- Ionic liquid mediated synthesis of 5-halouracil nucleosides: Key precursors for potential antiviral drugs
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Synthesis of antiviral 5-halouracil nucleosides, also used as key precursors for the synthesis of other potential antiviral drugs, has been demonstrated using ionic liquids as convenient and efficient reaction medium.
- Kumar, Vineet,Malhotra, Sanjay V.
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- Synthesis and complementary self-association of novel lipophilic π-conjugated nucleoside oligomers
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A series of lipophilic nucleosides comprising natural and non-natural bases that are π-conjugated to a short oligophenylene-ethynylene fragment has been synthesized. These bases comprise guanosine, isoguanosine, and 2-aminoadenosine as purine heterocycles, and cytidine, isocytosine and uridine as complementary pyrimidine bases. The hydrogen-bonding dimerization and association processes between complementary bases were also studied by 1H NMR and absorption spectroscopy in order to obtain the relevant association constants.
- Camacho-García,Montoro-García,López-Pérez,Bilbao,Romero-Pérez,González-Rodríguez
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- Transcription of Unnatural Fluorescent Nucleotides and their Application with Graphene Oxide for the Simple and Direct Detection of miRNA
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In this study we synthesized two differently sized fluorescent RNA nucleotides, rUthioTP and rUpyrTP, and examined their transcription ability using T7 RNA polymerase. The smaller rUthioTP could be incorporated and extended to produce a corresponding RNA sequence, but rUpyrTP could not. We then used this rUthioTP-containing fluorogenic transcription system, in conjunction with graphene oxide(GO), for the detection of miRNA 146a with high sensitivity and selectivity. This combination of a transcribed RNA product and GO is a simple in situ probing system for the detection of miRNA 146a—one that is less time consuming and more cost-effective.
- Le, Binh Huy,Seo, Young Jun
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- Protected pyrimidine nucleosides for cell-specific metabolic labeling of RNA
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RNA molecules can perform a myriad of functions, from the regulation of gene expression to providing the genetic blueprint for protein synthesis. Characterizing RNA expression dynamics, in a cell-specific manner, still remains a great challenge in biology. Herein we present a new set of protected alkynyl nucleosides for cell-specific metabolic labeling of RNA. We anticipate these analogs will find wide spread utility toward the goal of understanding RNA expression in complex cellular and tissue environments, even within living animals.
- Beasley, Samantha,Nguyen, Kim,Fazio, Michael,Spitale, Robert C.
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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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- Cerium(IV)-Mediated Halogenation at C-5 of Uracil Derivatives
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Treatment of protected uracil nucleosides 1 or 2 with elemental iodine or metal halogenides and ceric ammonium nitrate (CAN) at 80 deg C gave the corresponding protected 5-halouracil nucleosides 3a-f in excellent yields.Treatment of the resulting crude 3a-f with 0.1 M NaOMe/MeOH at ambient temperature gave the corresponding 5-halouridines 4a-f in high overall yields from 1 or 2.Further, 5-halouraciles 9a-f were prepared in good yields by treatment of 1,3-dimethyluracil (7) or uracil (8) with elemental iodine, metal halogenides, or hydrochloric acid and CAN.Halouridines 4a-e also were obtained in good yields by treatment of unprotected uracil nucleosides 5 or 6 with halogen sources as above and CAN.
- Asakura, Jun-ichi,Robins, Morris J.
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- Bifunctional inhibition of HIV-1 reverse transcriptase: A first step in designing a bifunctional triphosphate
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The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof of concept has so far been elusive. As a first step, we describe molecular modeling to guide focused chemical syntheses of conjugates having nucleoside (d4T) and nonnucleoside (TIBO) moieties tethered by a flexible polyethylene glycol (PEG) linker. A triphosphate of d4T-6PEG-TIBO conjugate was successfully synthesized that is recognized as a substrate by HIV-1 RT and incorporated into a double-stranded DNA.
- Piao, Dongyuan,Basavapathruni, Aravind,Iyidogan, Pinar,Dai, Guangxiu,Hinz, Wolfgang,Ray, Adrian S.,Murakami, Eisuke,Feng, Joy Y.,You, Fei,Dutschman, Ginger E.,Austin, David J.,Parker, Kathlyn A.,Anderson, Karen S.
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- Aptamer-based proximity labeling guides covalent RNA modification
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We describe the development of a proximity-induced bio-orthogonal inverse electron demand Diels-Alder reaction that exploits the high-affinity interaction between a dienophile-modified RhoBAST aptamer and its tetramethyl rhodamine methyltetrazine substrate. We applied this concept for covalent RNA labeling in proof-of-principle experiments.
- Englert, Daniel,Matveeva, Regina,Sunbul, Murat,Wombacher, Richard,J?schke, Andres
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- Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus
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Uridine-based nucleoside analogues have often been found to have relatively poor antiviral activity. Enzymatic assays, evaluating inhibition of influenza virus RNA polymerase, revealed that some uridine triphosphate derivatives displayed inhibitory activity on UTP incorporation into viral RNA. Here we report the synthesis, antiviral activity and enzymatic evaluation of novel ProTides designed to deliver the activated (monophosphorylated) uridine analogues inside the influenza virus-infected cells. After evaluation of the activation profile we identified two ProTides with moderate antiviral activity in MDCK cells (23a, EC99=49±38μM and 23b, EC99≥81μM) while the corresponding nucleoside analogue (2'-fluoro-2'-deoxyuridine) was inactive. Thus, at least in these cases the poor antiviral activity of the uridine analogues may be ascribed to poor phosphorylation.
- Meneghesso, Silvia,Vanderlinden, Evelien,Stevaert, Annelies,McGuigan, Christopher,Balzarini, Jan,Naesens, Lieve
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- Use of nucleoside phosphorylases for the preparation of 5-modified pyrimidine ribonucleosides
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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.
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- SYNTHESIS AND STRUCTURE OF HIGH POTENCY RNA THERAPEUTICS
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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.
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- Fluorescence-switching RNA for detection of bacterial ribosomes
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We have developed an efficient chemical system that allows quantification of bacterial ribosomes by fluorescence-based analysis. The key component in the system is the exciton-controlled fluorescent RNA aptamer, which recognizes neomycin B. The intensity of fluorescence from such a ribosome-sensing system increased drastically in the presence of Escherichia coli.
- Guo, Lihao,Okamoto, Akimitsu
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supporting information
p. 9406 - 9409
(2017/09/01)
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- Sulfur-containing uridine anticancer compound and intermediate and preparation method thereof
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The invention relates to a 4-sulfur-5-(2-halogenated vinyl)uridine compound which has the higher sensibility to UVA light and the anticancer activity and an intermediate and a preparation method of the compound. The method comprises the following steps that an iodination reaction is performed, a halogenating reaction is performed, hydroxyl on a sugar ring is protected, oxygen is replaced by sulfur, an O protection group is removed, and then 4-sulfur-5-(2-halogenated vinyl)uridine is obtained. The method has the advantages of being short in reaction time and high in yield and product purity, and the defects that in a traditional synthesis method, time and energy are consumed, and the yield is low are overcome. Beneficial conditions are supplied for further developing sulfur-containing nucleoside drugs.
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Paragraph 0040; 0057; 0058; 0059; 0060
(2016/10/09)
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- Direct One-Pot Synthesis of Nucleosides from Unprotected or 5-O-Monoprotected d -Ribose
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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
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p. 4604 - 4607
(2015/09/28)
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- COMPOUNDS AND THEIR USES IN PROTEIN BINDING ASSAYS
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The present invention relates to compounds and their use in competitive protein binding assays, for example for use with glycosyl transferase and/or glycoprocessing proteins. The present application also provides kits and apparatuses for use in the assays. In particular, the present invention provides a compound of the formula (I): wherein n is 1, 2 or 3; R1 is selected from -OH, -OPO3H, -OR4, -NHR4, R6; R2 and R3 are each independently selected from -H, -OH, optionally substituted -O- alkyl and -O-alkanoyl; R4 is selected from an optionally substituted mono or polysaccharide, -alkyl, -alkenyl, - alkynyl, and L-Z, where L is a linking agent and Z is a binding agent; R6 is an optionally substituted hydrocarbon group; A is either (i) a substituted heteroaryl group, the substituent on the heteroaryl group having a double bond conjugated to the heteroaryl group, or (ii) a substituted aryl group, the substituent on the aryl group having a double bond conjugated to the aryl group.
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Page/Page column 44
(2011/05/11)
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- One-flow, multistep synthesis of nucleosides by Bronsted acid-catalyzed glycosylation
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Nucleosides in flow: A general, scalable method of Bronsted acid-catalyzed nucleoside formation is described. Because of the high reaction temperatures readily available to the flow reaction format, mild Bronsted acids, particularly pyridinium triflates, can be used. A one-flow multistep synthesis of unprotected nucleosides is also reported (see scheme).
- Sniady, Adam,Bedore, Matthew W.,Jamison, Timothy F.
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supporting information; experimental part
p. 2155 - 2158
(2011/04/23)
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- Highly efficient method for C-5 halogenation of pyrimidine-based nucleosides in ionic liquids
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A novel, highly efficient, convenient, and benign methodology for C-5 halogenation of pyrimidine-based nucleosides has been developed using N-halosuccinimides as halogenating reagents without using any catalyst in ionic liquid medium. The ionic liquids were successfully recovered and reused for all the reactions. Georg Thieme Verlag Stuttgart.
- Kumar, Vineet,Yap, Jeremy,Muroyama, Andrew,Malhotra, Sanjay V.
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experimental part
p. 3957 - 3962
(2010/03/26)
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- A mild and efficient methodology for the synthesis of 5-halogeno uracil nucleosides that occurs via a 5-halogeno-6-azido-5,6-dihydro intermediate
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A mild and efficient methodology for the synthesis of 5-halogeno (iodo, bromo, or chloro) uracil nucleosides has been developed. 5-Halo-2'-deoxyuridines 4a-c (84-95%), 5-halouridines 7a-c (45-95%), and 5-haloarabinouridines 8a-c (65-95%) were synthesized in good to excellent yields by the reaction of 2'-deoxyuridine (2), uridine (5) and arabinouridine (6), respectively with iodine monochloride, or N-bromo (or chloro)succinimide, and sodium azide at 25-45°C. These C-5 halogenation reactions proceed via a 5-halo-6-azido-5,6-dihydro intermediate (3), from which HN3 is eliminated, to yield the 5-halogeno uracil nucleoside. The 5-halo-6-azido-5,6-dihydro intermediate products (10a, 10b) could be isolated from the reaction of 3',5'-di-O-acetyl-2'-deoxyuridine (9) with iodine monochloride or N-bromosuccinimide and sodium azide at 0°C. The isolation of 10a, 10b indicates that the C-5 halogenation reaction proceeds via a 5-halo-6-azido-5,6-dihydro intermediate.
- Kumar,Wiebe,Knaus
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p. 2005 - 2010
(2007/10/02)
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- Iodination with Silver Sulfate and Iodine. II. Uridines
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Iodination of uridines with iodine and silver sulfate at room temperature gives iodinated uridines in excellent yield.
- Sy, Wing-Wah
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p. 3391 - 3394
(2007/10/02)
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- Nucleic acid related compounds. 38. Smooth and high-yield iodination and chlorination at C-5 of uracil bases and p-toluyl-protected nucleosides
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Treatment of uracil bases and protected nucleosides with iodine monochloride (ICl) gave the corresponding 5-iodouracil products in over 95percent purified yields.Analogously facile chlorination was effected with iodobenzene dichloride (PhICl2).Protection of the nucleosides as p-toluyl esters provided reactants that were soluble in organic solvents and crystallized readily in high yields.
- Robins, Morris, J.,Barr, Philip J.,Giziewicz, Jerzy
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p. 554 - 557
(2007/10/02)
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- The bromination and iodination of N1-substituted uracils
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Reaction of N1-substituted uracils with bromine in water at pH=7 leads to 5-bromo-6-hydroxy-5,6-hydrouracils.For different N1-substituents these products were isolated and the relatively stable derivatives were characterized by 1H NMR and mass spectroscopy.On electrophilic iodination with iodide and chloramine-T in water no indications were obtained for the formation of such dihydrouracils except for uridine and deoxyuridine.However, on reaction of N1-substituted uracils with N-iodosuccinimide in CHCl3 containing ethanol, or in ethanol, 5-iodo-6-ethoxy-5,6-dihydrouracils could be isolated as reaction products.
- Bakker, Cees N. M.,Kaspersen, Frans M.
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p. 267 - 271
(2007/10/02)
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