- Design, synthesis, and biological evaluation of novel C5-modified pyrimidine ribofuranonucleosides as potential antitumor or/and antiviral agents
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Background: Nucleoside analogues are well-known antitumor, antiviral, and chemotherapeutic agents. Alterations on both their sugar and the heterocyclic parts may lead to significant changes in the spectrum of their biological activity and the degree of selective toxicity, as well as in their physicochemical properties. Method: C5-arylalkynyl-β-D-ribofuranonucleosides 3-6, 3?-deoxy 12-15, 3?-deoxy-3?-C-methyl-β-D-ribofurananucleosides 18-21 and 2?-deoxy-β-D-ribofuranonucleosides 23-26 of uracil, were synthesized using a one-step Sonogashira reaction under microwave irradiation and subsequent deprotection. Results: All newly synthesized nucleosides were tested for their antitumor or antiviral activity. Moderate cytostatic activity against cervix carcinoma (HeLa), murine leukemia (L1210) and human lymphocyte (CEM) tumor cell lines was displayed by the protected 3?-deoxy derivatives 12b, 12c, 12d, and the 3?-deoxy-3?-methyl 18a, 18b, 18c. The antiviral evaluation revealed appreciable activity against Coxsackie virus B4, Respiratory syncytial virus, Yellow Fever Virus and Human Coronavirus (229E) for the 3?-deoxy compounds 12b, 14, and the 3?-deoxy-3?-methyl 18a, 18c, 18d, accompanied by low cytotoxicity. Conclusion: This report describes the total and facile synthesis of modified furanononucleosides of uracil, with alterations on both the sugar and the heterocyclic portions. Compounds 12b, 14 and 18a,c,d showed noticeable antiviral activity against a series of RNA viruses and merit further biological and structural optimization investigations.
- Alexouli, Tania,Andrei, Graciela,Giannakas, Christos,Kollatos, Nikolaos,Komiotis, Dimitri,Manta, Stella,Mitsos, Christos,Panagiotopoulou, Aggeliki,Schols, Dominique,Tzioumaki, Niki
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p. 368 - 384
(2020/04/17)
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- Visibly Emitting Thiazolyl-Uridine Analogues as Promising Fluorescent Probes
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Microenvironment-sensitive fluorescent (ESF) nucleosides are powerful tools for nucleic acid research. The new 5-substituted uridine analogues are synthesized, which comprise a 4H-cyclopenta[d]thiazole ring obtained by the Hantzsch synthesis reaction of 5-thioamide-uridine with aromatic α-bromocarbonyl compounds. The emission maximum of new compounds is in the visible region. They exhibit strong solvent- A nd pH-dependent fluorescent properties, indicating their promising ability to be fluorescent probes.
- Li, Jinsi,Fang, Xuerong,Ming, Xin
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p. 4602 - 4610
(2020/05/01)
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- Stereoselective Synthesis of Highly Functionalized Arabinosyl Nucleosides through Application of an N-Nitro Protecting Group
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2′-Deoxy-2′,5-disubstituted arabinosyl uridine derivatives bearing a halogen (Cl, Br or I) at C2′ and an ethynyl group at C5 have been synthesized in 6 steps from 2′,3′,5′-tri-O-acetyl-5-iodo-uridine in overall yields of 61% (compound 3, Cl), 47% (compound 4, Br), and 19% (compound 5, I). Stabilization of a 2′-O-triflyl leaving group intermediate to overcome spontaneous intramolecular 2,2′-anhydro uridine formation was pivotal to the synthesis. Specifically, to favor SN2 reaction with a halogen nucleophile over intramolecular cyclization, the nucleophilicity of O-2 oxygen was reduced by incorporation of an adjacent electron withdrawing nitro substituent at N-3. The introduction of the 3-N-nitro group proceeded rapidly (nitronium trifluoroacetate, 1 min) and in quantitative yield. A one-pot method to remove the 3-N-nitro group by reductive nitration (zinc metal in acetic acid, 5 min) and the silyl protecting groups of the alkyne and 3′,5′ hydroxyls (fluoride reagent, 16 h) was established as the final synthetic step. This application of the 3-N-nitro protecting group addresses the significant shortfalls of the conventional approach to synthesis of 2′ modified nucleosides, wherein condensation of a 2′ modified sugar fragment with a pyrimidine base provides poor stereocontrol of N-glycosylation, low yields and incompatibility with 2′ iodo sugars.
- Hilko, David H.,Bornaghi, Laurent F.,Poulsen, Sally-Ann
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p. 11944 - 11955
(2018/09/25)
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- A solid-supported acidic oxazolium perchlorate as an easy-handling catalyst for the synthesis of modified pyrimidine nucleosides via Vorbrüggen-type N-glycosylation
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A solid-supported acidic oxazolium perchlorate was investigated as a heterogeneous catalyst in N-glycosylation reactions using silylated modified pyrimidines and an acylated ribose or glucose to afford the corresponding pyrimidine nucleosides. This salt is a nonhygroscopic and stable powder whose activity is comparable to that of 2-methyl-5-phenylbenzoxazolium perchlorate. A reaction with this polymer catalyst can be conducted on a gram scale. Reusability of the solid-supported catalyst was also investigated.
- Basu, Nabamita,Oyama, Kin-ichi,Tsukamoto, Masaki
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supporting information
p. 1921 - 1924
(2017/04/27)
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- Synthesis of 4-thio-5-(2′′-thienyl)uridine and cytotoxicity activity against colon cancer cells: In vitro
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A novel anti-tumor agent 4-thio-5-(2′′-thienyl)uridine (6) was synthesized and the in vitro cytotoxicity activity against mice colon cancer cells (MC-38) and human colon cancer cells (HT-29) was evaluated by MTT assay. The results showed that the novel compound had antiproliferative activity toward MC-38 and HT-29 cells in a dose-dependent manner. The cell cycle analysis by flow cytometry indicated that compound 6 exerted in tumor cell proliferation inhibition by arresting HT-29 cells in the G2/M phase. In addition, cell death detected by propidium iodide staining showed that compound 6 efficiently induced cell apoptosis in a concentration-dependent manner. Moreover, the sensitivity of human fibroblast cells to compound 6 was far lower than that of tumor cells, suggesting the specific anti-tumor effect of 4-thio-5-(2′′-thienyl)uridine. Taken together, novel compound 6 effectively inhibits colon cancer cell proliferation, and hence would have potential value in clinical application as an antitumor agent.
- Zhang, Xiaohui,Li, Depeng,Qin, Jianzhong,Xu, Yaozhong,Ma, Kedong
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p. 70099 - 70105
(2016/08/05)
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- NMR studies on 4-thio-5-furan-modified and 4-thio-5-thiophene-modified nucleosides
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Systematic NMR characterization of 4-thio-5-furan-pyrimidine nucleosides or 4-thio-5-thiophene-pyrimidine nucleosides (ribonucleosides and 2′-deoxynucleosides) was performed. All proton and carbon signals of 4-thio-5-thiophene-ribouridine and related analogues were unambiguously assigned. The orientations of the base (4-thiouridine or its deoxy analogue) relative to the ring (furan or thiophene) are explored by a NMR approach and further supported by X-ray crystallographic studies. The procedures presented here would be applicable to other modified nucleosides and nucleotides. Copyright
- Zhang, Xiao-Hui,Xu, Yao-Zhong
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p. 887 - 892
(2016/10/24)
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- NEW PRODUCTION METHOD FOR PYRIMIDINE NUCLEOSIDE DERIVATIVES
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PROBLEM TO BE SOLVED: To provide a method for producing pyrimidine nucleoside derivatives with excellent handleability. SOLUTION: A glycosyl donor of which OH groups at positions 1 and 2 are acylated and other OH groups are protected and a silylated pyrimidine derivative are reacted in the presence of an acid azole/pyridine conjugate of the following general formula (1) or (2) and a solvent. Acid azole/pyridine conjugate is excellent in handleability because it has no or low hygroscopicity. In the formula (1), A is -O- or -S-, in the formulae (1) and (2), R1-R8 are hydrocarbon groups which may be substituted, R1-R8 may form a ring by binding to other R1-R8, the acid azole/pyridine conjugate may comprise plurality of formula (1) and/or formula (2) as partial structures. Further, it may be bonded to a carrier via R1-R8. COPYRIGHT: (C)2015,JPO&INPIT
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Paragraph 0043; 0061
(2018/10/31)
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- Fluorescent nucleoside derivatives as a tool for the detection of concentrative nucleoside transporter activity using confocal microscopy and flow cytometry
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The abundance and function of transporter proteins at the plasma membrane are likely to be crucial in drug responsiveness. Functional detection of human concentrative nucleoside transporters (hCNTs) is of interest for predicting drug sensitivity because of their ability to transport most nucleoside-derived drugs. In the present study, two fluorescent nucleoside analogues, uridine-furan and etheno-cytidine, were evaluated as tools to study in vivo nucleoside transporter-related functions. These two molecules showed high affinity interactions with hCNT1 and hCNT3 and were shown to be substrates of both transporters. Both fluorescence microscopy and flow cytometry experiments showed that uridine-furan uptake was better suited for distinguishing cells that express hCNT1 or hCNT3. These data highlight the usefulness of fluorescent nucleoside derivatives, as long as they fulfill the requirements of confocal microscopy and flow cytometry, for in vivo analysis of hCNT-related function.
- Claudio-Montero, Ana,Pinilla-Macua, Itziar,Fernández-Calotti, Paula,Sancho-Mateo, Carlos,Lostao, Mar?a Pilar,Colomer, Dolors,Grandas, Anna,Pastor-Anglada, Mar?al
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p. 2158 - 2166
(2015/06/16)
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- Synthesis of modified pyrimidine nucleosides via Vorbrüggen-type N-glycosylation catalyzed by 2-methyl-5-phenylbenzoxazolium perchlorate
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Several acidic azolium salts prepared from oxazole, thiazole, and imidazole derivatives were investigated as catalysts in N-glycosylation reaction using a silylated modified pyrimidine and an acylated ribose or glucose to afford the corresponding pyrimidine nucleoside. Among the salts, 2-methyl-5- phenylbenzoxazolium perchlorate showed the highest catalytic activity. This salt is a nonhygroscopic crystalline compound that shows higher activity than the frequently used trimethylsilyl triflate. Reactions with this salt can be conducted in gram scales.
- Shirouzu, Hiroshi,Morita, Hiroki,Tsukamoto, Masaki
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supporting information
p. 3635 - 3639
(2014/05/20)
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- Synthesis and fluorescence properties of a full set of extended RNA base analogues
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The synthesis and photophysical characterization of a complete set of fluorescent RNA base analogues derived by conjugating benzofuran moiety at the 5- and 8-positions of pyrimidine and purine bases, respectively, are described. Benzofuran-modified pyrimidine and purine ribonucleoside analogues exhibit contrasting fluorescence properties. Pyrimidine analogues are moderately emissive with emission maximum in the visible region, and importantly, are highly sensitive to solvent polarity and viscosity changes. On the other hand, purine analogues are highly emissive and are minimally affected by solvation and viscosity effects. Thorough photophysical analysis reveals that the pyrimidine and purine ribonucleosides displaying distinct and probe-like fluorescence properties could be useful in designing nucleic acid based biophysical tools to study nucleic acid structure and function.
- Sabale, Pramod M,Nuthanakanti, Ashok,Srivatsan, Seergazhi G
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p. 1004 - 1013
(2013/09/12)
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- Systematic assignment of NMR spectra of 5-substituted-4-thiopyrimidine nucleosides
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Unambiguous characterization of 5-substituted-4-thiopyrimidine nucleosides (ribonucleosides and 2'-deoxynucleosides) was performed using NMR spectroscopy. Assignments of all proton and carbon signals of 5-bromo-4-thiouridine and related nucleosides were systematically carried out and firmly established by COSY and HMQC techniques. The NMR data of various 4-thiopyrimidine nucleosides are compared, and the key contributing factors discussed. The approach presented here is applicable to other modified nucleosides and nucleotides, as well as nucleobases. Copyright
- Zhang, Xiaohui,Wang, Jian,Xu, Yao-Zhong
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p. 523 - 529
(2013/09/02)
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- A chemo-enzymatic approach to specifically click-modified RNA
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The growing interest in single-molecule analysis of RNA calls for programmable enzymatic labeling strategies beyond the horizon of solid-phase synthesized RNAs. Herein we describe an easy and versatile chemo-enzymatic approach to label RNA at its termini or defined internal positions via click-chemistry.
- Dojahn, Claudine M.,Hesse, Marlen,Arenz, Christoph
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p. 3128 - 3130
(2013/06/05)
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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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scheme or table
p. 35 - 43
(2012/07/28)
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- Design, synthesis, and spectroscopic properties of extended and fused pyrrolo-dC and pyrrolo-C analogs
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The syntheses of four fluorescent nucleoside analogs, related to pyrrolo-C (PyC) and pyrrolo-dC (PydC) through the conjugation or fusion of a thiophene moiety, are described. A thorough photophysical analysis of the nucleosides, in comparison to PyC, is reported.
- Noé, Mary S.,Ríos, Andro C.,Tor, Yitzhak
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scheme or table
p. 3150 - 3153
(2012/09/22)
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- 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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experimental part
p. 821 - 834
(2010/08/20)
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- Water gelation abilities of alkylbenzyltriazole-appended 2′-deoxyribonucleoside and ribonucleoside
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Effective hydrogelators based on alkylbenzyltriazole-appended 2′-deoxyribonucleioside and ribonucleoside nucleobase-modified uridine were prepared and the dependence of gelation properties on the nature of single hydroxyl group was investigated. The nucleosides were synthesized by modifying the position of the uracin base with alkylbenzyltriazole units. The small molecular-based gelators of organic and aqueous solvents were prepared from amino acids, bis-ureas, sugars, nucleic acid, and steroids. It was found that the balance between the hydrophilic and hydrophobic characteristics and the nature of the gelators' interactions proved to be an important factors for the small molecular hydrogelators. It was also found that the uridine-based hydrogelators exhibited gelation behavior different to that of corresponding 2-deoxyuridine based systems. The results show that they possess relatively higher minimum gelation concentrations (MGC).
- Park, Sun Min,Shen, Yongcun,Kim, Byeang Hyean
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p. 610 - 612
(2008/03/14)
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- Synthesis of 5-haloethynyl- and 5-(1,2-dihalo)vinyluracil nucleosides: Antiviral activity and cellular toxicity
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In this article, we report the synthesis of hitherto unknown 5-haloethynyl and 5-(1,2-dihalo)vinyluracil nucleosides in the 2′-deoxy, 3′-deoxy- and ribosyl series, and we discuss their in vitro anti-HIV and anti-HCV activities and cellular toxicitites. As a result, on the basis of their selectivity index (SI) obtained with the HCV replicon system, but also on their cytotoxicity on peripheral blood mononuclear, CEM and VERO cell lines, the best compounds were the 5-bromoethynyluridine (SI = 3.2) and the 5-(1-chloro-2-iodo) vinyluridine (SI > 2.8).
- Escuret, Vanessa,Aucagne, Vincent,Joubert, Nicolas,Durantel, David,Rapp, Kimberly L.,Schinazi, Raymond F.,Zoulim, Fabien,Agrofoglio, Luigi A.
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p. 6015 - 6024
(2007/10/03)
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- No-carrier added synthesis of 18F-labelled nucleosides using Stille cross-coupling reactions with 4-[18F]fluoroiodobenzene
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The radiosyntheses of 5-(4′-[18F]fluorophenyl)-uridine [18F]-11 and 5-(4′-[18F]fluorophenyl)-2′- deoxy-uridine [18F]-12 are described. The 5-(4′-[ 18F]fluoro-phenyl)-substituted nucleosides were prepared via a Stille cross-coupling reaction with 4-[18F]fluoroiodobenzene followed by basic hydrolysis using 1M potassium hydroxide. The Stille cross-coupling reaction was optimized by screening various palladium complexes, additives and solvents. By using optimized labelling conditions (Pd2(dba) 3/CuI/AsPh3 in DMF/dioxane (1:1), 20min at 65°C), 550MBq of [4-18F]fluoroiodobenzene could be converted into 120MBq (33%, decay-corrected) of 5-(4′-[18F]fluorophenyl)-2′- deoxy-uridine [18F]-12 within 40min, including HPLC purification.
- Wuest, Frank R.,Kniess, Torsten
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p. 457 - 468
(2007/10/03)
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- A mild and effective iodination method using iodine in the presence of bis-(trifluoroacetoxy)iodobenzene
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Herein is described a mild and effective iodination method using bis(trifluoroacetoxy)iodobenzene iodine as reagent to be applied to electron deficient heterocyclic systems (protected indoles coumarin...). Moreover, sensitive protecting groups such as acetyl and tert butyldimethylsilyl were found to be stable under the new iodination reaction conditions.
- Benhida, Rachid,Blanchard, Pierre,Fourrey, Jean-Louis
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p. 6849 - 6852
(2007/10/03)
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- Pharmaceutical compositions of 5-substituted uracil compounds
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Pharmaceutical compositions containing 5-substituted uracil compounds are disclosed. The compositions are preferably in the form of a tablet or capsule.
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- Synthesis and properties of conformationally rigid cyclouridylic acids having covalent bonding linkers between the uracil 5-position and the 5′-phosphate group
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Conformationally rigid cyclouridylic acid derivatives 2 and 3 having ethylene and propylene bridges, respectively, between the uracil 5-position and the 5′-phosphate group were synthesized. These intramolecularly cyclized compounds have predominantly the ribose pucker of C3′-endo and the g+ orientation around the C4′-C5′ bond. Copyright
- Seio, Kohji,Kurasawa, Osamu,Wada, Takeshi,Sakamoto, Kensaku,Yokoyama, Shigeyuki,Sekine
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p. 1023 - 1032
(2007/10/03)
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- Synthesis and properties of conformationally rigid cyclouridylic acid having a covalent bonding linker between the uracil 5-position and the 5 phosphate group
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A novel cyclouridylic acid 1 having a propylene bridge between the uracil 5 position and the 5′-phosphate group was synthesized. The structure of 1 was analyzed by 1H NMR, and CD spectroscopy, which suggested that the cyclonucleotide 1 was highly stabilized in a considerably rigid g′/C3′-endo conformation with the base orientation of and. The molecular mechanics calculation of 1 gave a similar conclusion.
- Scio, Kohji,Wada, Takeshi,Sakamoto, Kensaku,Yokoyama, Shigeyuki,Sekine, Mitsuo
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p. 9515 - 9518
(2007/10/02)
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- In-cell Indirect Electrochemical Halogenation of Pyrimidine Bases and their Nucleosides to 5-Haloderivatives
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Reaction of anodically generated "halonium" species (LiX or Bu4NX, LiClO4, MeCN, Pt/Pt; I2, LiClO4, MeCN) with pyrimidine bases and their nucleosides leads to 5-halo compounds in good yields.
- Palmisano, G.,Danieli, B.,Santagostino, M.,Vodopivec, B.,Fiori, G.
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p. 7779 - 7782
(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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- 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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p. 4928 - 4933
(2007/10/02)
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