments having the basic structure of STR1 Also disclosed are methods of making and using the new compounds.
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- Chemical transformations of 6-[(1-methyl-4-nitro-5-imidazolyl)-thio]purine (azathioprine)
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The chemical transformations of 6-[(1-methyl-4-nitro-5-imidazolyl)thio]purine (azathiopurine)- hydrogenation, acetylation, alkylation by lower alkyl halides at positions 7 and 9 of the purine ring, hydrolytic cleavage at the C(6)-S and S-C(5) bonds - were studied.
- Kochergin,Aleksandrova,Korsunskii
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p. 311 - 318
(2007/10/03)
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- Stability of disodium salt of inosine phosphate in aqueous solutions
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The HPLC method for the separation of the disodium salt of inosine phosphate (PIN) and the product of its transformation, inosine (IN) and hypoxanthine (HP) were developed and validated. The hydrolysis kinetics of disodium salt of inosine phosphate was studied in aqueous solution at 353 K over a pH range of 0,45-12,13.
- Jelinska,Lewandowski
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p. 331 - 335
(2007/10/03)
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- Gene therapy of cancer: activation of nucleoside prodrugs with e. colipurine nucleoside phosphorylase
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During the last few years, many gene therapy strategies have been developed for various disease targets. The development of anticancer gene therapy strategies to selectively generate cytotoxic nucleoside or nucleotide analogs is an attractive goal. One such approach involves the delivery of herpes simplex virus thymidine kinase followed by the acyclic nucleoside analog ganciclovir. We have developed another gene therapy methodology for the treatment of cancer that has several significant attributes. Specifically, our approach involves the delivery of E. coli purine nucleoside phosphorylase, followed by treatment with a relatively non-toxic nucleoside prodrug that is cleaved by the enzyme to a toxic compound. .This presentation describes the concept, details our search for suitable prodrugs, and summarizes the current biological data. Copyright
- Secrist III, John A.
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p. 745 - 757
(2007/10/03)
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- Binding of substrates by purine nucleoside phosphorylase (PNP) from Cellulomonas sp. - Kinetic and spectrofluorimetric studies
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Dissociation constants and stoichiometry of binding for interaction of Cellulomonas sp. purine nucleoside phosphorylase with its substrates: inosine/guanosine, orthophosphate, guanine/hypoxanthine and D-ribose-1- phosphate were studied by kinetic and spectrofluorimetric methods.
- Wielgus-Kutrowska,Tebbe,Wierzchowski,Shugar,Saenger,Koellner,Bzowska
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p. 871 - 872
(2007/10/03)
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- L-nucleoside analogues as potential antimalarials that selectively target Plasmodium falciparum adenosine deaminase
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The L-stereoisomer analogues of D-coformycin selectively inhibited P. falciparum adenosine deaminase (ADA) in the picomolar range (L-isocoformycin, K(i) 7 pM; L-coformycin, K(i) 250 pM). While the L-nucleoside analogues, L- adenosine, 2,6-diamino-9-(L-ribofuranosyl)purine and 4-amino- 1 -(L- ribofuranosyl)pyrazolo[3,4-d]-pyrimidine were selectively deaminated by P. falciparum ADA, L-thioinosine and L-thioguanosine were not. This is the first example of 'non-physiological' L-nucleosides that serve as either substrates or inhibitors of malarial ADA and are not utilised by mammalian ADA.
- Brown, David M.,Netting, Andrew G.,Chun, Byoung K.,Choi, Yongseok,Chu, Chung K.,Gero, Annette M.
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p. 2521 - 2532
(2007/10/03)
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- Synthesis and some properties of 6-(ω-aroylbutylthio)purines
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A series of 6-(ω-aroylthio)purines, which have not been described in the literature, has been obtained by the reaction of 6-purinethione with ω-chlorovalerophenone and its substituted derivatives. Some properties of the compounds synthesized have been studied, viz. reaction at the carbonyl group, methylation, and hydrolysis. 1999 KluwerAcademic/Plenum Publishers.
- Gromov,Skachilova,Aleksandrova,Kochergin
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p. 1225 - 1229
(2007/10/03)
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- Inhibition of nitrous acid-dependent tyrosine nitration and DNA base deamination by flavonoids and other phenolic compounds
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Exposure of tyrosine or DNA bases to acidic nitrite at low pH results in the nitration of tyrosine and the formation of base deamination products, respectively. At pH 1, hypoxanthine and xanthine are formed from the deamination of adenine and guanine, respectively, whereas under the same conditions, uracil is not detected. The yield of 3-nitrotyrosine derived from interaction of equimolar nitrite and tyrosine at pHI is approximately 50% of that obtained from equimolar peroxynitrite-tyrosine interactions at pH 7.4. The ability of a range of plant phenolic constituents to prevent damage mediated by acidic nitrite was also examined in comparison with the activity of vitamin C. The epicatechin/gallate family of flavonols, constituents of green tea, red wine, etc., demonstrates the most extensive inhibitory properties against both tyrosine nitration and base deamination. The results also show that ascorbic acid is a poor inhibitor of nitration or deamination under acidic conditions such as those of the stomach. The ability of plant phenolics to scavenge reactive nitrogen species derived from acidic nitrite may contribute to the protective effects of tea polyphenols against gastric cancer.
- Oldreive, Ceri,Zhao, Kaicun,Paganga, George,Halliwell, Barry,Rice-Evans, Catherine
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p. 1574 - 1579
(2007/10/03)
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- High pressure in enzyme catalyzed organic reactions
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Adenosine deaminase and lipases catalyzed hydrolysis under high pressure were described. The hydrolysis by both enzymes was facilitated by high pressures. This technique was used for the kinetical resolution of racemic highly modified nucleosides having biological activities.
- Katagiri, Nobuya,Yamaguchi, Masahiko,Kaneko, Chikara
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p. 1023 - 1043
(2007/10/03)
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- Base modification and strand breakage in isolated calf thymus DNA and in DNA from human skin epidermal keratinocytes exposed to peroxynitrite or 3- morpholinosydnonimine
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Exposure of isolated calf thymus DNA and human skin epidermal keratinocytes to peroxynitrite or the peroxynitrite generator, 3- morpholinosydnonimine (SIN-1), led to extensive DNA base modification. Large increases in xanthine and hypoxanthine, possible deamination products of guanine and adenine, respectively, and in 8-nitroguanine were observed, but only small changes in some oxidized base products were seen. This pattern of damage suggests that hydroxyl radicals were not major contributors to base modification caused by peroxynitrite, as OH· is known to cause multiple oxidative modifications to all four DNA bases. Instead, it seems that reactive nitrogen species play a much greater role in the mechanism of base damage, producing both nitration and deamination of purine bases when DNA or whole cells are exposed to peroxynitrite. If this pattern of damage is unique to peroxynitrite, it might act as a marker of cellular damage by this species in vivo.
- Spencer, Jeremy P. E.,Wong, Jon,Jenner, Andrew,Aruoma, Okezie I.,Cross, Caroll E.,Halliwell, Barry
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p. 1152 - 1158
(2007/10/03)
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- Reactions of Nitric Oxide with Amines in the Presence of Dioxygen
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Nitric oxide (NO), a multifaceted bioregulatory agent and an environmental pollutant, can effectively convert aromatic amines to the corresponding triazenes under aerobic conditions, but not under anaerobic conditions.Nucleic acid bases and nucleosides are also determinated via hydrolysis of the diazonium ion products with exposure to aerobic NO solution.A peroxynitrite radical or nitrogen dioxide is suggested to be the ultimate reactive species.
- Nagano, Tetsuo,Takizawa, Hiromasa,Hirobe, Masaaki
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p. 8239 - 8242
(2007/10/02)
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- Administering particular compounds against various parasites, mycoplasmas, other indications and other infections
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One or more compounds are administered against one or more kinds of parasites and/or one or more diseases caused by such parasites, against one or more kind of Mycoplasma and/or one or more diseases caused by such Mycoplasmas and/or against one or more of the following indications or infections (a) hairy leukoplakia, (b) oral candidosis, (c) mouth ulcerations-aphthous/herpetic/bacterial, (d) fungal candida, (e) human papilloma virus, (f) molluscum contagiosum, (g) squamous oral carcinoma, (h) Kaposi's sarcoma oral lesions, (i) periodontitis, (j) necrotizing gingivitis, (k) orofacial herpes zoster, and (1) rotaviruses. The present invention furthermore provides specific formulations including such compound(s).
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- Synthesis of 2'-deoxyisoinosine and related 2'-deoxyribonucleosides
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Various 2-substituted purine and pyrrolo[2,3-d]pyrimidine 2'-deoxyribonucleosides with methylthio (13a), chloro (13b), methoxy (9b), and oxo (2, 3) substituents at C(2) are prepared. They are obtained either via stereoselective nucleobase-anion glycosylation or by base transformation. A three-step synthesis of the unknown 2'-deoxyisoinosine (2) from 2'-deoxyguanosine (15) is described. Compound 2 as well as its 7-deazapurine derivative 3 exhibit strong fluorescence.
- Seela,Chen,Bindig,Kazimierczuk
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p. 194 - 202
(2007/10/02)
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- 4'-substituted nucleosides
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Nucleosides compounds of Formula I: STR1 wherein B is a purine or a pyrimidine; X and X' are H; Y is H; Y' is OH, F or H; or Y' and X' together makes a bond; Z is STR2 where n is zero, one, two or three; or Y' and Z together form a cyclic phosphate ester; Z' is --CN, --CH3, CH2 N3 or --CH2 J, where J is a halogen atom; or Z' and Y' together are --CH2 O--; and pharmaceutically acceptable esters, ethers, amides, N-acyl moieties and salts thereof.
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- SYNTHESIS AND SOME PROPERTIES OF 6-β-OXOALKYL(ARALKYL, HETARALKYL, CYCLOALKYL)THIOPURINES
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The reaction of 6-purinethione with α-haloketones has given a series of new 6-β-oxoalkyl(aralkyl, hetaralkyl, cycloalkyl)thiopurines.Their alkylation in position 9 and acid hydrolysis to hypoxanthine and its 9-alkyl derivatives has been studied.The hydrolysis of the acetals of 6-formylmethylthiopurine and the oxidation of 6-(2,3-dihydroxypropyl)thiopurine leads to 6-formylmethylthiopurine, which shows a ring-chain tautomerism and exists in the form of 7-hydroxy-7,8-dihydrothiazolopurine.
- Kochergin, P. M.,Gromov, M. Yu.,Aleksandrova, E. V.,Skachilova, S. Ya.
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p. 1335 - 1339
(2007/10/02)
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- Purines. LI. Synthesis and biological activity of hypoxanthine 7-N-oxide and related compounds
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A detailed account is given of the first chemical synthesis of hypoxanthine 7-N-oxide (5), which started from coupling of 6-chloro-5-nitro-4(3H)-pyrimidinone (7) with N-(4-methoxybenzyl)phenacylamine, generated in situ from the hydrochloride (8), and proceeded through cyclization of the resulting phenacylamino pyrimidinone (9) and removal of the 4-methoxybenzyl group. The results of catalytic hydrogenolysis, methylation followed by catalytic hydrogenolysis, and rearrangement under acidic conditions of 5 supported the correctness of the assigned structure. An ultraviolet spectroscopic approach suggested that the neutral species of 5 exists in H2O mainly as the N(7)-OH tautomer (21). In the in vitro bioassay of antileukemic activity against murine L5178Y cells, 5 was weakly cytotoxic, with IC50 of 100 μg/ml. It did not show any antimicrobial activity even at 1000 μg/ml. None of the 9-(4-methoxybenzyl) (11) and O-methyl (12, 13, and 14) derivatives was found to be antileukemic or antimicrobial.
- Ogawa,Nishii,Nohara,Saito,Itaya,Fujii
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p. 612 - 616
(2007/10/02)
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- Use of particular compounds for manufacture of pharmaceutical formulations for treatment against various parasites, mycoplasmas, other indications and other infections
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One or more compounds are used for the manufacture of a pharmaceutical formulation for treatment against one or more kinds of parasites and/or one or more diseases caused by such parasites, against one or more kind of Mycoplasma and/or one or more diseases caused by such Mycoplasmas and/or against one or more of the following indications or infections (a) hairy leukoplakia, (b) oral candidosis, (c) mouth ulcerations-aphthous/herpetic/bacterial, (d) fungal candida, (e) human papilloma virus, (f) molluscum contagiosum, (g) squamous oral carcinoma, (h) Kaposi's sarcoma oral lesions, (i) periodontitis, (j) necrotizing gingivitis, (k) orofacial herpes zoster, and (l) rotaviruses. The present invention furthermore provides specific formulations including such compound(s).
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- Viral treatment system
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This invention relates to pharmaceutical formulations of compounds and drugs for treatment against viruses and prions (proteinaceous infectious particles) eg. CMV, Herpes Simplex, Hepatitis B, Scapie Creutzfeldt-Jakob Disease, in particular for drug treatment of persons and animals suffering from certain retroviral infections, and of persons suffering from infection by retroviruses related to human immuno-deficiency viruses (HIV), and for prophylactic drug treatment of persons who may be suffering from such infections. The anti-viral pharmaceutical formulations according to the invention have the general formula:
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