- The 2′-caged-tethered-siRNA shows light-dependent temporal controlled RNAi activity for GFP gene into HEK293T cells
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Small interfering RNA (siRNA) exhibits gene-specific RNAi activity by the formation of RISC complex with mRNA of gene. The structural modification of siRNA at appropriate positions affects the structure of RISC complex and then RNAi activity. The modified siRNA are mostly prepared from the incorporation of sugar ring modified, and nucleobase modified RNA nucleotides. It is learned that the introduction of the sterically hindered nucleoside at the specific position of siRNA, severely affects siRNA-RISC complex formation. This report describes the syntheses of bulkier siRNA from 2′-caged-tethered-siRNAs, containing bulkier photolabile protecting group (o-nitrobenzyl) at 2′-position of ribose nucleoside. Importantly, these 2′-caged-siRNAs exhibit the light-dependent RNA interference (RNAi) activity into HEK293T cells for the GFP gene expression. The 2′-caged-siRNAs are synthesized by caging the sense and antisense strand of siRNA. The biochemical evaluations of these caged-siRNAs show that antisense-strand caged-siRNAs decrease RNAi activity temporarily in dark while enhancing RNAi activity, almost like control, after exposure withUV- light. However, 2′-caged sense strand siRNA increase RNAi activity temporarily while decreasing RNAi activity after exposure with light. These caged-siRNAs are also stable in the serum (fetal bovine serum) as like native siRNA. Hence these results strongly support that 2′-caged-tethered-siRNAs are promising analogues to control RNAi activity by UV-light.
- Bollu, Amarnath,Hassan, Md. Khurshidul,Dixit, Manjusha,Sharma, Nagendra K.
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Read Online
- Simple and High radiochemical yield synthesis of 2'-Deoxy-2'-[18F]fluorouridine via a new nosylate precursor
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We synthesized 2'-deoxy-2'-[18F]fluorouridine (7) as a radiotracer for positron emission tomography from a new nosylate precursor (6). This new precursor was synthesized from uridine in four steps. The overall synthetic yield was 9.4 percent and we have high stability of >98 percent purity up to 6 months at 4 deg C. The optimal manual [18F]fluorination conditions were 30 mg of the precursor 6 in 500 μl of acetonitrile at 145 deg C for 15 min with 370 MBq of [18F]fluoride. The [18F]fluorination yield was 76.5 +/- 2.7 percent (n = 3). After hydrolysis of protecting groups with 1N HCl and purification by HPLC, the overall radiochemical yield and purity were 26.5 +/- 1.4 percent and 98.2 +/- 2.5 percent, respectively. The preparation time was 70.0 +/- 10.5 min (n = 3 for each result). We also developed an automated method with a radiochemical yield and purity of 24.0 +/- 2.8 and 98.0 +/- 1.5 percent (n = 10) using a GE TracerLab MX chemistry module. This new nosylate precursor for 2'-deoxy-2'-[18F]fluorouridine synthesis showed higher radiochemical yields and reproducibility than previous methods.
- Kang, Se Han,Oh, Seung Jun,Yoon, Mi Kyung,Ryu, Jin Sook,Lee, Won Koo,Choi, Sun Joo,Park, Kyung Pae,Moon, Dae Hyuk
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Read Online
- 2′,3′-Anhydrouridine
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The previously unreported title compound 4 is readily obtained by treating 2,2′-anhydro-1-β-D-arabinofuranosyluracil 1 with sodium hydride in dry dimethyl sulfoxide at room temperature.
- Miah, Anwar,Reese, Colin B.,Song, Quanlai
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Read Online
- METHODS AND REAGENTS FOR SYNTHESIZING NUCLEOSIDES AND ANALOGUES THEREOF
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The present invention relates to methods and intermediates for the synthesis of nucleosides and nucleoside analogues (NAs). More specifically, the present invention relates to methods of synthesizing nucleosides and NAs, using simple achiral materials by a 'one-pot' proline-catalyzed halogenation of a heteroaryl-substituted acetaldehyde together with a tandem enantioselective aldol reaction followed by a reduction or organometallic addition and cyclization (annulation) reaction involving halide displacement.
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Paragraph 0066; 00288-00290
(2021/10/02)
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- Synthesis of 2′-aminouridine derivatives as an organocatalyst for Diels-Alder reaction?
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To develop a novel asymmetric organocatalyst based on a ribonucleoside skeleton, we designed and synthesized 2′-aminouridine derivatives. The synthesized 2′-aminouridines having bulky substituents at both base and sugar moieties could catalyze the Diels-Alder reaction between cinnamaldehyde and cyclopentadiene. However, the optical purities of the resulting products were unexpectedly low.
- Wakamatsu, Hideaki,Itoh, Moeko,Natori, Yoshihiro,Yoshimura, Yuichi
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p. 365 - 383
(2019/08/12)
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- Site of azido substitution in the sugar moiety of azidopyrimidine nucleosides influences the reactivity of aminyl radicals formed by dissociative electron attachment
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In this work, electron-induced site-specific formation of neutral π-type aminyl radicals (RNH·) and their reactions with pyrimidine nucleoside analogs azidolabeled at various positions in the sugar moiety, e.g., at 2′-, 3′-, 4′-, and 5′- sites along with a model compound 3-azido-1-propanol (3AZPrOH), were investigated. Electron paramagnetic resonance (EPR) studies confirmed the site and mechanism of RNH· formation via dissociative electron attachment-mediated loss of N2 and subsequent facile protonation from the solvent employing the 15N-labeled azido group, deuterations at specific sites in the sugar and base, and changing the solvent from H2O to D2O. Reactions of RNH· were investigated employing EPR by warming these samples from 77 K to ca. 170 K. RNH· at a primary carbon site (5′-azido-2′,5′-dideoxyuridine, 3AZPrOH) facilely converted to a σ-type iminyl radical (R=N·) via a bimolecular H-atom abstraction forming an α-azidoalkyl radical. RNH· when at a secondary carbon site (e.g., 2′-azido-2′-deoxyuridine) underwent bimolecular electrophilic addition to the C5=C6 double bond of a proximate pyrimidine base. Finally, RNH· at tertiary alkyl carbon (4′-azidocytidine) underwent little reaction. These results show the influence of the stereochemical and electronic environment on RNH· reactivity and allow the selection of those azidonucleosides that would be most effective in augmenting cellular radiation damage.
- Mudgal, Mukesh,Dang, Thao P.,Sobczak, Adam J.,Lumpuy, Daniel A.,Dutta, Priya,Ward, Samuel,Ward, Katherine,Alahmadi, Moaadh,Kumar, Anil,Sevilla, Michael D.,Wnuk, Stanislaw F.,Adhikary, Amitava
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p. 11357 - 11370
(2020/12/23)
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- RELEASABLE CONJUGATES
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The present application provides compounds of Formula (B), or pharmaceutically acceptable salts thereof, wherein D is a residue of a biologically active drug, which underdo hydrolysis under physiological conditions to release the biologically active drug and which are useful in the treatment of disorders that could be beneficially treated with the drug.
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Page/Page column 173
(2018/09/28)
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- A (2 'R) -2' - deoxy -2 '- fluoro -2' - methyl urea glucoside preparation method (by machine translation)
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The invention discloses a (2 'R) -2' - deoxy -2 '- fluoro -2' - methyl urea glucoside (type I) synthetic method. Cheap and easily available starting material, through the hydroxyl protection, cyclization, the links such as fluoride, obtains the type I compound. (by machine translation)
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Paragraph 0018
(2017/02/28)
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- Regioselective Mitsunobu Reaction of Partially Protected Uridine
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Mitsunobu reaction of partially acylated uridine proceeds with high regioselectivity for intramolecular SN2 anhydro linkage closuring. Under the reaction conditions, an isomeric mixture of diacyl uridine derivatives with either free 2′- or 3′-hydroxyl group was transformed into a single cyclonucleosidic product, 2,2′-anhydro-3′,5′-di-O-acyluridine. This paper presents a possible mechanism of the reactions, the explanation of observed phenomenon based on semiempirical and density functional theory (DFT) calculations and possible utility of this synthetic pathway.
- Szlenkier, Maurycy,Kamel, Karol,Boryski, Jerzy
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p. 410 - 425
(2016/08/05)
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- 3-methyl uridine and 4-methyl cytidine nucleoside compound, synthetic method and its pharmaceutical use
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The invention discloses a 3-methyluridine and 4-methylcytidine nucleosides compound and a synthesis method and pharmaceutical application thereof, belonging to the field of medicinal chemistry. The compound has a structural formula as shown in the specification. The compound has the effects of simultaneously modifying sugar rings and basic groups, increasing the activity of the compound and reducing the toxicity, provides a good application prospect for development of like medicines and can be applied to preparation of anti-HBV (Hepatitis B virus) medicines. The synthesis method is simple and feasible and provides conditions for mass synthesis of the compound.
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Paragraph 0021; 0034
(2016/10/08)
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- Versatile synthesis of 2′-amino-2′-deoxyuridine derivatives with a 2′-amino group carrying linkers possessing a reactive terminal functionality
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2,2′-Anhydrouridine has been successfully converted into the appropriate 2′-amino-2′-deoxyuridine derivatives in a reaction with isothiocyanates obtained from amino acids or α,ω-diaminoalkanes. The initially formed oxazolidine-2-thione ring is cleaved under basic conditions into the corresponding 2′-amino(substituted)-2′-deoxyuridine derivatives. The implemented additional terminal functionality in the substituent attached to the 2′-amino group allows further modifications with e.g., fluorophore moiety.
- Gondela, Andrzej,Tomczyk, Mateusz D.,Przypis, ?ukasz,Walczak, Krzysztof Z.
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p. 5626 - 5632
(2016/08/17)
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- Design and synthesis of 2′-Deoxy-2′-[(1,2,3)Triazol-1-Yl]uridines using click chemistry approach
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A series of novel nucleosides bearing a 1,2,3-triazole moiety at the 2′-position of the sugar moiety has been synthesized starting from 2′-azidouridine and using the copper (I)-catalyzed Huisgen-Sharpless-Meldal 1,3-dipolar cycloaddition reaction. The reactions proceeded in overall yield of 52-82% and gave almost exclusively the 1,4-disubstituted 1,2,3-triazoles. The 2′-azidouridine was synthesized from uridine in two steps, and reacted with a variety of differently substituted alkynes to give the desired 2′-triazole-substituted uridine derivatives.
- Kumar, Surender
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p. 371 - 378
(2015/05/05)
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- Cu(I)-catalyzed efficient synthesis of 2'-triazolo-nucleoside conjugates
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A small library of thirty-two 2'-triazolyl uridine and 2'-triazolyl-5-methyluridine has been synthesized by Cu(I)-catalyzed condensation of 2'-azido-2'-deoxyuridine and 2'-azido-2'-deoxy-5-methyluridine with different alkynes and aryl propargyl ethers in almost quantitative yields. Triazolo-nucleoside conjugates, which can be evaluated for different biological activity for suitable drug development, were unambiguously identified on the basis of 1H NMR, 13C NMR, IR, and HRMS data analysis. These compounds have been synthesized for the first time and have not been reported in the literature earlier.
- Mathur,Rana,Olsen,Parmar,Prasad
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p. 701 - 710
(2015/05/13)
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- PROBE OF IODINE-123 MARKER THYMIDINE (FLT)ANALOGUE [123I]-IARAU
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A tumor radiation probe of iodine-123 marker thymidine (FLT) analogue [123I]-IaraU is disclosed. Commercial available uridine is used as the raw material for the synthesis of the precursor. A radioactive iodine-123 is marked on an alkaline group of uridine to obtain [123I]-IaraU, which is distinguishable from [18F]-FLT marking 18F on a glycosyl group to obtain a novel tumor radiation probe. The marking procedures include mixing the marker precursor with Na [123I] solution, acetic acid and hydrogen peroxide solution, and the solution of chloroform and sodium hydroxide. The sonication time increases from 1 minute to 10 minutes, so that [123I]-IaraU has radiologically chemical purity of higher than 98% and radiological specific activity of not less than 0.196 GBq/umole, and the yield can increase from 8% to 40%. Its radioactive specific activity, yield and purity reach to the degree for the use in biological experiments, while reducing production cost.
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Paragraph 0016-0017
(2014/03/25)
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- Synthesis and properties of 2′-O-neopentyl modified oligonucleotides
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2′-O-Neopentyldeoxyuridine (Un) was synthesized and incorporated into a series of oligodeoxyribonucleotides. Single and triple incorporations in various arrangements were performed. The Watson and Crick pairing properties with complementary DNA and RNA were investigated by UV melting curves, CD spectroscopy, and molecular dynamic simulations. The results were compared to those obtained with DNA-DNA and DNA-RNA duplexes involving dU at the same positions. Oligonucleotides containing Un clearly demonstrated their ability to form duplexes with both complementary DNA and RNA but with higher stabilities for the DNA-RNA duplexes similar to the one of the parent DNA-RNA duplex. Investigations into the thermodynamic properties of these 17-base-pair duplexes revealed ΔG values (37 °C) that are in line with the measured T m values for both the DNA-DNA and DNA-RNA duplexes. CD spectroscopic structural investigations indicated that the conformations of the DNA-DNA and DNA-RNA duplexes involving Un are similar to those of the dT-rA and dU-rA containing duplexes. Only small changes in intensities and weak blue shifts were observed when three Uns were incorporated into the duplexes. The results of the molecular dynamic simulations showed, for the six duplexes involving the modified nucleoside Un, calculated curvatures similar to those of the corresponding unmodified duplexes without base-pair disruption. The neopentyl group is able to be accommodated in the minor grooves of both the DNA-DNA and RNA-DNA duplexes. However, molecular dynamic simulations indicated that the Uns adopt a C2′-exo sugar pucker conformation close to an A-helix type without perturbing the C2′-endo sugar pucker conformations of their 2′-deoxynucleoside neighbours. These results confirm the potential of 2′-O-neopentyldeoxyuridine as a nucleoside surrogate for oligonucleotide based therapeutic strategies.
- Mathis, Gerald,Bourg, Stephane,Aci-Seche, Samia,Truffert, Jean-Christophe,Asseline, Ulysse
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p. 1345 - 1357
(2013/05/09)
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- Synthesis of spin-labeled riboswitch RNAs using convertible nucleosides and DNA-catalyzed RNA ligation
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Chemically stable nitroxide radicals that can be monitored by electron paramagnetic resonance (EPR) spectroscopy can provide information on structural and dynamic properties of functional RNA such as riboswitches. The convertible nucleoside approach is used to install 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and 2,2,5,5-tetramethylpyrrolidin-1-oxyl (proxyl) labels at the exocyclic N4-amino group of cytidine and 2′-O-methylcytidine nucleotides in RNA. To obtain site-specifically labeled long riboswitch RNAs beyond the limit of solid-phase synthesis, we report the ligation of spin-labeled RNA using an in vitro selected deoxyribozyme as catalyst, and demonstrate the synthesis of TEMPO-labeled 53 nt SAM-III and 118 nt SAM-I riboswitch domains (SAM = S-adenosylmethionine).
- Büttner, Lea,Seikowski, Jan,Wawrzyniak, Katarzyna,Ochmann, Anne,H?bartner, Claudia
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p. 6171 - 6180
(2013/10/21)
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- Unprecedented C-selective interstrand cross-linking through in situ oxidation of furan-modified oligodeoxynucleotides
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Chemical reagents that form interstrand cross-links have been used for a long time in cancer therapy. They covalently link two strands of DNA, thereby blocking transcription. Cross-link repair enzymes, however, can restore the transcription processes, causing resistance to certain anti-cancer drugs. The mechanism of these cross-link repair processes has not yet been fully revealed. One of the obstacles in this study is the lack of sufficient amounts of well-defined, stable, cross-linked duplexes to study the pathways of cross-link repair enzymes. Our group has developed a cross-link strategy where a furan moiety is incorporated into oligodeoxynucleotides (ODNs). These furan-modified nucleic acids can form interstrand crosslinks upon selective furan oxidation with N-bromosuccinimide.We here report on the incorporation of the furan moiety at the 20-position of a uridine through an amido or ureido linker. The resulting modified ODNs display an unprecedented selectivity for cross-linking toward a cytidine opposite the modified residue, forming one specific cross-linked duplex, which could be isolated in good yield. Furthermore, the structure of the formed cross-linked duplexes could be unambiguously characterized.
- De Beeck, Marieke Op,Madder, Annemieke
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supporting information; experimental part
p. 796 - 807
(2011/04/15)
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- Synthesis of 2′-N-formamido nucleosides and biological evaluation
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The 2′-N-formamide derivatives of adenosine, cytidine, and 9-β-D-arabinofuranosyladenine were synthesized and tested (as triphosphate) for their substrate capacities for the HCV NS5B polymerase.
- Abramov, Mikhail,Renders, Marleen,Herdewijn, Piet
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scheme or table
p. 1042 - 1050
(2010/09/05)
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- Synthesis and solution conformation studies of the modified nucleoside N4,2′-O-dimethylcytidine (m4Cm) and its analogues
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The dimethylated ribosomal nucleoside m4Cm and its monomethylated analogues Cm and m4C were synthesized. The conformations (syn vs anti) of the three modified nucleosides and cytidine were determined by CD and 1D NOE difference spectroscopy. The ribose sugar puckers were determined by the use of proton coupling constants. The position of modification (e.g., O vs N methylation) was found to have an effect on the sugar pucker of cytidine.
- Mahto, Santosh K.,Chow, Christine S.
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p. 8795 - 8800
(2008/12/23)
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- 2′-Lipid-modified oligonucleotides via a 'Staudinger-Vilarrasa' reaction
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We report a new access to 2′-amido-2′-deoxyuridine via a Staudinger-Vilarrasa coupling reaction for the preparation of lipid-modified oligonucleotides. One or two lipidic moieties were inserted within the oligonucleotidic sequence (LONs) leading to a repertoire of original antagomir-like molecules targeting micro RNA (miRNA or miR). Melting temperature (Tm) experiments revealed that the stability of the duplexes depends on the lipid position and the number of lipid moieties inserted within the oligonucleotide sequence. Single lipid conjugations of positions 11 and 19 of LONs targeting miR-122 do not destabilize the duplexes.
- Chapuis, Hubert,Bui, Laurent,Bestel, Isabelle,Barthélémy, Philippe
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supporting information; body text
p. 6838 - 6840
(2009/04/07)
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- Method for the synthesis of cyclouridine
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Method for the synthesis of possibly substituted cyclic derivatives of uridine, of formula (II) wherein R is chosen in the group that comprises: hydrogen, halogen and C1-4 alkyl, the method comprising the step of reacting a possibly substituted uridine of formula (III) wherein R has the same meanings as in formula (II), and glycerol carbonate in the presence of an alkaline carbonate at a temperature of 70°C-130°C.
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Page/Page column 7
(2008/12/09)
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- New telluride-mediated elimination for novel synthesis of 2′,3′-didehydro-2′,3′-dideoxynucleosides
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(Chemical Equation Presented) Several 2′,3′-dideoxynucleosides (ddNs) and 2′,3′-didehydro-2′,3′-dideoxynucleosides (d4Ns) are FDA-approved anti-HIV drugs. Via conveniently synthesized 2,2′-anhydronucleosides, we have developed a novel synthesis of d4Ns by discovering and applying a new telluride-mediated elimination reaction. Our experiment results show that after substitution of 2,2′-anhydronucleosides with a telluride monoanion, a telluride intermediate is formed, and its elimination leads to formation of the olefin products (d4Ns). Our mechanistic study indicates that this telluride-assisted reaction consists of two steps: substitution (or addition) and elimination. By using dimethyl ditelluride (0.1 equiv) as the reagent, d4Ns can be synthesized with yields up to 90% via this telluride-mediated elimination. Our novel strategy has great potential to simplify synthesis of these drugs and to further reduce cost of AIDS treatment and will also facilitate development of novel d4N and ddN analogues.
- Sheng, Jia,Hassan, Abdalla E. A.,Huang, Zhen
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p. 3725 - 3729
(2008/09/20)
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- Synthesis of 5-radioiodoarabinosyl uridine analog for probing the HSV-1 thymidine kinase gene
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Tumor cells transduced with herpes simplex virus thymidine kinase gene have been intensively applied to the field of positron emission tomography via imaging of its substrate. As a pilot synthesis approach, a facile preparation of 5-[125I]iodoarabinosyl uridine starting from commercially available uridine is reported herein.
- Lin, Kun-I.,Chiang, Li-Wu,Wu, Chien-Hung,Chen, Shao-Wei,Yu, Chung-Shan
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p. 563 - 568
(2008/02/10)
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- A simple and efficient synthesis of puromycin, 2,2′-anhydro- pyrimidine nucleosides, cytidines and 2′,3′-anhydroadenosine from 3′,5′-O-sulfinyl xylo-nucleosides
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Synthesis of antibiotics, puromycin and 3 ′-amino-3 ′-deoxy-N 6 ,N 6 -dimethyladenosine 11 was achieved by utilizing the cyclic sulfite 6a of the xylo -3 ′,5 ′-dihydroxy group as a new protective group. The key synthetic step is the deprotection of the sulfite moiety through the intramolecular cyclization of 2-α-carbamate 7 . In a similar manner, 2,2 ′-anhydro-pyrimidine nucleosides 15 , ribo -cytidines 17 and 2 ′,3 ′-anhydroadenosine 14 were prepared in high yields from the corresponding sulfites 4 , 5 , and 6b , respectively. Copyright Taylor & Francis Group, LLC.
- Takatsuki, Ken-Ichi,Ohgushi, Sumito,Kohmoto, Shigeo,Kishikawa, Keiki,Yamamoto, Makoto
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p. 719 - 734
(2007/10/03)
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- Synthesis of 2′-amino-2′-deoxyuridine modified by 1,8-naphthalimide
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A simple and efficient synthetic route of 2′-amino-2′- deoxyuridine was studied. 2′-Amino-2′-deoxyuridine was incorporated into 1,8-naphthalimides in the 2′-position of 2′-sugar via linking arms of different lengths. A convenient method for the synthesis of the conjugates was adopted. Copyright Taylor & Francis Group, LLC.
- Li, Heting,Jiang, Zhiqin,Wang, Xin,Zheng, Chao
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p. 1933 - 1940
(2007/10/03)
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- Chemical Synthesis of Selenium-Modified Oligoribonucleotides and Their Enzymatic Ligation Leading to an U6 SnRNA Stem-Loop Segment
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The derivatization of nucleic acids with selenium is highly promising to facilitate nucleic acids structure determination by X-ray crystallography using the multiwavelength anomalous dispersion (MAD) technique. The foundation for such an approach has been laid by Huang, Egli, and co-workers and was exemplified on small DNA duplexes. Here, we present a comprehensive study on the preparation of RNAs containing 2′-Se-methylpyrimidine nucleoside labels. This includes the synthesis of a novel 2′-Semethylcytidine phosphoramidite 11 and its incorporation into oligoribonucleotides by solid-phase synthesis. Deprotection of the oligonucleotides is achieved in the presence of millimolar amounts of threo-1,4-dimercapto-2,3-butandiol (DTT). With this additive, oxidation products and follow-up side-products are suppressed and acceptable HPLC traces of the crude material are obtained, so far tested for sequences of up to 22-mers. Moreover, an extensive investigation on the enzymatic ligation of the selenium-containing oligoribonucleotides demonstrates the high flexibility of the selenium approach. Our target sequence, an U6 snRNA stem-loop motif comprising all naturally occurring nucleoside modifications beside the Selabel is achieved by ligation using T4 RNA ligase.
- Hoebartner, Claudia,Micura, Ronald
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p. 1141 - 1149
(2007/10/03)
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- 2'-SUBSTITUTED RNA PREPARATION
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A process for the preparation of a compound of formula (1): is provided, which comprises the reaction a compound of formula (2): with a compound of formula Al(OR)3 under substantially anhydrous conditions. X, and X1 are each independently H or a protecting group, B is a base; R is an alkyl, alkoxyalkyl, alkenyl or alkynyl group, each of which may be optionally substituted, and L is a leaving group.
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- Stereodefined synthesis of O3′-labeled uracil nucleosides. 3′-[17O]-2′-azido-2′-deoxyuridine 5′-diphosphate as a probe for the mechanism of inactivation of ribonucleotide reductases
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Thermolysis of a 2′-[16O]-O-benzoyl-[17O]-5′-O-(tert- butyldimethylsilyl)-O2,3′-cyclouridine derivative gave the more stable 3′-[17O]-O-benzoyl-[16O]-5′-O-(tert- butyldimethylsilyl)-O2,2′-cyclouridine isomer, which was converted into 3′-[17O]-2′-azido-2′-deoxyuridine by deprotection and nucleophilic ring opening at C2′ with lithium azide. The 5′-diphosphate was prepared by nucleophilic displacement of the 5′-O-tosyl group with tris(tetrabutylammonium) hydrogen pyrophosphate. Model reactions gave 16O and 18O isotopomers, and base-promoted hydrolysis of an O2,2′-cyclonucleoside gave stereodefined access to 3′-[18O]-1-(β-D-arabinofuranosyl)uracil. Inactivation of ribonucleoside diphosphate reductase with 2′-azido-2′-deoxynucleotides results in appearance of EPR signals for a nitrogen-centered radical derived from azide, and 3′-[17O]-2′-azido-2′-deoxyuridine 5′-diphosphate provides an isotopomer to perturb EPR spectra in a predictable manner.
- Wnuk, Stanislaw F.,Chowdhury, Saiful M.,Garcia Jr., Pedro I.,Robins, Morris J.
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p. 1816 - 1819
(2007/10/03)
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- Design, synthesis and enzymatic activity of highly selective human mitochondrial thymidine kinase inhibitors
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Highly selective arabinofuranosyl nucleosides, which inhibit the mitochondrial thymidine kinase (TK-2) without affecting the closely related herpes simplex virus type 1 thymidine kinase (HSV-1 TK), varicella-zoster virus thymidine kinase (VZV-TK), cytosolic thymidine kinase (TK-1) or the multifunctional Drosophila melanogaster deoxyribonucleoside kinase (Dm-dNK), have been obtained. SAR studies indicate a close relation between the length of the substituent at the 2′ position of the arabinofuranosyl moiety and the inhibitory activity.
- Manfredini, Stefano,Baraldi, Pier G.,Durini, Elisa,Porcu, Luca,Angusti, Angela,Vertuani, Silvia,Solaroli, Nicola,De Clercq, Erik,Karlsson, Anna,Balzarini, Jan
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p. 1329 - 1332
(2007/10/03)
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- Synthesis of oligodeoxyribonucleotide bearing 2'-S-alkyl residue and its effect on the duplex stability
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2'-Deoxy-2'-S-hexyluridine derivative was synthesized from 2,2'- anhydrouridine and 1-hexanethiol and incorporated into an oligodeoxyribonucleotide. The thermal stability of the duplexes formed by the 2'-S-hexyl modified ODN with either the complementary DNA or RNA strand was decreased compared to the unmodified counterparts.
- Ozaki, Hiroaki,Sato, Yuichi,Azuma, Sadaji,Sawai, Hiroaki
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p. 593 - 601
(2007/10/03)
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- Conversion of uridine into 2'-O-(2-methoxyethyl)uridine and 2'-O-(2- methoxyethyl)cytidine
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Reaction between aluminium 2-methoxyethoxide and 2,2'-anhydro-1-β-D- arabinofuranosyluracil 6 gives 2'-O-(2-methoxyethyl)uridine 9 in high yield. Compound 9 is converted into 2'-O-(2-methoxyethyl)cytidine 11 in good yield.
- Legorburu, Urtzi,Reese, Colin B.,Song, Quanlai
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p. 5635 - 5640
(2007/10/03)
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- 2′,3′-Anhydrouridine. A useful synthetic intermediate
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2,2′-Anhydro-1-(β-D-arabinofuranosyl)uracil 1 reacts with sodium hydride in dry DMSO to give 2′,3′-anhydrouridine 2. When the latter compound 2 is heated below its melting point or treated with triethylamine in methanol, it isomerises back to the 2,2′-anhydronucleoside 1. Treatment of compound 1 with sodium ethanethiolate or the sodium salt of benzyl mercaptan in the presence of an excess of the corresponding thiol in DMA gives 2′-S-ethyl-or 2′-S-benzyl-2′-thiouridine (4 or 11) in high yield; however, treatment of the 2,2′-anhydronucleoside 1 first with sodium hydride in DMA and then with a deficiency (with respect to sodium hydride) of ethanethiol or benzyl mercaptan gives the corresponding 3′-S-ethyl or 3′-S-benzyl derivative (3 or 12) in high yield. When the 2,2′-anhydronucleoside 1 is allowed to react with an excess of potassium tert-butoxide in DMSO, the 3′,5′-anhydronucleoside 13 is obtained in good yield. The latter compound 13 undergoes hydrolysis in aqueous trifluoroacetic acid to give 1-(β-D-xylofuranosyl)uracil 14 in high yield. The 3′-S-benzyl derivative 12 is converted by Raney nickel desulfurisation into 3′-deoxyuridine 15 which, in turn, is converted into 3′-deoxycytidine 17 in good yield. X-Ray crystallographic data relating to compounds 11 and 12 are also reported.
- Miah, Anwar,Reese, Colin B.,Song, Quanlai,Sturdy, Zoe,Neidle, Stephen,Simpson, Ian J.,Read, Martin,Rayner, Emma
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p. 3277 - 3283
(2007/10/03)
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- Simple and effective method for the synthesis of 3′,5′-substituted 1-β-D-arabinofuranosyluracil
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3′,5′-Substituted arabinofuranosyluracil is a starting compound in 2′-modifications. A convenient and effective method is proposed for the synthesis of 1-(3′,5′-di-o-trityl-β-D-arabinofuranosyl)uracil by successive reactions of 2,2′-cyclization of uridine, 3′,5′-tritylation of the 2,2′-anhydrouridine, and hydrolytic cleavage of the 2,2′-anhydro bond. 1997 Plenum Publishing Corporation.
- Zablotskaya,Segal,Pedersen
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p. 835 - 837
(2007/10/03)
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- Efficient synthesis of 2'-amino-2'-deoxypyrimidine 5'- triphosphates
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The synthesis of 2'-amino-2'-deoxypyrimidine 5'-triphosphates is described. The 2'-amino-2'-deoxyuridine 5'-triphosphate is obtained from uridine in four steps with 25% overall yield. The 2'-amino-2'-deoxycytidine 5'-triphosphate is obtained from uridine in seven steps with 13% overall yield.
- McGee,Vargeese,Zhai,Kirschenheuter,Settle,Siedem,Pieken
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p. 1329 - 1339
(2007/10/02)
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- A Novel One-step Procedure for the Conversion of Thymidine into 2,3'-Anhydrothymidine
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2,3'-Anhydrothymidine (3) is obtained in ca. 65percent yield by heating thymidine (2) with an excess of diphenyl sulphite in dimethylacetamide solution; (3) reacts with lithium azide to give 3'-azido-3'-deoxythymidine in good yield.
- Rao, T. Sudhakar,Reese, Colin B.
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p. 997 - 998
(2007/10/02)
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- SYNTHESES AND ALKALINE HYDROLYSES OF 2,2'-IMINO- AND 2,2'-(SUBSTITUTED IMINO)-1-(2'-DEOXY-β-D-ARABINOFURANOSYL)URACILS
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In order to examine the possibility of 'up' amination of sugar part of pirimidine nucleosides through pyrimidine N-cyclonucleosides, 2,2'-imino-1-(2'-deoxy-β-D-arabinofuranosyl)uracil (6g) and various N-substituted derivatives of (6g), (6a-f) were synthesized by amination-cyclization reactions of 2'-O-tosyl-2,5-anhydrouridine (5).The latter was synthesized from 2,5'-anhydrouridine (4) by 2',3'-O- dibutylstannylation followed in situ tosylation.N-p-Methoxyphenylisocytidine (7) obtainable from (4) was also cyclized to (6d) by treatment with 1,1'carbonyldi-imidazole. 2,2'-Arylamino analoques (6c,d) were hydrolysed with 2M NaOH-MeOH (1:1) e xtremely rapidly to give 2'-deoxy-2'arylamino uracil-arabinosides (8a,b).The 2',3'-dideoxy-2',3'-(N-phenyl)imino analoque of arabinoside (8a),(9), was used for the purpose of structural corroboration of (8a,b).Similar dehydrative cyclization of (6g) gave the 5',N-anhydro derivative, compound (10), while alkali-treatment gave a fragmentation product, imidazopyrimidin-7(8H)-one (11).Spectroscopic arquments which support structures (6), (10), and (11) are also presented.
- Minamoto, Katsumaro,Azuma, Kishiko,Tanaka, Toshihiro,Iwasaki, Hiroshi,Eguchi, Shoji,et al.
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p. 2955 - 2962
(2007/10/02)
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- 17O NMR of Nucleosides. 3 - Chemical Shifts of Substituted Uridines and Ribothymidines
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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.
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p. 885 - 894
(2007/10/02)
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- Reaction of Uridine and Uridine 5'-Phosphate with Diiminosuccinonitrile and Cyanogen Bromide in Aqueous Solution. Direct Synthesis of the 2,2'-Anhydronucleoside Linkage at 2 deg C
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Reaction of uridine with diiminosuccinonitrile (DISN) at 2 deg C in aqueous solution yields 2,2'-anhydrouridine 3-carbamate (7) (54percent) along with 2,2'-anhydrouridine (8) (10percent), arabinofuranosyluracil (9) (9percent), uridine 2',3'-carbonate (10) (5percent), uridine 2'-carbamate (11) (3percent), and uridine 3'-carbamate (12) (9percent).A similar distribution of reaction products was obtained when BrCN was used in place of DISN.The same reaction products were isolated from the reaction of DISN or BrCN with uridine 5'-phosphate after the phosphate grouping was cleaved from the initial reaction product mixture with alkaline phosphatase.A reaction pathway is proposed in which the imidocarbonate derivative 6 is a common intermediate for product formation.The vicinal 2',3'-hydroxyl groups are essential for reaction as shown by the failure to form stable reaction products with thymidine (17).Adenosine (13), which has vicinal 2',3'-hydroxyl groups, is converted to a mixture of the 2'- and 3'-carbamates (15 and 16) via an imidocarbonate (14) intermediate with DISN or BrCN.The relevance of these studies to chemical evolution is discussed.
- Ferris, J. P.,Yanagawa, H
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p. 2121 - 2125
(2007/10/02)
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- Syntheses of 1-(β-D-Arabinofuranosyl)-pyrimidines
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New synthetic methods of 1-(β-D-arabinofuranosyl)-pyrimidines are described. 1-(β-D-arabinofuranosyl)-uracil, 1-(β-D-arabinofuranosyl)-5-fluorouracil, 1-(β-D-arabinofuranosyl)-thymine, and 1-(β-D-arabinofuranosyl)-cytosine can be obtained in a high yield by the splitting of the anhydrobond in 2,2'-anhydropyrimidines in dipolar aprotic solvents, such as HMPT, DMF, and DMSO, respectively, in the presence of activated elemental copper.Unlike the formation of cyclopyrimidines ribonucleosides are directly transformed to the corresponding arabinofuranosyl derivatives by the reaction with diphenylcarbonate and NaHCO3 in the presence of copper.The reaction proceeds probably via an intermediate formation of the cycloproduct.Further aspects on the mechanism are described.
- Cech, D.,Schwarz, B.,Pein, C. D.
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p. 387 - 392
(2007/10/02)
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- 4-(1,2,4-Triazol-1-yl)- and 4-(3-Nitro-1,2,4-triazol-1-yl)-1-(β-D-2,3,5-tri-O-acetylarabinofuranosyl)pyrimidin-2(1H)-ones. Valuable Intermediates in the Synthesis of Derivatives of 1-(β-D-Arabinofuranosyl)cytosine (Ara-C)
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Treatment of the acetylated derivative (3b), which was prepared from uridine in 86 percent overall yield, with tri(1H-1,2,4-triazol-1-yl)phosphine oxide gave compound (6a) in high yield, and with 3-nitro-1,2,4-triazole and diphenyl phosphorochloridate it gave compound (6b) in high yield.When the former product (6a) was allowed to react with ammonia, methylamine, dimethylamine, and morpholine at room temperature, and the products further deacetylated if necessary, ara-C (1; R1=R2=H) and its corresponding 4-N-alkyl derivatives (1; R1=H, R2=Me), (1: R1=R2=Me), and 1,R2= -(CH2)2O(CH2)2-> were obtained in very high yields. 4-N-Phenyl-ara-C (1; R1=H, R2=Ph) was obtained in high yield when compound (6a) or (6b) was heated with aniline in pyridine solution and the products then deacetylated.The nitro-compound (6b) was converted into the ara-C derivative (1; R1=H, R2=CH2CO2Me), and the sulphide (7) was obtained following the deacetylation of the products of the reaction between the 1,2,4-triazolyl derivative (6a), toluene-p-thiol, and triethylamine.
- Divakar, K.J.,Reese, Colin B.
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p. 1171 - 1176
(2007/10/02)
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