- High-yielding cascade enzymatic synthesis of 5-methyluridine using a novel combination of nucleoside phosphorylases
-
A novel combination of Bacillus halodurans purine nucleoside phosphorylase (BhPNP1) and Escherichia coli uridine phosphorylase (EcUP) has been applied to a dual-enzyme, sequential, biocatalytic one-pot synthesis of 5-methyluridine from guanosine and thymine. A 5-methyluridine yield of >79% on guanosine was achieved in a reaction slurry at a 53 mM (1.5% w/w) guanosine concentration. 5-Methyluridine is an intermediate in synthetic routes to thymidine and the antiretroviral drugs zidovudine and stavudine.
- Visser, Daniel F.,Rashamuse, Konanani J.,Hennessy, Fritha,Gordon, Gregory E.R.,Van Zyl, Petrus J.,Mathiba, Kgama,Bode, Moira L.,Brady, Dean
-
-
Read Online
- Identification of Flavin Mononucleotide as a Cell-Active Artificial N6-Methyladenosine RNA Demethylase
-
N6-Methyladenosine (m6A) represents a common and highly dynamic modification in eukaryotic RNA that affects various cellular pathways. Natural dioxygenases such as FTO and ALKBH5 are enzymes that demethylate m6A residues in mRNA. Herein, the first identification of a small-molecule modulator that functions as an artificial m6A demethylase is reported. Flavin mononucleotide (FMN), the metabolite produced by riboflavin kinase, mediates substantial photochemical demethylation of m6A residues of RNA in live cells. This study provides a new perspective to the understanding of demethylation of m6A residues in mRNA and sheds light on the development of powerful small molecules as RNA demethylases and new probes for use in RNA biology.
- Xie, Li-Jun,Yang, Xiao-Ti,Wang, Rui-Li,Cheng, Hou-Ping,Li, Zhi-Yan,Liu, Li,Mao, Lanqun,Wang, Ming,Cheng, Liang
-
-
Read Online
- General Principles for Yield Optimization of Nucleoside Phosphorylase-Catalyzed Transglycosylations
-
The biocatalytic synthesis of natural and modified nucleosides with nucleoside phosphorylases offers the protecting-group-free direct glycosylation of free nucleobases in transglycosylation reactions. This contribution presents guiding principles for nucleoside phosphorylase-mediated transglycosylations alongside mathematical tools for straightforward yield optimization. We illustrate how product yields in these reactions can easily be estimated and optimized using the equilibrium constants of phosphorolysis of the nucleosides involved. Furthermore, the varying negative effects of phosphate on transglycosylation yields are demonstrated theoretically and experimentally with several examples. Practical considerations for these reactions from a synthetic perspective are presented, as well as freely available tools that serve to facilitate a reliable choice of reaction conditions to achieve maximum product yields in nucleoside transglycosylation reactions.
- Kaspar, Felix,Giessmann, Robert T.,Hellendahl, Katja F.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
-
-
Read Online
- Two-step efficient synthesis of 5-methyluridine via two thermostable nucleoside phosphorylase from Aeropyrum pernix
-
5-Methyluridine has been synthesized in high yield using guanosine and thymine as starting materials in the presence of highly thermostable recombinant purine nucleoside phosphorylase (PNP) and uridine phosphorylase (UP) obtained from hyperthermophilic aerobic crenarchaeon Aeropyrum pernix. Key reaction parameters such as pH, temperature, concentration of buffer and substrates were investigated. At the optimal conditions, 5-methyluridine was achieved in yield 85% with a guanosine conversion of 96% in 10 ml scale. The process can be performed at high temperature, which will highly increase the solubility of substrates, therefore, this process is suitable for the industry application.
- Zhu, Shaozhou,Ren, Lu,Wang, Jianjun,Zheng, Guojun,Tang, Pingwah
-
-
Read Online
- 17O NMR of Nucleosides. 3 - Chemical Shifts of Substituted Uridines and Ribothymidines
-
Uridine and ribothymidine derivatives, bearing different substituents at C-5 and enriched (Ca 50percent) with 17O in the O-4 and O-2 carbonyls, have been studied via 17O NMR in both acetonitrile and aqueous solvents.The solvent shift differences between acetonitrile and water at O-4 (30-42 ppm) and O-2 (13-16 ppm) vary significantly from each other, but the chemical shift changes induced by changing the substituent at C-5 correlated well only with the O-4 shifts and the electron-withdrawing ability of the substituent.Examination of the 17O shifts of model compounds reconfirms the predominance of keto tautomers for both carbonyls.The significance of the solvent shifts and substituent shifts are discussed with respect to the electronic structure of the nucleoside base rings, and with respect to the hydrogen-bonding abilities of the carbonyl groups.Other nucleoside derivatives studied include those in which the 17O enrichment is in the ring linking the base to the sugar moiety in a pyrimidine cyclonucleoside, in the sugar hydroxy groups and in the phosphodiester linkage of a highly strained ring system in a nucleoside cyclic monophosphate.
- Schwartz, Herbert M.,MacCoss, Malcolm,Danyluk, Steven S.
-
-
Read Online
- Synthesis of 5-Methyluridine and Its 5'-Mercapto-, 2-Amino-, and 4',5'-Unsatured Analogues
-
The stereospecific cis-hydroxylation of 1-(2,3-dideoxy-β-D-glyceropent-2-enofuranosyl)thymine (1) into 1-β-D-ribofuranosylthymine (2) by osmium tetroxyde is described.Treatment of 2',3'-O,O-isopropylidene-5-methyl-2,5'-anhydrouridine (8) with hydrogen sulfide or methanolic ammonia afforded 5'-deoxy-2',3'-O,O-isopropylidene-5'-mercapto-5-methyluridine (9) and 2',3'-O,O-isopropylidene-5-methyl-isocytidine (10), respectively.The action of ethanolic potassium hydroxide on 5'-deoxy-5'-iodo-2',3'-O,O-isopropylidene-5-methyluridine (7) gave rise to the corresponding 1-(5-deoxy-β-D-erythropent-4-enofuranosyl)5-methyluracil (13) and 2-O-ethyl-5-methyluridine (14).The hydrogenation of 2 and its 2',3'-O,O-isopropylidene derivative 4 over 5percent Rh/AL2O3 as catalyst generated diastereoisomers of corresponding 5-methyl-5,6-dihydrouridine (17 and 18).
- kari, Vinko,Matuli-Adami, Jasenka
-
-
Read Online
- A catalytic method for chemoselective detritylation of 5′-tritylated nucleosides under mild and heterogeneous conditions using silica sulfuric acid as a recyclable catalyst
-
A rapid, mild and highly efficient procedure for the chemoselective deprotection of triphenylmethyl (trityl, Tr), p-anisyldiphenylmethyl (monomethoxytrityl, MMT) and di-(p-anisyl)phenylmethyl (dimethoxytrityl, DMT) groups from nucleoside trityl ethers has been established. The deprotection was achieved at room temperature, using a catalytic amount of silica sulfuric acid (SSA) in acetonitrile. The trityl nucleosides were deprotected in 2-17 min without any depurination. These conditions are compatible with other acid sensitive hydroxyl protecting groups such as p-methoxybenzyl (PMB), isopropylidene, cyclohexylidene, di-(p-anisyl)methylidene, triisopropylsilyl (TIPS) and t-butyldimethylsilyl (TBDMS).
- Khalafi-Nezhad, Ali,Parhami, Abolfath,Soltani Rad, Mohammad Navid,Zolfigol, Mohammad Ali,Zare, Abdolkarim
-
-
Read Online
- A short de novo synthesis of nucleoside analogs
-
Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of D- or L-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2′- and C4′-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.
- Adluri, Bharanishashank,Britton, Robert,Campeau, Louis-Charles,Cohen, Ryan,Lehmann, Johannes,Meanwell, Michael,Silverman, Steven M.,Wang, Yang
-
-
Read Online
- Stabilization of Escherichia coli uridine phosphorylase by evolution and immobilization
-
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
-
-
Read Online
- Thermodynamic Reaction Control of Nucleoside Phosphorolysis
-
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
-
p. 867 - 876
(2020/01/24)
-
- Use of nucleoside phosphorylases for the preparation of 5-modified pyrimidine ribonucleosides
-
Enzymatic transglycosylation, a transfer of the carbohydrate moiety from one heterocyclic base to another, is catalyzed by nucleoside phosphorylases (NPs) and is being actively developed and applied for the synthesis of biologically important nucleosides. Here, we report an efficient one-step synthesis of 5-substitited pyrimidine ribonucleosides starting from 7-methylguanosine hydroiodide in the presence of nucleoside phosphorylases (NPs).
- Alexeev, Cyril S.,Drenichev, Mikhail S.,Dorinova, Evgeniya O.,Esipov, Roman S.,Kulikova, Irina V.,Mikhailov, Sergey N.
-
-
- SYNTHESIS AND STRUCTURE OF HIGH POTENCY RNA THERAPEUTICS
-
This invention provides expressible polynucleotides, which can express a target protein or polypeptide. Synthetic mRNA constructs for producing a protein or polypeptide can contain one or more 5′ UTRs, where a 5′ UTR may be expressed by a gene of a plant. In some embodiments, a 5′ UTR may be expressed by a gene of a member of Arabidopsis genus. The synthetic mRNA constructs can be used as pharmaceutical agents for expressing a target protein or polypeptide in vivo.
- -
-
-
- Larger laboratory scale synthesis of 5-methyluridine and formal synthesis of its L-enantiomer
-
A larger laboratory scale synthesis (>60 g per run) of 5-methyluridine is presented. The critical intermediate 1,2-O-isopropylidene-α-D-ribofuranose was prepared from very cheap D-glucose via D-allose. Its L-enantiomer was obtained from L-arabinose via L-glucose, and also from L-xylose. {figure presented}.
- Thiesen, Luciano J. Hoeltgebaum,Cabral, Nadia,Joselice E Silva, Maria,Bezerra, Gilson,Doboszewski, Bogdan
-
p. 249 - 264
(2017/06/19)
-
- Effective synthesis of nucleosides utilizing O-acetyl-glycosyl chlorides as glycosyl donors in the absence of catalyst: Mechanism revision and application to silyl-hilbert-johnson reaction
-
An effective synthesis of nucleosides using glycosyl chlorides as glycosyl donors in the absence of Lewis acid has been developed. Glycosyl chlorides have been shown to be pivotal intermediates in the classical silyl-Hilbert-Johnson reaction. A possible mechanism that differs from the currently accepted mechanism advanced by Vorbrueggen has been proposed and verified by experiments. In practice, this catalyst-free method provides easy access to Capecitabine in high yield.
- Liang, Chengyuan,Ju, Weihui,Ding, Shunjun,Sun, Han,Mao, Gennian
-
supporting information
(2017/01/24)
-
- From organocatalysed desilylations to high-yielding benzylidenations of electron-deficient benzaldehydes
-
A new type of organoprecatalyst (MeSCH2Cl/KI) for desilylation and benzylidenation reactions has been designed. Both reactions are user friendly and high yielding (71->99%) and have fast reaction rates. The desilylation of iodo silyl ethers was achieved with no sequential etherification side reactions like those seen for reactions when using TBAF. In the application of the catalytic system to a 6-TBDMS ether of a glucoside, glucoside benzylidenations using electron-deficient benzaldehydes were achieved in 87% yield compared with the previously reported yields of 69-77%. Altogether, 14 benzylidenation reactions were realised using silyloxy alcohols and electrondeficient benzaldehydes instead of their activated acetal forms. In terms of reaction rates and yields, the order of the benzylidenations is p-fluorobenzaldehyde > benzaldehyde > p-anisaldehyde, and a possible mechanism is discussed. These experiments have preliminarily differentiated this cost-effective catalytic system from the classic Lewis acids.
- Niu, Qun,Xing, Linlin,Li, Chunbao
-
p. 358 - 364
(2017/06/19)
-
- Synthetic method for 5-methyluridine
-
The invention discloses a synthetic method for 5-methyluridine. The synthetic method is optimized based on a 5-methyluridine chemical synthesis method; the key points are that a byproduct trimethylsilyl acetate in a condensation reaction is separated, and reacts with ammonia to generate hexamethyldisilazane which can be repeatedly utilized; meanwhile, tail gas generated by the reaction is absorbed by absolute methanol to obtain aminomethanol, which can be used in an alcoholysis reaction during the synthesis of 5-methyluridine. The synthetic method for 5-methyluridine provided by the invention combines the advantages of the 5-methyluridine chemical synthesis method and optimizes the defects in production, so that on one hand, a utilization rate of a trisilicane protective group is increased, on the other hand, emission of waste liquor and waste gas is reduced, thereby overcoming the defect that the chemical synthesis method is not environment-friendly while being free of affecting the total yield.
- -
-
Paragraph 0046
(2017/01/17)
-
- PRODUCTION METHOD OF NUCLEOSIDE COMPOUND
-
PROBLEM TO BE SOLVED: To provide a production method of a nucleoside compound by which an isotopic labeled nucleoside compound can be produced efficiently. SOLUTION: A production method of a nucleoside compound comprises obtaining a target nucleoside compound by the base exchange reaction of a raw material nucleoside compound and a base in the solution containing a phosphoric acid ion by a nucleoside phosphorylase, wherein the target nucleoside compound is labeled with a stable isotope or a radioisotope. COPYRIGHT: (C)2015,JPOandINPIT
- -
-
Paragraph 0032-0033
(2017/03/24)
-
- Direct One-Pot Synthesis of Nucleosides from Unprotected or 5-O-Monoprotected d -Ribose
-
New, improved methods to access nucleosides are of general interest not only to organic chemists but to the greater scientific community as a whole due their key implications in life and disease. Current synthetic methods involve multistep procedures employing protected sugars in the glycosylation of nucleobases. Using modified Mitsunobu conditions, we report on the first direct glycosylation of purine and pyrimidine nucleobases with unprotected d-ribose to provide β-pyranosyl nucleosides and a one-pot strategy to yield β-furanosides from the heterocycle and 5-O-monoprotected d-ribose.
- Downey, A. Michael,Richter, Celin,Pohl, Radek,Mahrwald, Rainer,Hocek, Michal
-
p. 4604 - 4607
(2015/09/28)
-
- Intramolecular participation of amino groups in the cleavage and isomerization of ribonucleoside 3′-phosphodiesters: The role in stabilization of the phosphorane intermediate
-
A dinucleoside-3′,5′-phosphodiester model, 5′-amino- 4′-aminomethyl-5′-deoxyuridylyl-3′,5′-thymidine, incorporating two aminomethyl functions in the 4′-position of the 3′-linked nucleoside has been prepared and its hydrolytic reactions studied over a wide pH range. The amino functions were found to accelerate the cleavage and isomerization of the phosphodiester linkage in both protonated and neutral form. When present in protonated form, the cleavage of the 3′,5′-phosphodiester linkage and its isomerization to a 2′,5′-linkage are pH-independent and 50-80 times as fast as the corresponding reactions of uridylyl-3′,5′-uridine (3′,5′-UpU). The cleavage of the resulting 2′,5′-isomer is also accelerated, albeit less than with the 3′,5′-isomer, whereas isomerization back to the 3′,5′-diester is not enhanced. When the amino groups are deprotonated, the cleavage reactions of both isomers are again pH-independent and up to 1000-fold faster than the pH-independent cleavage of UpU. Interestingly, the 2′- to 3′-isomerization is now much faster than its reverse reaction. The mechanisms of these reactions are discussed. The rate accelerations are largely accounted for by electrostatic and hydrogen-bonding interactions of the protonated amino groups with the phosphorane intermediate. Amino accelerator: Intramolecular amino groups promote cleavage and isomerization of ribonucleoside phosphodiester bonds in both protonated and deprotonated forms. The most likely mechanistic explanation is facilitation of the first step of the reaction, that is, formation of the cyclic phosphorane intermediate, by concomitant proton transfer. The magnitude of this facilitation differs greatly between the 2′- and 3′-isomers (see figure). Copyright
- Lain, Luigi,L?nnberg, Harri,L?nnberg, Tuomas
-
p. 12424 - 12434
(2013/09/23)
-
- Photochemical control of RNA structure by disrupting π-stacking
-
Photolabile nucleotides that disrupt nucleic acid structure are useful mechanistic probes and can be used as tools for regulating biochemical processes. Previous probes can be limited by the need to incorporate multiple modified nucleotides into oligonucleotides and in kinetic studies by the rate-limiting step in the conversion to the native nucleotide. Photolysis of aryl sulfide 1 produces high yields of 5-methyluridine, and product formation is complete in less than a microsecond. Aryl sulfide 1 prevents RNA hairpin formation and complete folding of the preQ1 class I riboswitch. Proper folding is achieved in each instance upon photolysis at 350 nm. Aryl sulfide 1 is a novel tool for modulating RNA structure, and formation of 5-methyluridine within a radical cage suggests that it will be useful in kinetic studies.
- Resendiz, Marino J. E.,Schoen, Arne,Freire, Ernesto,Greenberg, Marc M.
-
p. 12478 - 12481
(2012/09/05)
-
- Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation
-
Five ribofuranosyl pyrimidine nucleosides and their corresponding 1,2,3-triazole derivatives have been synthesized and characterized. Their inhibitory action to Ribonuclease A has been studied by biochemical analysis and X-ray crystallography. These compounds are potent competitive inhibitors of RNase A with low μM inhibition constant (Ki) values with the ones having a triazolo linker being more potent than the ones without. The most potent of these is 1-[(β-d-ribofuranosyl)-1,2,3-triazol-4-yl]uracil being with Ki = 1.6 μM. The high resolution X-ray crystal structures of the RNase A in complex with three most potent inhibitors of these inhibitors have shown that they bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B1 subsite while the triazole moiety binds at the main subsite P1, where P-O5′ bond cleavage occurs, and the ribose at the interface between subsites P1 and P0 exploiting interactions with residues from both subsites. The effect of a susbsituent group at the 5-pyrimidine position at the inhibitory potency has been also examined and results show that any addition at this position leads to a less efficient inhibitor. Comparative structural analysis of these RNase A complexes with other similar RNase A - ligand complexes reveals that the triazole moiety interactions with the protein form the structural basis of their increased potency. The insertion of a triazole linker between the pyrimidine base and the ribose forms the starting point for further improvement of these inhibitors in the quest for potent ribonucleolytic inhibitors with pharmaceutical potential.
- Parmenopoulou, Vanessa,Chatzileontiadou, Demetra S.M.,Manta, Stella,Bougiatioti, Stamatina,Maragozidis, Panagiotis,Gkaragkouni, Dimitra-Niki,Kaffesaki, Eleni,Kantsadi, Anastassia L.,Skamnaki, Vassiliki T.,Zographos, Spyridon E.,Zounpoulakis, Panagiotis,Balatsos, Nikolaos A.A.,Komiotis, Dimitris,Leonidas, Demetres D.
-
p. 7184 - 7193
(2013/01/15)
-
- Lactobacillus Fermentum N-Desoxyribosyl Transferases and the Use Thereof for Enzymatic Synthesis of 2', 3' - Didesoxynucleosides and 2',3'- Didehydro-2',3'- Didesoxynucleosides
-
The inventive method for evaluating an X protein encoded by an Lactobacillus fermentum (L. fermentum ) ntd gene in such a way that the characteristics thereof are modified consists a) in obtaining the Lactobacillus fermentum (L. fermentum ) ntd gene mutants by random mutagenesis, b) in transforming cells containing a [P-] phenotype provided with vectors containing mutated nucleic acids obtained at the stage a) coding for the thus modified X* proteins, wherein P- means that said cells are auxotrophic for a substance P produced by the action of X on a natural substrate S, c) in culturing said cells in a medium comprising a substrate S*, wherein S* is an analog to the natural substrate S of the protein X and d) in selecting the cells [P-::X*] which survived at the stage c) and ijn which the proteins X* are capable of carrying out the biosynthesis of the product P based on the substrate S*. The mutated L. fermentum N-desoxyribosyl transferases have an N-didesoxyribosyl transferase activity, corresponding nucleic acids, expression vectors, host cells containing said vectors and an application for the enzymatic synthesis of 2′,3′-didesoxynucleosides and 2′,3′-didehydro-2′,3′-didesoxynucleosides.
- -
-
Page/Page column 6-8
(2008/06/13)
-
- Synthesis of a 2′-Se-thymidine phosphoramidite and its incorporation into oligonucleotides for crystal structure study
-
(Chemical Equation Presented) To investigate nucleic acids with selenium derivatization for crystallography, we report the first synthesis of 2′-methylseleno-thymidine phosphoramidite and its incorporation into DNAs and RNAs by solid-phase synthesis with over 99% coupling yield. The d(GT SeGTACAC)2 crystal structure was also determined at 1.40 A resolution using Se phasing, revealing that this Se derivatization did not cause significant structure perturbation, consistent with our UV melting study. In addition, we observed that the Se modification largely facilitated the crystallization.
- Sheng, Jia,Jiang, Jiansheng,Salon, Jozef,Huang, Zhen
-
p. 749 - 752
(2007/10/03)
-
- New acyclonucleosides: Synthesis and anti-HIV activity
-
The synthesis of new acyclic nucleosides is described. These syntheses were accomplished by various methods: glycosylation, selective or total deprotection, oxidation/reduction, chlorination or azidation of hydroxyl groups. The compounds were characterized with NMR, mass and IR spectroscopy. Antiviral properties of these compounds were evaluated on HIV-1 infected cell lines. Copyright Taylor & Francis, Inc.
- Hadj-Bouazza, Amel,Zerrouki, Rachida,Krausz, Pierre,Laumond, Geraldine,Aubertin, Anne Marie,Champavier, Yves
-
p. 1249 - 1263
(2007/10/03)
-
- 2'-deoxy-L-nucleosides
-
This invention provides processes for the preparation of compounds having the structure: wherein X and Y are same or different, and H, OH, OR, SH, SR, NH2, NHR′, or NR′R″Z is H, F, Cl, Br, I, CN, or NH2. R is hydrogen, halogen, lower alkyl of C1-C6 or aralkyl, NO2, NH2, NHR′, NR′R″, OH, OR, SH, SR, CN, CONH2, CSNH2, CO2H, CO2R′, CH2CO2H, CH2CO2R′, CH═CHR, CH2CH═CHR, or C═CR. R′ and R″ are same or different, and lower alkyl of C1-C6. R13 is hydrogen, alkyl, acyl, phosphate (monophosphate, diphosphate, triphosphate, or stabilized phosphate) or silyl; and
- -
-
Page/Page column 36
(2010/02/11)
-
- CBr4-photoirradiation protocol for chemoselective deprotection of acid labile primary hydroxyl protecting groups
-
CBr4-photoirradiation protocol was found to be a mild, highly efficient and selective method for deprotection of isopropylidene, benzylidene, triphenylmethyl and tert-butyldimethylsilyl protecting groups on sugar molecules. The conditions of this reaction can also be used to cleave peptides off from acid-labile resin linkers in solid-phase peptide synthesis.
- Chen, Ming-Yi,Patkar, Laxmikant N.,Jan, Mi-Dan,Lee, Adam Shih-Yuan,Lin, Chun-Cheng
-
p. 635 - 639
(2007/10/03)
-
- Anti-HCV nucleoside derivatives
-
The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.
- -
-
-
- Antisense Inhibition of vascular endothelial growth factor receptor-1 expression
-
Antisense compounds, compositions and methods are provided for modulating the expression of vascular endothelial growth factor receptor-1. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding vascular endothelial growth factor receptor-1. Methods of using these compounds for modulation of vascular endothelial growth factor receptor-1 expression and for treatment of diseases associated with expression of vascular endothelial growth factor receptor-1 are provided.
- -
-
-
- Lipid esters of nucleoside monophosphates and their use as immunosuppressive drugs
-
The present invention is directed to new nucleoside monophosphate derivatives of lipid ester residues of general formula (I) wherein R1 represents an optionally substituted alkyl chain having 1-20 carbon atoms; R2 represents hydrogen, an optionally substituted alkyl chain having 1-20 carbon atoms; R3, R4 and R5 represent hydrogen, hydroxy, azido, amino, cyano, or halogen; X represents a valence dash, oxygen, sulfur, a sulfinyl or sulfonyl group; Y represents a valence dash, an oxygen or sulfur atom; B represents a purine and/or pyrimidine base; with the proviso that at least one of the residues R3 or R5 is hydrogen; to their tautomers and their physiologically acceptable salts of inorganic and organic acids and/or bases, as well as to processes for their preparation, and to drugs containing said compounds.
- -
-
-
- 5-Substituted UTP derivatives as P2Y2 receptor agonists
-
A series of 5-alkyl-substituted UTP derivatives, which had been synthesized previously with a moderate degree of purity, was resynthesized, purified, and characterized. Synthetic and purification procedures were optimized. New spectroscopic data, including 13C- and 31P NMR data, are presented. Phosphorylation reactions yielded a number of side products, such as the 2'-, 3'-, and 5'-monophosphates, the 2',3'-cyclic monophosphates, and the 2',3'-cyclic phosphates of the 5'-triphosphates. Furthermore, raw products were contaminated with inorganic phosphates, including cyclometatriphosphate, phosphate, and pyrophosphate. The uracil nucleotides were investigated for their potency to increase intracellular calcium concentrations by stimulation of P2Y2 receptors (P2Y2R) on NG108- 15 cells, a mouse neuroblastoma x glioma cell line, and in human basal epithelial airway cells, including a cystic fibrosis (CF/T43) cell line. UTP exhibited EC50 values of ca. 1 μM (in NG108-15 cells) and of 0.1 μM (in CF/T43 cells), respectively. 5-Substituted UTP derivatives were agonists at the P2Y2R, but were less potent than UTP. 5-Ethyl-UTP, for example, exhibited an EC50 value of 99 μM at P2Y2R of NG108-15 cells and proved to be a full agonist. With increasing volume of the 5- substituent of UTP derivatives, P2Y2 activity decreased.
- Knoblauch, Bernd H.A.,Mueller, Christa E.,Jaerlebark, Leif,Lawoko, Grace,Kottke, Thomas,Wikstroem, Martin A.,Heilbronn, Edith
-
p. 809 - 824
(2007/10/03)
-
- 2',3'-O-phosphonoalkylidene derivatives of ribonucleosides: Synthesis and reactivity
-
A novel type of nucleotide analogues, the 2',3'-O-(1- diethylphosphono)alkylidene derivatives of ribonucleosides was prepared by redox reaction of diethyl chlorophosphite with various nucleoside orthoesters. Some of these compounds undergo interesting rearrangements when treated with nucleophiles. The configuration of the title compounds was determined by 2D-ROESY experiments. Biological activity of partially protected nucleotide analogues is also discussed.
- Endova, Magdalena,Masojidkova, Milena,Budesinsky, Milos,Rosenberg, Ivan
-
p. 11151 - 11186
(2007/10/03)
-
- Process for producing 5-methyluridine and purification by sedimentation velocity
-
The present provides a process for obtaining high-purity 5-methyluridine crystals from nucleic acid ingredients as starting materials using a microorganism. The process comprises culturing a microorganism, removing part or the whole of the culture medium ingredients, conducting the enzyme reaction by the microorganism, crystallizing 5-methyluridine formed, and separating the obtained crystals from other impurity crystals on the basis of a difference in the precipitation rate.
- -
-
-
- Synthesis of 5-Methylisocytidine Derivatives
-
N2-Substituted 5-methylisocytidine derivatives were synthesized from S2-methyl-2-thiothymine either by direct substitution of the methylthio group by an amino group and subsequent condensation with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose to give the acetylated nucleoside or by the opposite sequence first preparing an acetylated 5,S2-dimethyl-2-thiouridine followed by treatment with the appropriate amine.
- Abdel-Rahman,Pedersen,Nielsen
-
p. 455 - 459
(2007/10/03)
-
- 1-(3'-fluoro-2',3'-dideoxy-β-D-ribofuranosyl)-5-substituted pyrimidine nucleosides
-
A 2',3'-deoxy-3'-fluoro-pyrimidine nucleoside having the formula: STR1 wherein R1 is OH or NH2 ; R2 is CF3, CH2 CH2 CH3, STR2 CH2 OCH3, CH2 SCH3, CH=CH2 CH=CH--CH3, C CH, C C--CH3 or CH2 --C CH; or a pharmaceutically acceptable salt thereof. These nucleoside analogs exhibit antiviral activity against HIV.
- -
-
-
- Nucleosides. Part LIX. The 2-(4-nitrophenyl)ethylsulfonyl (Npes) group: A new type of protection in nucleoside chemistry
-
The 2-(4-nitrophenyl)ethylsulfonyl (npes) group is developed as a new sugar OH-blocking group in the ribonucleoside series. Its cleavage can be performed in a β-eliminating process under aprotic conditions using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the most effective base. Since sulfonates do not show acyl migration, partial protection of 1,2-cis-diol moieties is possible leading to new types of oligonucleotide building blocks. A series of Markiewicz-protected ribonucleosides 1-10 is converted into their 2'-O-[2-(4-nitrophenyl)ethylsulfonyl] derivatives 29-38 in which the 5'-O-Si bond can be cleaved by acid hydrolysis forming 39-45. Subsequent monomethoxytritylation leads to 46-50, and desilylation affords the 5'-O-(monomethoxytrityl)-2'-O-[2-(4-nitrophenyl)ethylsulfonyl]ribonucl eosides 51-55. Acid treatment to remove trityl groups do also not harm the npes group(→ 56-58). Unambiguous syntheses of fully blocked 2'-O-[2-(4-nitrophenyl)ethylsulfonyl]ribonucleosides 96-102 are achieved from the corresponding 3'-O-(tert-butyl)dimethylsilyl derivatives. Furthermore, various base-protected 5'-O-(monomethoxytrityl)- and 5'-O-(dimethoxytrityl)ribonucleosides, i.e. 59-77, are treated directly with 2-(4-nitrophenyl)ethylsulfonyl chloride forming in all cases a mixture of the 2',3'-di-O- and the two possible 2'- and 3'-O-monosulfonates 107-148 which can be separated into the pure components by chromatographic methods. The npes group is more labile towards DBU cleavage than the corresponding base-protecting 2-(4-nitrophenyl)ethyl (npe) and 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) groups allowing selective deblocking which is of great synthetic potential.
- Pfister,Schirmeister,Mohr,Farkas,Stengele,Reiner,Dunkel,Gokhale,Charubala,Pfleiderer
-
p. 1705 - 1737
(2007/10/02)
-
- A Facile Route to Pyrimidine-Based Nucleoside Olefins: Application to the Synthesis of d4T (Stavudine)
-
An efficient synthetic route to nucleoside olefins in the uridine, cytidine, and thymidine series is described which utilizes the Garegg-Samuelsson iodine/triphenylphosphine/imidazole-promoted deoxygenation of the 2',3'-hydroxyl groups as the key step.Cyclopentadiene ketal protection was employed for all the nucleoside 2',3'-hydroxyls to facilitate blocking of the 5'-hydroxyl and the pyrimidine nitrogens with the benzyl or 4-methoxybenzyl (PMB) groups.Deblocking of the cyclopentylidene group followed by olefination of the resulting diols provided protected nucleoside olefins 18-20.Starting with 5-methyluridine 4 and utilizing the 4-methoxybenzyl group for 5',N3 protection, the overall scheme provided the anti-HIV compound d4T (1) after deprotection of the PMB groups.The dibenzylhypoxanthine nucleoside diol 17 derived from inosine gave either unreacted starting material or decomposition products under several sets of conditions.
- Luzzio, Frederick A.,Menes, Michael E.
-
p. 7267 - 7272
(2007/10/02)
-
- Facile synthesis of thymidine derivatives by cross-coupling of 5-halogenouridine derivatives with trimethylaluminum
-
An efficient method for the introduction of a methyl group in the 5-position of uridine derivatives is described. This method involves three steps: protection of 5-halogenouridines 4 and 5 with hexamethyldisilazane, a palladium-catalyzed cross-coupling of the pertrimethylsilylated nucleosides with trimethylaluminum, and subsequent deprotection to afford the corresponding thymidine derivatives 6 in high overall yields.
- Hirota,Kitade,Kanbe,Isobe,Maki
-
p. 213 - 215
(2007/10/02)
-
- 2'-O,5-dimethyluridine: A total synthesis and single crystal X-ray diffraction study
-
A new method for the synthesis of 2'-O,5-dimethyluridine (5) has provided the title compound in a higher yield. Application of a one-pot ribosylation methodology resulted in an efficient, high yield synthesis of 5-methyluridine (ribothymine, 3b). An X-ray diffraction analysis of 5 disclosed the conformation of the sugar moiety of this nucleoside as anti, N(3'-endo), g+.
- Lewis,Revankar,Hogan
-
p. 1309 - 1316
(2007/10/02)
-
- One-electron-reduction potentials of pyrimidine bases, nucleosides, and nucleotides in aqueous solution. Consequences for DNA redox chemistry
-
The reduction potentials in aqueous solution of the pyrimidine bases, nucleosides, and nucleotides of uracil (U) and thymine (T) were determined using the technique of pulse radiolysis with time-resolved spectrophotometric detection. The electron adducts of U and T were found to undergo reversible electron exchange with a series of ring-substituted N-methylpyridinium cations with known reduction potential. From the concentrations of the pyrimidine electron adducts and the reduced N-methylpyridinium compounds at electron-transfer equilibrium, the thermodynamical equilibrium constants were obtained and from these the reduction potentials. The results show U and T and their nucleosides and nucleotides to have very similar reduction potentials, ～ -1.1 V/NHE at pH 8, i.e., the effect of methylation at C5, C6, or of substitution at N1 is small, ≤0.1 V. In the case of cytosine (C) the electron adduct is protonated (probably at N3), even up to pH 13. The protonated adduct (C(H)?) undergoes a reversible electron transfer with the N-methylpyridinium cations. This is accompanied in one direction by transfer of a proton but by that of a water molecule in the other direction. As a result of the protonation of the electron adduct, the effective ease of reduction of C in aqueous solution is similar to that of U and T. It is suggested that in DNA the tendency for C?- to be protonated (by its complementary base G) is larger by ≥10 orders of magnitude than that for protonation of T?- by its complementary base A. This results in C and not T being the most easily reduced base in DNA. A further consequence is that lack of neutralization by intrapair proton transfer of T?- enables the irreversible extra-pair protonation on C6 of the radical anion to take place.
- Steenken,Telo,Novais,Candeias
-
p. 4701 - 4709
(2007/10/02)
-
- Effects of Xanthine Oxidase on Synthesis of 5-Methyluridine by the Ribosyl Transfer Reaction
-
In the presence of xanthine oxidase, 5-methyluridine was synthesized from inosine and thymine by the ribosyl transfer reaction using purine nucleoside phosphorylase and pyrimidine nucleoside phosphorylase.The hypoxanthine formed was converted into urate via xanthine by xanthine oxidase.After inosine was completely consumed, an equilibrium state, in which 5-methyluridine, thymine, ribose-1-phosphate, and phosphate were involved, was achieved.At the equilibrium state, maximum yield of 5-methyluridine was obtained.The equilibrium constant of the reaction ( K = /) was 0.062.Based on the equilibrium constant, the yield of 5-methyluridine depended on a ratio of initial concentrations of inosine and phosphate, on condition that the initial concentrations of inosine and thymine were the same.The yields of 5-methyluridine in the presence and absence of xanthine oxidase were 76 and 33percent, respectively, when the initial concentrations of inosine, thymine, and phosphate were 5 mM each.
- Hori, Nobuaki,Uehara, Kyouko,Mikami, Yoichi
-
p. 1071 - 1074
(2007/10/02)
-
- Synthesis of beta-thymidine
-
A process is provided in which a mixture of alpha- and beta-anomers is converted selectively to the desired beta-thymidine. The process involves the following steps: (a) converting a mixture of alpha- and beta-anomers of tetra-O-acylribofuranose to tri-O-acyl-β-ribothymidine; (b) converting tri-O-acyl-β-ribothymidine to β-ribothymidine; (c) converting β-ribothymidine to 2,2'-anhydro-β-thymidine; (d) converting 2,2'-anhydro-β-thymidine to 2'-halo-2'-deoxy-5-methyluridine; and (e) converting 2'-halo-2'-deoxy-5-methyluridine to beta-thymidine. The mixture of alpha- and beta-anomers of tetra-O-acylribofuranose may be produced by any suitable procedure such as by converting lower alkyl ribofuranoside to the tetra-O-acylribofuranose mixture. The lower alkyl ribofuranosides may in turn be produced by various methods. However, a desirable way of effecting this conversion involves use of D-ribose as the starting material which is converted to the lower alkyl ribofuranoside.
- -
-
-
- A SIMPLE AND GENERAL ENTRY TO 5-SUBSTITUTED URUDINES BASED ON THE REGIOSELECTIVE LITHIATHION CONTROLLED BY A PROTECTING GROUP IN THE SUGAR MOIETY
-
Lithiathion of 2',3',5'-tris-O-(tert-butyldimethylsilyl)uridine with sec-BuLi/TMEDA occurs at the C-5 position with a high regioselectivity and subsequent reactions of the resulting C-5 lithiated species with a variety of electrophiles provides a general entry to 5-substituted uridines.
- Hayakawa, Hiroyuki,Tanaka, Hiromichi,Obi, Kikoh,Itoh, Masayuki,Miyasaka, Tadashi
-
-
- Reactions of pyrimidine nucleosides with aqueous alkalies: kinetics and mechanisms.
-
Kinetics for the reactions of various cytosine and uracil nucleosides and their alkyl derivatives with aqueous sodium hydroxide have been studied by liquid chromatography. Blocking of the glycosyl hydroxyl groups with alkyl groups and changes in the glycon moiety configuration have been observed to exert only moderate effects on the rate of deamination of cytosine nucleosides. Methylation of the 4-amino group retards deamination considerably, while a methyl substituent at C5 is rate accelerating and at C6 only moderately rate retarding. These findings have been accounted for by a mechanism involving a rate limiting bimolecular displacement of the 4-amino group by a hydroxide ion. Analogous comparisons with uracil nucleosides suggest that the decomposition of uridine is initiated by an intermolecular attack of hydroxide ion on the C5 atom of the base moiety. In contrast, beta-D-arabino- and beta-D-lyxo-furanosyl derivatives appear to be cleaved via an intramolecular nucleophilic attack of the ionized 2'-hydroxyl group.
- L?nnberg,Suokas,K?ppi,Darzynkiewicz
-
p. 798 - 805
(2007/10/02)
-
- SYNTHETIC ROUTE TO 5-SUBSTITUTED URIDINES VIA A NEW TYPE OF DESULFURIZATIVE STANNYLATION
-
Phenylthio group at the C-6 position of uridine serves as the protecting group during lithiation at the C-5 position with lithium 2,2,6,6-tetramethylpiperidine.Reactions of the resulting C-5 lithiated species with various types of electrophiles furnish 5-substituted 6-phenylthiouridine derivatives.The phenylthio group in these products can be removed by a new type of desulfurizative stannylation with tributyltin hydride followed by protonolysis.The whole sequence constitutes a new route to 5-substituted uridines.Application of this method to 2'-deoxyuridine is also described.
- Tanaka, Hiromichi,Hayakawa, Hiroyuki,Obi, Kikoh,Miyasaka, Tadashi
-
p. 4187 - 4196
(2007/10/02)
-
- LITHIATION OF 5,6-DIHYDROURIDINE: A NEW ROUTE TO 5-SUBSTITUTED URIDINES
-
2',3'-O-Isopropylidene-5'-O-methoxymethyl-5,6-dihydrouridine (2) was found to serve as an "amide α-anion" upon lithiation with LDA.Reactions of the anion with acid chlorides followed by phenylselenation and oxidative elimination furnished 5-acyluridines.For the preparation of 5-alkyluridines, initial introduction of phenylselenenyl group at the C-5 of 2 appeared to be effective.Alkylation of its α-selenenyl carbanion and subsequent generation of 5,6-double bond produced 5-alkyluridines.These routes constitute a new entry to 5-substituted uridines.
- Hayakawa, Hiroyuki,Tanaka, Hiromichi,Miyasaka, Tadashi
-
p. 1675 - 1684
(2007/10/02)
-
- DESULFURIZATIVE STANNYLATION OF URACIL DERIVATIVES
-
Phenylthio group in the C-6 or C- position of uracil moiety can be removed by radical mediated stannylation with tributyltin hydride followed by protonolysis, providing a new route to 5-substituted uridines.
- Tanaka, Hiromichi,Hayakawa, Hiroyuki,Obi, Kikoh,Miyasaka, Tadashi
-
p. 6229 - 6232
(2007/10/02)
-
- Conversion of 2'-Deoxyuridine into Thymidine and Related Studies
-
Unprotected 2'-deoxyuridine is converted into thymidine in three steps by a procedure which is equally effective for the 5-methylation of uridine and even more effective for the conversion of 1-β-D-arabinofuranosyluracil into its 5-methyl derivative.
- Reese, Colin B.,Sanghvi, Yogesh S.
-
p. 877 - 879
(2007/10/02)
-
