- Origin of difference between one-electron redox potentials of guanosine and guanine: Electrochemical and quantum chemical study
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Cyclic voltammetry was used to measure the rates of the chemical oxidation of guanine (G), guanosine (Gs), 2a?2-deoxyguanosine (dG), and 2a?2-deoxyguanosine 5a?2-monophosphate (dGMP) by electrochemically generated tris(2,2a?2-bipyridyl)ruthenium(III). The numeric fit of voltammograms to an ECCCE type of mechanism provided the equilibrium and rate constants of the two-step chemical oxidation of the guanine species. One-electron redox potentials evaluated from the equilibrium constant of the first electron uptake follow the sequence G + and partly from the higher difference in the hydration energy between the deprotonated radical Gs(-H) and the parent Gs, which compensate for the lower ionization potential of Gs compared to that of G.
- Langmaler, Jan,Samec, Zdeneì?k,Samcovaì?, Eva,Hobza, Pavel,Rì?eha, David
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- Kinetics of hydrolysis of 8-(arylamino)-2′-deoxyguanosines
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The 8-(arylamino)-2′-deoxyguanosines, or C-8 adducts, are the major adducts formed by reaction of N-arylnitrenium ions derived from carcinogenic and mutagenic amines with 2′-deoxyguanosine (d-G) and guanosine residues of DNA. The hydrolysis kinetics of three C-8 adducts 1a-c were determined by UV and HPLC methods at 20 °C under acidic, neutral, and mildly alkaline conditions. At pH 2+2 (Scheme 2). The C-8 adducts are 2- to 5-fold more reactive than d-G under these conditions. At 3 +. Under these conditions the hydrolysis kinetics are accelerated by 40- to 1300-fold over that of d-G. The rate increase appears to be caused by a combination of steric acceleration of C-N bond cleavage and a decrease in the ionization constant of 1H+, Ka1, due to the electron-donating properties of the arylamino C-8 substituent. Under neutral pH conditions a slow (kobs ≈ 10-8 s-1 to 5 × 10-7 s-1) spontaneous cleavage of the C-N bond of the neutral nucleoside, 1, occurs that has not been previously reported for simple purine nucleosides. Finally, under mildly alkaline conditions a process consistent with spontaneous decomposition of the anion 1- or OH--induced decomposition of 1 is observed. The latter process has been observed for other purine nucleosides, including the closely related 1d, and involves nucleophilic attack of OH- on C-8 to cleave the imidazole ring of the purine.
- Novak, Michael,Ruenz, Megan,Kazerani, Shahrokh,Toth, Krisztina,Nguyen, Thach-Mien,Heinrich, Brian
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- π-Interactions of modified nucleobases. On mesomeric purine betaines with inversed charge properties
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Intermolecular interactions of modified nucleobases with altered charge properties in relation to natural systems are studied. We prepared conjugated mesomeric betaines of purines and examined their properties by semiempirical calculations, IH
- Schmidt, Andreas,Karl Kindermann, Markus
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- REACTION OF GUANOSINE DERIVATIVES WITH PHOSPHORUS TRICHLORIDE IN ACETONE
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2',3'-Di-O-protected guanosine derivatives (Ia and Ib) were allowed to react with phosphorus trichloride in acetone to give the N-2-(1-methyl-1-phosphono)ethylguanosine derivatives (IIIa and 3b).
- Honjo, Mikio,Maruyama, Tokumi,Sato, Sumiko,Marumoto, Ryuji
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- Novel use of a guanosine prodrug approach to convert 2′,3′-didehydro-2′,3′-dideoxyguanosine into a viable antiviral agent
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Transient kinetic studies with human immunodeficiency virus (HIV) type 1 reverse transcriptase suggest that nucleotide analogs containing the 2′,3′-didehydro-2′,3′-dideoxy ribose ring structure present in D4T (stavudine) triphosphate are among the most effective alternative substrates. For unclear reasons, however, the corresponding purine nucleoside, 2′,3′-didehydro-2′,3′-dideoxyguanosine (D4G), was found to be inactive in cell culture. We have found that the previously reported lack of activity of D4G is primarily due to solution instability, and in this report we describe a novel use of a guanosine prodrug approach to stabilize the nucleoside. D4G was modified at the 6 position of the purine ring to contain a cyclopropylamino group yielding the prodrug, cyclo-D4G. An evaluation of cyclo-D4G revealed that the prodrug possessed anti-HIV activity. In addition, cyclo-D4G had increased stability, lipophilicity, and solubility, as well as decreased toxicity relative to D4G, suggesting that further study is warranted.
- Ray, Adrian S.,Yang, Zhenjun,Chu, Chung K.,Anderson, Karen S.
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- Physicochemical properties of carbovir, a potential anti-HIV agent
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(±)-Carbovir [(±)-9-[4α-(hydroxymethyl)-cyclopent-2-ene-1α-yl]guanine; NSC 614846] is a novel carbocyclic nucleoside analogue which has been shown to be a potent and selective inhibitor of HIV in vitro. As part of an effort to develop a parenteral formulation for subsequent clinical and toxicological evaluation of this compound, the aqueous solution stability of carbovir as a function of pH and temperature and various physicochemical properties of carbovir including its pK(a), solubility versus pH and solvent composition, and octanol-water partition coefficient have been examined. Ultraviolet spectrophotometry indicated that carbovir has pK(a) values of 3.15 and 9.68, respectively, at 25°C and 0.01 ionic strength. The acqueous solubility of carbovir over the pH range 7-10.5 was consistent with that expected of a weak acid with a pK(a) of 9.65 and an intrinsic solubility of 1.24 mg/mL. Due to the limited solubility of carbovir at physiological pH, methods for solubilizing carbovir in aqueous solution were explored, including propylene glycol-water cosolvents and complexation with hydroxypropyl-β-cyclodextrin. As expected for carbovir, a semipolar compound with an octanol-water partition coefficient of 0.29, propylene glycol:water cosolvents were not highly effective in enhancing solubility. Complex formation between carbovir and 2-hydroxypropyl-β-cyclodextrin was found to be more effective, with a K(1:1) of 105 M-1 for the complexation. The pH profiles generated at 50, 70, and 90°C were accounted for by acid-catalyzed degradation at low pH leading to the formation of quanine and a neutral degradation pathway which dominates above pH 4. Prototype lyophilized formulations containing (after reconstitution) 10 mg/mL of carbovir at a pH of 10.6 were developed and evaluated.
- Anderson,Chiang
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- THE EFFECT OF METAL ION COMPLEX FORMATION ON ACIDIC DEPURINATION OF 2'-DEOXYADENOSINE AND 2'-DEOXYGUANOSINE
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The substitution inert N7-(dien)Pt(II) complex of 2'-deoxyguanosine has been shown to undergo acidic depurination 200 times less readily than the uncomplexed nucleoside, whereas the corresponding N1- and N7-complexes of 2'-deoxyadenosine are depurinated almost as rapidly as the nucleoside itself.These observations have been compared to the influences that several substitution labile metal ions exerted on the rate of depurination.Accordingly, the effects of (dien)Pd(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) ions on the acidic hydrolysis of 2'-deoxyadenosine and 2'-deoxyguanosine have been accounted for by competitive attachment of protons and metal ions to the N1 and N7 sites.The applicability of metal ions in chemical DNA sequencing is briefly discussed.
- Arpalahti, Jorma,Kaeppi, Rainer,Hovinen, Jari,Loennberg, Harri,Chattopadhyaya, Jyoti
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- Low-energy, low-yield photoionization, and production of 8-oxo-2a?2-deoxyguanosine and guanine from 2a?2-deoxyguanosine
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Experiments employing electron scavenging methods and high performance liquid chromatography with mass spectrometry detection indicate that electrons, formed via one-photon ionization, guanine (G) and small amounts of 8-oxo-2a?2-deoxyguanosine (8-oxo-dG)
- Papadantonakis, George A.,Tranter, Robert,Brezinsky, Kenneth,Yang, Yanan,Van Breemen, Richard B.,LeBreton, Pierre R.
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- Nitrogen-Doped Carbon Supported Co/Ni Bimetallic Catalyst for Selectively Reductive N-Formylation of Nitroso in Guanine Synthesis
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A nitrogen-doped carbon supported Co/Ni bimetallic catalyst 2wt%Co/Ni@NC-700-10 was prepared and found to be efficient in the reductive N-formylation of 2,4-diamino-5-nitroso-6-hydroxypyrimidine (DANHP) to 2,4-diamino-5-formyl-6-hydroxypyrimidine (DAFHP) for the synthesis of guanine. Under optimal conditions, the conversion of DANHP reached up to 95.6% with a DAFHP selectivity of 97.6%. The characterization results revealed that the cobalt/nickel nanoparticles of the catalyst uniformly dispersed and encapsulated in the nitrogen-dopped carbon, and the catalyst has the characters of large surface area, as well as uniform dispersion and small diameters of metal nanoparticles in the form of Co/Ni alloy, which endowed its good catalytic performance in the reaction. Graphical abstract: [Figure not available: see fulltext.]
- Liu, Peng,Shi, Dongxu,Wang, Ke,Zhang, Hong-yu,Zhang, Yuecheng,Zhao, Jiquan
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- Method for synthesizing guanine by guanosine hydrolysis method (by machine translation)
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The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing guanine by a guanosine hydrolysis method. After the reaction is completed, the pH of the system is adjusted to 20 °C - 35 °C, and pH of the system is adjusted to neutral, filtered and collected to obtain a guanine wet product. The method has the advantages of high yield of guanine products, high purity, high reaction yield 96.0-98 .0percent, product purity 99.5-99 .8percent, simple operation process, short production period, low single batch reaction time and 1 hour, and is suitable for industrial mass production. (by machine translation)
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Paragraph 0031-0070
(2020/08/02)
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- Method for synthesizing 2-amino-6-chloropurine
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The invention discloses a method for synthesizing 2-amino-6-chloropurine, and belongs to the field of organic chemical synthesis. The synthesis method of the 2-amino-6-chloropurine comprises the following steps: enabling 6-hydroxyl-2,4,5-triaminopyrimidine to react with trimethyl orthoformate to generate guanine, and enabling the guanine to react with hydrogen chloride and hydrogen peroxide to generate 2-amino-6-chloropurine. The method has the advantages of short reaction time, high yield, no generation of a large amount of three wastes, simple operation, and facilitation of industrial production.
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Paragraph 0021-0035
(2020/09/08)
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- Preparation method and application of 2, 4-diamino-6-hydroxy-5-formamidopyrimidine
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The invention discloses a preparation method of 2, 4-diamino-6-hydroxy-5-carboxamido pyrimidine. The preparation method comprises the following step: carrying out an acylation reaction on 2, 4-diamino-5-nitroso-6-hydroxypyrimidine in formamide and water under the catalytic action of a catalyst A to obtain the 2, 4-diamino-6-hydroxy-5-carboxamido pyrimidine. The invention also discloses a preparation method of guanine formate or guanine. The preparation method of guanine formate or guanine comprises the following step: reacting the 2, 4-diamino-6-hydroxy-5-formamidopyrimidine in formic acid toobtain guanine. According to the synthesis methods of the 2, 4-diamino-6-hydroxy-5-formamidopyrimidine and guanine, the production process is greatly shortened, the generation amount of three wastes is greatly reduced, the product quality of the guanine product meets related quality requirements, and the molar yield is higher than that of the guanine product prepared by the prior art. Therefore, the preparation methods disclosed by the invention are efficient, economic, green and environment-friendly preparation methods.
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Paragraph 0073-0083
(2020/09/20)
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- Sources of 2,5-diaminoimidazolone lesions in DNA damage initiated by hydroxyl radical attack
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The present study reports radiation-chemical yields of 2.5-diaminoimidazolone (Iz) derivatives in X-irradiated phosphate-buffered solutions of guanosine and double-stranded DNA. Various gassing conditions (air, N20/O2 (4:1), N2O, vacuum) were employed to elucidate the contribution of several alternative pathways leading to Iz in reactions initiated by hydroxyl radical attack on guanine. In all systems, Iz was identified as the second by abundance guanine degradation product after 8-oxoguanine, formed in 1:5 (guanosine) and 1:3.3 (DNA) ratio to the latter in air-saturated solutions. Experimental data strongly suggest that the addition of molecular oxygen to the neutral guanine radical G(-H)? plays a major in Iz production in oxygenated solutions of double-stranded DNA while in other systems it may compete with recombination of G(-H)? with superoxide and/or alkyl peroxyl radicals. The production of Iz through hydroxyl radical attack on 8-oxoguanine was also shown to take place although the chemical yield of Iz (ca 6%) in this process is too low to compete with the other pathways. The linearity of Iz accumulation with dose also indicates a negligible contribution of this channel to its yield in all systems.
- Thomas, Caroline Suzanne,Pollard, Hannah Catherine,Razskazovskiy, Yuriy,Roginskaya, Marina
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p. 517 - 524
(2020/09/07)
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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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- Triaminopyrimimelamino 2, 4, 5- pyrimidine formate -6- and preparation method and application thereof
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The invention discloses 2,4,5-triamido-6-hydroxy pyrimidine formate and a preparation method. The preparation method comprises the following steps: enabling 2,4-diamido-5-nitro-6-hydroxy pyrimidine toreact with hydrogen in catalyst A and alkaline solution B, and obtaining 2,4,5-triamido-6-hydroxyl pyrimidine; and enabling a hydrogenation product to perform the salt forming reaction with formic acid to obtain 2,4,5-triamido-6-hydroxy pyrimidine formate. The invention discloses a method for preparing guanine by utilizing the 2,4,5-triamido-6-hydroxy pyrimidine formate. The preparation method isshort in production route, and high in molar yield, wherein the total molar yield is 90 percent or higher. The solvent can be recycled and generally used, the content of the salt and strong acid in the production wastewater can be greatly reduced, and the emission amount is little. The pyrimidine formate is a brand new compound. The pyrimidine formate is used for substituting the pyrimidine sulfate to prepare the guanine, so that a great amount of sulfate can be prevented from flowing into the production wastewater.
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Paragraph 0055; 0059-0067; 0071-0076
(2019/11/29)
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- Preparation methods of 2,4-diamido-5-nitroso-6-hydroxypyridine and guanine
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The invention discloses a preparation method of 2,4-diamido-5-nitroso-6-hydroxypyridine. The preparation method comprises the following steps: (1) in a sodium methoxide methanol solution, carrying outa ring-closure reaction between methyl cyanoacetate and guanidine salt; (2) adding recycled absolute methanol to be diluted, filtering and recycling byproduct sodium nitrate; (3) concentrating a filter liquor, and recycling absolute methanol; (4) adding water to destroy excessive sodium methoxide, concentrating and recycling water-containing methyl alcohol; (5) in a diluted methane acid solution,carrying out a nitrosation reaction among an obtained concentrate, sodium nitrite and a nitrosation mother liquor; (6) after the reaction ends, carrying out cooling crystallization, filtering, takinga filter liquor as the nitrosation mother liquor to be used indiscriminately, and drying an obtained filter cake to obtain the 2,4-diamido-5-nitroso-6-hydroxypyridine. According to the preparation method, indiscriminate use of the nitrosation mother liquor and recycling of sodium nitrate and methyl alcohol are realized, and simultaneously the diluted methane acid solution is used for replacing concentrated sulfuric acid used, in the prior art, to carry out the nitrosation reaction, so that the recycling of a solvent and a reagent is facilitated, and the displacement of waste water is reduced.
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Paragraph 0078; 0079; 0080
(2018/10/19)
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- Silica Metal Oxide Vesicles Catalyze Comprehensive Prebiotic Chemistry
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It has recently been demonstrated that mineral self-assembled structures catalyzing prebiotic chemical reactions may form in natural waters derived from serpentinization, a geological process widespread in the early stages of Earth-like planets. We have s
- Mattia Bizzarri, Bruno,Botta, Lorenzo,Pérez-Valverde, Maritza Iveth,Saladino, Raffaele,Di Mauro, Ernesto,García-Ruiz, Juan Manuel
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p. 8126 - 8132
(2018/05/29)
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- A 2, 4 - diamino - 5 - nitro - 6 - hydroxy pyrimidine preparation method and application thereof (by machine translation)
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The present invention provides a 2, 4 - diamino - 5 - nitro - 6 - hydroxy pyrimidine preparation method, comprises the following steps: in a sulfuric acid solution, 2, 4 - diamino - 6 - hydroxy pyrimidine with nitric acid nitration; after the reaction is complete, the cooling crystallization, filtering, washing, drying, to obtain 2, 4 - diamino - 5 - nitro - 6 - hydroxy pyrimidine; the invention also provides a method for preparing nitro pyrimidine 2, 4, 5 - c amino - 6 - hydroxy pyrimidine method, comprises the following steps: N in the catalyst under the action of the, nitro pyrimidine in the lye A with C1 - C4 alcohol in the mixed solution, react with hydrogen; the method of the invention preparation of guanine, not the production of the inorganic salt as a by-product, waste water generation and emissions is lowered to that of the existing technology 1/6 - 1/8. (by machine translation)
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Paragraph 0063-0067
(2018/05/01)
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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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- Novel method for preparing guanine
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A novel method for preparing guanine is characterized in that 2,4,5-triamino-6-hydroxypyrimidinesulfate and formic acid are fully mixed, and formamide is added and reacts for 8-15 h to obtain guanine. Recycling of solvents and reagents is effectively achieved, the method is environmentally friendly and economical, effective recycling of resources is achieved, and sustainable development of enterprises is benefited. Besides, the guanine prepared through the method is high in purity and good in appearance.
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Paragraph 0014; 0024-0043
(2017/06/02)
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- 5-Carboxamido-5-formamido-2-iminohydantoin, in Addition to 8-oxo-7,8-Dihydroguanine, Is the Major Product of the Iron-Fenton or X-ray Radiation-Induced Oxidation of Guanine under Aerobic Reducing Conditions in Nucleoside and DNA Contexts
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Exogenously and endogenously produced reactive oxygen species attack the base and sugar moieties of DNA showing a preference for reaction at 2′-deoxyguanosine (dG) sites. In the present work, dG was oxidized by HO? via the Fe(II)-Fenton reaction or by X-ray radiolysis of water. The oxidized lesions observed include the 2′-deoxynucleosides of 8-oxo-7,8-dihydroguanine (dOG), spiroiminodihydantoin (dSp), 5-guanidinohydantoin (dGh), oxazolone (dZ), 5-carboxamido-5-formamido-2-iminohydantoin (d2Ih), 5′,8-cyclo-2′-deoxyguanosine (cyclo-dG), and the free base guanine (Gua). Reactions conducted with ascorbate or N-acetylcysteine as a reductant under aerobic conditions identified d2Ih as the major lesion formed. Studies were conducted to identify the role of O2 and the reductant in product formation. From these studies, mechanisms are proposed to support d2Ih as a major oxidation product detected under aerobic conditions in the presence of the reductant. These nucleoside observations were then validated in oxidations of oligodeoxynucleotide and λ-DNA contexts that demonstrated high yields of d2Ih in tandem with dOG, dSp, and dGh. These results identify dG oxidation to d2Ih to occur in high yields leading to a hypothesis that d2Ih could be found from in cells stressed with HO?. Further, the distorted ring structure of d2Ih likely causes this lesion to be highly mutagenic. (Chemical Equation Presented)
- Alshykhly, Omar R.,Fleming, Aaron M.,Burrows, Cynthia J.
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p. 6996 - 7007
(2015/07/27)
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- Cytotoxicity of guanine-based degradation products contributes to the antiproliferative activity of guanine-rich oligonucleotides
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Guanine-rich oligonucleotides (GROs) have attracted considerable attention as anticancer agents, because they exhibit cancer-selective antiproliferative activity and can form G-quadruplex structures with higher nuclease resistance and cellular uptake. Recently, a GRO, AS1411 has reached phase II clinical trials for acute myeloid leukemia and renal cell carcinoma. The antiproliferative activity of GROs has been associated with various protein targets; however the real mechanisms of action remain unclear. In this study, we showed evidence that antiproliferative activity of GROs (including AS1411) is mainly contributed by the cytotoxicity of their guanine-based degradation products, such as monophosphate deoxyguanosine (dGMP), deoxyguanosine (dG) and guanine. The GROs with lower nuclease resistance exhibited higher antiproliferative activity. Among nucleotides, nucleosides and nucleobases, only guanine-based compounds showed highly concentration-dependent cytotoxicity. Our results suggest that it is necessary to reconsider the cancer-selective antiproliferative activity of GROs. Since guanine-based compounds are endogenous substances in living organisms, systematic studies of the cytotoxicity of these compounds will provide new information for the understanding of certain diseases and offer useful information for drug design.
- Zhang, Nan,Bing, Tao,Liu, Xiangjun,Qi, Cui,Shen, Luyao,Wang, Linlin,Shangguan, Dihua
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p. 3831 - 3838
(2015/06/25)
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- Molybdopterin biosynthesis: Trapping of intermediates for the MoaA-catalyzed reaction using 2′-deoxyGTP and 2′-chloroGTP as substrate analogues.
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MoaA is a radical S-adenosylmethionine (AdoMet) enzyme that catalyzes a complex rearrangement of guanosine-5'-triphosphate (GTP) in the first step of molybdopterin biosynthesis. In this paper, we provide additional characterization of the MoaA reaction product, describe the use of 2′-chloroGTP to trap the GTP C3′ radical, generated by hydrogen atom transfer to the 5′-deoxyadenosyl radical, and the use of 2′-deoxyGTP to block a late step in the reaction sequence. These probes, coupled with the previously reported trapping of an intermediate in which C3′ of the ribose is linked to C8 of the purine, allow us to propose a plausible mechanism for the MoaA-catalyzed reaction.
- Mehta, Angad P.,Abdelwahed, Sameh H.,Xu, Hui,Begley, Tadhg P.
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p. 10609 - 10614
(2014/08/18)
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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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- 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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- 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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- Stability of N-glycosidic bond of (5′ S)-8,5′-Cyclo-2′- deoxyguanosine
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8,5′-Cyclopurine deoxynucleosides are unique tandem lesions containing an additional covalent bond between the base and the sugar. These mutagenic and genotoxic lesions are repaired only by nucleotide excision repair. The N-glycosidic (or C1′-N9) bond of 2′-deoxyguanosine (dG) derivatives is usually susceptible to acid hydrolysis, but even after cleavage of this bond of the cyclopurine lesions, the base would remain attached to the sugar. Here, the stability of the N-glycosidic bond and the products formed by formic acid hydrolysis of (5′S)-8,5′-cyclo-2′-deoxyguanosine (S-cdG) were investigated. For comparison, the stability of the N-glycosidic bond of 8,5′-cyclo-2′,5′-dideoxyguanosine (ddcdG), 8-methyl-2′-deoxyguanosine (8-Me-dG), 7,8-dihydro-8-oxo-2′- deoxyguanosine (8-Oxo-dG), and dG was also studied. In various acid conditions, S-cdG and ddcdG exhibited similar stability to hydrolysis. Likewise, 8-Me-dG and dG showed comparable stability, but the half-lives of the cyclic dG lesions were at least 5-fold higher than those of dG or 8-Me-dG. NMR studies were carried out to investigate the products formed after the cleavage of the C1′-N9 bond. 2-Deoxyribose generated α and β anomers of deoxyribopyranose and deoxyribopyranose oligomers following acid treatment. S-cdG gave α- and β-deoxyribopyranose linked guanine as the major products, but α and β anomers of deoxyribofuranose linked guanine and other products were also detected. The N-glycosidic bond of 8-Oxo-dG was found exceptionally stable in acid. Computational studies determined that both the protonation of the N7 atom and the rate constant in the bond breaking step control the overall kinetics of hydrolysis, but both varied for the molecules studied indicating a delicate balance between the two steps. Nevertheless, the computational approach successfully predicted the trend observed experimentally. For 8-Oxo-dG, the low pKa of O8 and N3 prevented appreciable protonation, making the free energy for N-glycosidic bond cleavage in the subsequent step very high.
- Das, Rajat S.,Samaraweera, Milinda,Morton, Martha,Gascon, Jose A.,Basu, Ashis K.
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p. 2451 - 2461
(2013/01/15)
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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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- Stabilization of Escherichia coli uridine phosphorylase by evolution and immobilization
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Mutation and immobilization techniques were applied to uridine phosphorylase (UP) from Escherichia coli in order to enhance its thermal stability and hence productivity in a biocatalytic reaction. UP was evolved by iterative saturation mutagenesis. Compared to the wild type enzyme, which had a temperature optimum of 40 °C and a half-life of 9.89 h at 60 °C, the selected mutant had a temperature optimum of 60 °C and a half-life of 17.3 h at 60 °C. Self-immobilization of the native UP as a Spherezyme showed a 3.3 fold increase in thermostability while immobilized mutant enzyme showed a 4.4 fold increase in thermostability when compared to native UP. Combining UP with the purine nucleoside phosphorylase from Bacillus halodurans allows for synthesis of 5-methyluridine (a pharmaceutical intermediate) from guanosine and thymine in a one-pot transglycosylation reaction. Replacing the wild type UP with the mutant allowed for an increase in reaction temperature to 65 °C and increased the reaction productivity from 10 to 31 g l-1 h -1.
- Visser, Daniel F.,Hennessy, Fritha,Rashamuse, Justice,Pletschke, Brett,Brady, Dean
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experimental part
p. 279 - 285
(2011/10/09)
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- An integrated chemo-enzymatic route for preparation of β-thymidine, a key intermediate in the preparation of antiretrovirals
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A chemo-enzymatic method for production of β-thymidine, an intermediate in the synthesis of antiretrovirals, is described. Guanosine and thymine were converted by means of enzymatic transglycosylation to yield 5-methyluridine (5-MU), which was reproducibly synthesised at a 10-20-L scale in 85% yield at a final product concentration of ～80 g?L-1. A downstream processing (DSP) protocol was designed to remove reaction components interfering with the subsequent synthetic step. The crystallised 5-MU produced in the biocatalytic reaction was found to behave similarly to commercially available 5-MU, and the integration of the initial biocatalytic and subsequent three-step chemical process to β-thymidine was successfully demonstrated at bench scale.
- Gordon, Gregory E. R.,Bode, Moira L.,Visser, Daniel F.,Lepuru, M. Jerry,Zeevaart, Jacob G.,Ragubeer, Nasheen,Ratsaka, Molala,Brady, Dean,Walwyn, David R.
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experimental part
p. 258 - 265
(2011/10/04)
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- HUMANIZED ANTI-EGFL7 ANTIBODIES AND METHODS USING SAME
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The present invention concerns antibodies to EGFL7 and the uses of same.
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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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- Studies on the synthesis of N′-acetyl AZA-analogues of Ganciclovir - Unexpected liability of N′-(2-hydroxyethyl)-azanucleosides under basic conditions
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The O′-pivaloyl diesters of N′-acetyl-azanucleosides were obtained from N-[1,3-di(pivaloyloxy)prop-2-yl]-N-(pivaloyloxymethyl)acetamide and a silylated nucleobase under Vorbruggen′s conditions. Unexpectedly, de-pivaloylation of the diesters under basic conditions afforded the corresponding nucleobase and N-acetylserinol. Mechanistic investigations showed that these products result from the following cascade of spontaneous transformations initiated by the mono de-pivaloylation of the starting diesters. N′-Deacetylation of the resultant mono-esters via the intramolecular N-O acetyl migration is the key step of the cascade; the corresponding NH-azanucleosides in the form of O-acetyl-O′-pivaloyl diesters are formed. Fragmentation of these diester intermediates gives the nucleobase and O-acetyl-O'-pivaloylserinol. Conversion of the latter to N-acetylserinol involves the selective O-N acetyl migration followed by de-pivaloylation of the resulting N-acetyl-O-pivaloylserinol. Copyright Taylor and Francis Group, LLC.
- Koszytkowska-Stawinska, Mariola
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p. 768 - 785
(2011/05/04)
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- ANTIBODIES TO INSULIN-LIKE GROWTH FACTOR RECEPTOR
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The invention provides various antibodies that bind to insulin-like growth factor-I receptor (IGF-1R), methods for making such antibodies, compositions and articles incorporating such antibodies, and their uses in treating, for example, cancer or aging. The antibodies include murine, chimeric, and humanized antibodies.
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- ANTIBODIES TO LYMPHOTOXIN-ALPHA
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The invention provides various antibodies that bind to lymphotoxin-α, methods for making such antibodies, compositions and articles incorporating such antibodies, and their uses in treating, for example, an autoimmune disorder. The antibodies include murine, chimeric, and humanized antibodies.
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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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- Antibodies and immunoconjugates and uses therefor
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Anti-STEAP-1 antibodies and immunoconjugates thereof are provided. Methods of using anti-STEAP-1 antibodies and immunoconjugates thereof are provided.
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- Fe(II) phthalocyanine catalyzed oxidation of dGMP by molecular oxygen
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We show that iron(II)-phthalocyanines are able to catalyze guanosine oxidation by molecular oxygen in the presence of reducing agents such as ascorbic acid and 2-mercaptoethanol. The products of 5′-monophosphate-2′-deoxyguanosine (dGMP) oxidation were dir
- Kuznetsova, Aleksandra A.,Solovyeva, Lyudmila I.,Kaliya, Oleg L.,Lukyanets, Evgeniy A.,Knorre, Dmitri G.,Fedorova, Olga S.
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experimental part
p. 4335 - 4338
(2010/04/24)
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- BINDING POLYPEPTIDES WITH OPTIMIZED SCAFFOLDS
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The invention provides variant heavy chain variable domains (VH) with increased folding stability. Libraries comprising a plurality of these polypeptides are also provided. In addition, compositions and methods of generating and using these polypeptides and libraries are provided.
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- One-step synthesis of lumazine and xanthine: First co-crystal of lumazine and perchloric acid with a unique monohydrated hydronium ion (H 5O2+) mediated supramolecular assembly of the lumazine dimer
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A perchloric acid mediated one-step synthesis of lumazine derivatives from pterins and xanthine from guanine is reported. However, 2-pivaloylamino derivatives of pterins underwent simple hydrolysis of the pivaloylamino group generating free pterin compounds, but the 2-oxo derivatives, that is, the lumazine compounds, were not obtained. A novel supramolecular assembly is constructed by the unique hydrogen bonding of H5O2 + bridging two hydrogen-bonded dimers of lumazine to form the co-crystal 21 with aqueous perchloric acid. In contrast, N2-pivaloyl- 6-bromo-5-deazapterin was simply hydrolysed to form the protonated deazapterin 22, which forms a unique six-membered cyclic hydrogen-bonded structure leading to the generation of a polymeric supramolecular assembly. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Goswami, Shyamaprosad,Maity, Annada C.,Fun, Hoong-Kun
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p. 4056 - 4064
(2008/02/13)
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- Genomic library of cyanophage s-2l and functional analysis
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The invention relates to the genome sequence and the nucleotide sequences coding for polypeptides of cyanophage S-2L. According to the invention, the polypeptides include, but are not limited to, polypeptides involved in the synthesis, transcription and replication of purine bases. In particular, determining the genome of cyanophage S-2L is useful for supplying genes which, expressed in recombinant bacteria, enable the synthesis of DNA monomers incorporating base D (2,6 diaminopurine instead of base A (adenine), thereby producing chemically-remodelled nucleic acids in the bacteria.
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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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p. 1476 - 1485
(2008/02/10)
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- Phosphodiester cleavage of guanylyl-(3′,3′)-(2′-amino- 2′-deoxyuridine): Rate acceleration by the 2′-amino function
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Hydrolytic reactions of the structural analogue of guanylyl-(3′, 3′)-uridine, guanylyl-(3′,3′)-(2′-amino-2′- deoxyuridine), having one of the 2′-hydroxyl groups replaced with an amino function, have been followed by RP HPLC in the pH range 0-13 at 90°C. The results are compared to those obtained earlier with guanylyl-(3′,3′) -uridine, guanylyl-(3′,3′)-(2′,5′-di-O-methyluridine), and uridylyl-(3′,5′)-uridine. Under basic conditions (pH > 8), the hydroxide ion-catalyzed cleavage of the P-O3′ bond (first-order in [OH-]) yields a mixture of 2′-amino-2′-deoxyuridine and guanosine 2′,3′-cyclic phosphate which is hydrolyzed to guanosine 2′- and 3′-phosphates. Under these conditions, guanylyl-(3′, 3′)-(2′-amino-2′-deoxyuridine) is 10 times less reactive than guanylyl-(3′,3′)-uridine. Under acidic and neutral conditions (pH 3-8), where the pH-rate profile for the cleavage consists of two pH-independent regions (from pH 3 to pH 4 and from 6 to 8), guanylyl-(3′,3′)- (2′-amino-2′-deoxyuridine) is considerably reactive. For example, in the latter pH range, guanylyl-(3′,3′)-(2′-amino-2′- deoxyuridine) is more than 2 orders of magnitude more labile than guanylyl(3′,3′)-(2′,5′-di-O-methyluridine), while in the former pH range the reactivity difference is 1 order of magnitude. Under very acidic conditions (pH +]) compete with the cleavage. The Zn2+-promoted cleavage ([Zn2+] = 5 mmol L-1) is 15 times faster than the uncatalyzed reaction at pH 5.6. The mechanisms of the reactions of guanylyl-(3′,3′)-(2′-amino-2′-deoxyuridine) are discussed, particularly focusing on the possible stabilization of phosphorane intermediate and/or transition state via an intramolecular hydrogen bonding by the 2′-amino group.
- Ora, Mikko,Linjalahti, Heidi,Loennberg, Harri
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p. 1826 - 1832
(2007/10/03)
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- Agents for corneal or intrastromal administration to treat or prevent disorders of the eye
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Methods and preparations for treating disorders of the eye and/or causing dissolution of corneal proteoglycans and organized healing of corneal stroma, softening of the cornea for non-surgical refractive correction of eyesight, removing corneal haze and opacification, inhibiting fibroblasts and preventing corneal fibrosis and scar formation, treating pterigiums and treating corneal neovascularization as well as iris neovascularization. Preparations containing a) urea, b) urea derivatives (e.g., hydroxyurea, thiourea), c) antimetabolites, e) urea, urea derivatives, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidinium, guanidinium chloride, guanidinium salts, thymidine, thymitadine, uradine, uracil, cysteine), reduced thioctic acid, uric acid, calcium acetyl salicylate, ammonium sulfate, isopropyl alcohol, ethanol, polyethylene glycol, polypropylene glycol or other compound capable of causing nonenzymatic dissolution of the corneal protoeglycans or f) any of the possible combinations thereof, are administered to the eye in therapeutically effective amounts.
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- Hydrolytic reactions of guanosyl-(3′,3′)-uridine and guanosyl-(3′,3′)-(2′,5′-di-O-methyluridine)
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Hydrolytic reactions of guanosyl-(3′,3′)-uridine and guanosyl-(3′,3′)-(2′,5′-di-O-methyluridine) have been followed by RP HPLC over a wide pH range at 363.2 K in order to elucidate the role of the 2′-hydroxyl group as a hydrogen-bond donor upon departure of the 3′-uridine moiety. Under neutral and basic conditions, guanosyl-(3′,3′)-uridine undergoes hydroxide ion-catalyzed cleavage (first order in [OH-]) of the P-O3′ bonds, giving uridine and guanosine 2′,3′-cyclic monophosphates, which are subsequently hydrolyzed to a mixture of 2′- and 3′-monophosphates. This bond rupture is 23 times as fast as the corresponding cleavage of the P-O3′ bond of guanosyl-(3′,3′)-(2,5′-di-O-methyluridine) to yield 2′,5′-O-dimethyluridine and guanosine 2′,3′-cyclic phosphate. Under acidic conditions, where the reactivity differences are smaller, depurination and isomerization compete with the cleavage. The effect of Zn2+ on the cleavage of the P-O3′ bonds of guanosyl-(3′,3′)-uridine is modest: about 6-fold acceleration was observed at [Zn2+] = 5 mmol L-1 and pH 5.6. With guanosyl-(3′,3′)-(2′,5′-di-O-methyluridine) the rate-acceleration effect is greater: a 37-fold acceleration was observed. The mechanisms of the partial reactions, in particular the effects of the 2′-hydroxyl group on the departure of the 3′-linked nucleoside, are discussed.
- Kiviniemi, Anu,Loennberg, Tuomas,Ora, Mikko
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p. 11040 - 11045
(2007/10/03)
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- Bisheterocyclic synthesis and antimicrobial studies on some biologically significant 2-[N-(3′-chloro-4′-substituted azetidinone-2)] amino-4-hydroxypurines
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Present communication describes the synthesis of a series of 2-[N-(3′-chloro-4′-substituted azetidinone-2)] amino-4-hydroxypurines 4a-h. 2-Amino-4-hydroxypurine 2 formed by the [4+1] cycloaddition of 2, 5, 6-triamino-4-hydroxypyrimidine with formic acid is subjected to diazotisation followed by coupling with an appropriate active methylene compound under alkaline conditions. The product is treated with chloroacetyl chloride in the presence of triethyl amine and 1, 4-dioxane to yield 2-[N-(3′-chloro-4′-substituted azetidinone-2)]amino-4-hydroxypurines 4a-h. The structures of the compounds have been established on the basis of spectroscopic data. All the compounds have been tested for their antimicrobial activity against B. subtilis, E. coli, P. diminuta, S. aureus and B. pumilus. They show significant antimicrobial activity.
- Sharma, Pratibha,Kumar, Ashok,Sharma, Shikha
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p. 385 - 388
(2007/10/03)
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- A prototype solid phase synthesis of pteridines and related heterocyclic compounds
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The development of a versatile solid phase synthesis of bicyclic polyaza heterocycles including pteridines, purines, and deazapurines is described. The strategy comprises the linking of a pre-formed pyrimidine through a thioether at the 2 or 4 position to a polystyrene resin, the cyclisation of the second ring, and the direct or oxidative cleavage of the product from the resin by nucleophilic substitution. This provides not only for substituent variation in the second ring, but also for variation at the site of cleavage. Limitations in the scope of the methodology are set by the intrinsic reactivity of pyrimidinyl 2- or 4-thioethers which, whilst undergoing ready nitration at C5, are surprisingly difficult to alkylate and acylate.
- Gibson, Colin L.,La Rosa, Salvatore,Suckling, Colin J.
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p. 1909 - 1918
(2007/10/03)
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- Peptide nucleic acid precursors and methods of preparing same
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Novel and efficient syntheses create novel piperazinone intermediates which facilitate the production and use of PNAs. Such syntheses and the products enhance the feasibility of a system which permits the rapid identification of PNA oligomers useful as therapeutics, diagnostics and/or gene characterization tools. A first component of the system is a universal PNA library that most preferably incorporates one or more universal nucleotide bases into carefully selected positions within each oligomer species thereby providing the library with the screening ability of a much larger library. The second component of the system is a high throughput screening system that includes a number of assays designed to provide information on the binding activities of the different PNAs to a target nucleotide sequence (generally, a DNA or RNA sequence). The third component is a software system especially designed to provide rapid analysis of the data collected from the high throughput screening system and to determine therefrom the sequence base identities and sequence lengths of PNA oligomers most likely to bind to and appropriately affect the target molecule.
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- Poly(ether-thioether), poly(ether-sulfoxide) and poly(ether-sulfone) nucleic acids
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A compound comprising a poly(ether-thioether), poly(ether-sulfoxide) or poly(ether-sulfone) backbone bearing a plurality of ligands that are individually bound to chiral carbon atoms located within the backbone, at least one of the ligands including a moiety such as a naturally occurring nucleobase, a nucleobase binding group or a DNA interchelator; a process of synthesizing the compound, monomers to be used in this process and their synthesis process and processes for using the compound in biochemistry and medicine.
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- Modified guanines representing O6-alkylation by the cyclophosphamide metabolites acrolein and chloroacetaldehyde: Synthesis, stability, and ab initio studies
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Alkylation of DNA by acrolein and/or chloroacetaldehyde may result in the mutations that lead to the therapy-induced leukemia associated with cyclophosphamide (and ifosfamide) treatment. O6-(n-Propanalyl)guanine (O6-PAG) and O6-(ethanalyl)guanine (O6-EAG) were synthesized for use as authentic standards in investigations of DNA alkylation by acrolein and chloroacetaldehyde, respectively. Preparation of the O-methyl oximes of these aldehydes aided in confirming the structural assignments of O6-PAG and O6-EAG. HPLC was used to study the stability of O6-PAG under a variety of conditions. The decomposition of O6-PAG was attributed to an α,β-elimination reaction resulting in the formation of guanine and acrolein. In 0.1 M phosphate-DMSO (9:1), O6-PAG (1-10 mM) had a half-life of approximately h (pH 7.4, 37 °C). In 0.05 M Tris-DMSO (9:1), the apparent half-life of O6-PAG (1-10 mM) was approximately 16 h (pH 7.4, 37 °C). The increased lifetime under the latter conditions was attributed to a reversible reaction between Tris and the aldehydic functionality of O6-PAG to give a more stable oxazolidine. Under conditions similar to those that would be used for hydrolysis of DNA [0.1 M HCl-DMSO (98:2), pH 1.3, 70 °C, 30 min], there was an estimated 10-35% loss of O6-PAG. Under the same conditions, O6-EAG had apparent half-lives of 6.6 h (phosphate-DMSO) and 2.5 days (Tris-DMSO) and the estimated loss at pH 1.3 over 30 min (70 °C) was 15-20%. Ab initio quantum chemical calculations were used to understand the energy factors that underlie the occurrence of O- versus N-alkylations as well as possible, subsequent intramolecular cyclizations. Simulations of the free energies of reactions between acrolein and guanine indicated that N-alkylation was favored over O6-alkylation and that cyclizations to tautomers were most favorable if they involved the N-1 or NH2 positions.
- Balu, Narayanan,Gamcsik, Michael P.,Colvin, Michael E.,Colvin, O. Michael,Dolan, M. Eileen,Ludeman, Susan M.
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p. 380 - 387
(2007/10/03)
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- A solid-state 17O nuclear magnetic resonance study of nucleic acid bases
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We report a systematic solid-state 17O NMR study of free nucleic acid bases: thymine (T), uracil (U), cytosine (C), and guanine (G). Site-specifically 17O-enriched samples were synthesized: [2-17O]thymine (1), [4-17O]thymine (2), [2-17O]uracil (3), [4-17O]uracil (4), [2-17O]cytosine (5), and [6-17O]guanine monohydrate (6). Magic-angle-spinning (MAS) and static 17O NMR spectra were acquired at 11.75 T for compounds 1-6, from which information about the 170 chemical shift and electric field gradient tensors was obtained. Extensive quantum chemical calculations were performed at the B3LYP/6-311++G(d,p) level of theory for 17O NMR properties in various molecular models. The calculated 17O NMR tensors are highly sensitive to the description of intermolecular hydrogen-bonding interactions at the target oxygen atom. A reasonably good agreement between experimental solid-state 17O NMR data and B3LYP/6-311++G(d,p) calculations is achievable only in molecular cluster models where a complete hydrogen-bond network is considered. Using this theoretical approach, we also investigated the 17O NMR tensors in two unusual structures: guanine- and uracil-quartets.
- Wu, Gang,Dong, Shuan,Ida, Ramsey,Reen, Nitin
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p. 1768 - 1777
(2007/10/03)
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- Process for the preparation of guanine
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A process for the preparation of guanine, by reacting 2,4-diamino-5-formylamino-6-hydroxypyrimidine (DAFHP) with formic acid, in the absence of formalize. The process may be conducted with the addition of water and at reflux temperature.
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- Composition of matter having bioactive properties
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Particles of coordinated complex comprising a basic, hydrous polymer and a capacitance adding compound, as well as methods for their production, are described. These complexes exhibit a high degree of bioactivity making them suitable for a broad range of applications through their incorporation into conventional vehicles benefiting from antimicrobial and similar properties.
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- Process for preparing guanine under superatmospheric pressure
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A process for preparing guanine, in which 2,4-diamino-5-formylamino-6-hydroxypyrimidine (DAFHP) in formic acid is reacted at superatmospheric pressure, optionally in the absence of formamide and/or in the presence of catalytic amounts of an additive which acts as a reducing agent.
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