- Synthesis and Antiviral Activity of 5-Thien-2-yl-2'-deoxyuridine Analogues
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A number of 5-heteroaromatic-substituted 2'-deoxyuridines were synthesized from 5-iodo-2'-deoxyuridine using tetraorganotin reagents and palladium complexes as catalyst.The palladium-catalyzed cross-coupling reaction between 5-iodo-2'-deoxyuridine and stannylated heteroaromatics was optimized for the synthesis of the 5-thien-3-yl-2'-deoxyuridine and 5-furan-3-yl-2'-deoxyuridine. 5-(5-Iodothien-2-yl)-2'-deoxyuridine was used as starting material for the synthesis of 5-(5-methylthien-2-yl)-2'-deoxyuridine, 5-(5-vinylthien-2-yl)-2'-deoxyuridine, and 5-(5-ethynylthien-2-yl)-2'-deoxyuridine. 5-(5-Nitrothien-2-yl)-2'-deoxyuridine was synthesized using ceric ammonium nitrate as reagent. 5-(Isoxazol-5-yl)-2'-deoxyuridine was synthesized from 5-(3-oxopropyn-1-yl)-2'-deoxyuridine.Finally, 5-(5-chlorothien-2-yl)-β-D-arabinofuranosyluracil and 5-(5-bromothien-2-yl)-β-D-arabinofuranosyluracil were obtained by halogenation of 5-thien-2-yl-β-D-arabinofuranosyluracil.Introduction of an alkyl substitutent in the 5-position of the thienyl group of 5-thien-2-yl-2'-deoxyuridine or substitution of the 2-deoxyribofuranose ring by an arabinofuranose moiety gave decreased activity against HSV-1 and VZV replication when compared with the 5''-halogenated-5-thien-2-yl-2'-deoxyuridines. 5-(5-Bromothien-2-yl)-2'-deoxyuridine caused prompt healing of HSV-1 keratitis when administered as eye drops (0.2percent) to rabbits.
- Wigerinck, Piet,Kerremans, Luc,Claes, Paul,Snoeck, Robert,Maudgal, Prabhat,et al.
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- NMR conformational analysis of p-tolyl furanopyrimidine 2′-deoxyribonucleoside and crystal structure of its 3′,5′-di- O-acetyl derivative
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The conformation of a representative molecule of a new, potent class of antiviral-active modified nucleosides is determined. A bicyclic nucleoside, 3-(2′-deoxy-β-d-ribofuranosyl)-6-(4-methylphenyl)-2,3-dihydrofuro[2, 3-d]pyrimidin-2-one, shows C2′-endo and C3′-endo ribose conformations in solution (63:37, 37°C; DMSO-d6), as determined by 1H NMR studies. The crystal structure of a 3′,5′-di-O- acetyl-protected derivative (monoclinic, P21, a/b/c = 6.666(1)/12.225(1)/24.676(2) A, β = 90.24(1)°, Z = 4) shows exclusively C2′-endo deoxyribose puckering. The base is found in the anti position both in solution and in crystalline form.
- Esho, Noor,Desaulniers, Jean-Paul,Davies, Brian,Chui, Helen M.-P.,Rao, Meneni Srinivasa,Chow, Christine S.,Szafert, Slawomir,Dembinski, Roman
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- Radiosynthesis of the anticancer nucleoside analogue Trifluridine using an automated 18F-trifluoromethylation procedure
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Trifluoromethyl groups are widespread in medicinal chemistry, yet there are limited 18F-radiochemistry techniques available for the production of the complementary PET agents. Herein, we report the first radiosynthesis of the anticancer nucleoside analogue trifluridine, using a fully automated, clinically-applicable 18F-trifluoromethylation procedure. [18F]Trifluridine was obtained after two synthetic steps in 99%, and a molar activity of 0.4 GBq μmol-1 ± 0.05. Biodistribution and PET-imaging data using HCT116 tumour-bearing mice showed a 2.5 %ID g-1 tumour uptake of [18F]trifluridine at 60 minutes post-injection, with bone uptake becoming a prominent feature thereafter. In vivo metabolite analysis of selected tissues revealed the presence of the original radiolabelled nucleoside analogue, together with deglycosylated and phosphorylated [18F]trifluridine as the main metabolites. Our findings suggest a potential role for [18F]trifluridine as a PET radiotracer for elucidation of drug mechanism of action.
- King, Alice,Doepner, Andreas,Turton, David,Ciobota, Daniela M.,Da Pieve, Chiara,Wong Te Fong, Anne-Christine,Kramer-Marek, Gabriela,Chung, Yuen-Li,Smith, Graham
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- 5-Iodo-4-thio-2′-deoxyuridine: Synthesis, structure, and cytotoxic activity
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The novel nucleoside 5-iodo-4-thio-2′-deoxyuridine (4) was synthesized and fully characterized by IR, NMR, and MS. Its structure was determined by single-crystal X-ray diffraction. Compound 4 absorbs strongly at 346 nm and is minimally toxic to human tumour cells, but its cytotoxicity is substantially enhanced by low dose UVA radiation. The combined use of 4 and UVA offers a promising route to selectively and effectively kill proliferating cells.
- Zhang, Xiao-Hui,Yin, Hong-Yan,Trigiante, Giuseppe,Brem, Reto,Karran, Peter,Pitak, Mateusz B.,Coles, Simon J.,Xu, Yao-Zhong
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- Synthesis of C-5 substituted nucleosides via palladium-catalyzed coupling of dienes and amines
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The palladium-catalyzed coupling of C-5 iodopyrimidine nucleosides; 1,2-, 1,3-, or 1,ω-dienes; and amines provides a novel and efficient method for the preparation of a wide variety of C-5 aminoalkyl-substituted nucleosides. Adding certain Lewis acids, particularly zinc salts, improves the yields significantly. Secondary amines are the most effective amines for this process. Acyclic and cyclic dienes have been successfully employed. Protection of the 3′- and 5′-hydroxyl groups of iodouridine is required in order to obtain good yields when the coupling process is carried out on 1,3-dienes or long chain or branched non-conjugated dienes.
- Larock, Richard C.,Wang, Yao,Dong, Xiaoyang,Yao, Tuanli
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- Design, synthesis, and anticancer activities of novel perfluoroalkyltriazole-appended 2′-deoxyuridines
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We have focused on the C5-modification of 2′-deoxyuridine with substituted heterocycles for bioactivity, such as antiviral or anticancer activity. Herein, we report a novel class of nucleoside analogues with perfluoroalkyltriazole moiety as an anticancer drug candidate.
- Park, Sun Min,Yang, Heeju,Park, Song-Kyu,Kim, Hwan Mook,Kim, Byeang Hyean
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- Synthesis of carbohydrate-conjugated furo[2,3-d]pyrimidine by 'Click Chemistry'
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Compounds belonging to a new type of furo[2,3-d]pyrimidine nucleoside conjugated with carbohydrate were synthesized by Sonogashira coupling and 'click chemistry'. Their structures were confirmed on the basis of various types of spectroscopy. Georg Thieme Verlag Stuttgart.
- Jin, Xuanye,Ding, Haixin,Yang, Ruchun,Xiao, Qiang,Ju, Yong
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- Synthesis and properties of oligonucleotides containing a cholesterol thymidine monomer
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Highly selective base-pair recognition makes DNA a suitable building block for orderly self-assembled structures. For some applications in nanotechnology DNA complexes need to be fixed onto surfaces. To fulfil this requirement on lipid membranes we have synthesised a thymidine monomer modified with a cholesterol moiety. Solution studies show that the melting temperature (Tm) of the duplex, with adjacent cholesterols on each strand, is much higher than that of the unmodified duplex. Copyright Taylor & Francis Group, LLC.
- Durand, Adeline,Brown, Tom
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- Mechanism-based inactivation of thymidylate synthase by 5-(3-fluoropropyn-1-yl)-2'-deoxyuridine 5'-phosphate
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5-Fluoropropynyl-2'-deoxyuridine 5'-phosphate (3) was designed as a mechanism-based inactivator of thymidylate synthase (TS). The inhibitor was synthesized from 5-iodo-2'-deoxyuridine and propargyl alcohol by palladium-catalyzed coupling, followed by fluorination and selective phosphorylation. Incubation of TS with 3, in the presence or absence of the CH2H4folate cofactor, caused rapid, irreversible inactivation of the enzyme. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Kalman, Thomas I.,Nie, Zhe,Kamat, Ashwini
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- Multicolor live-cell chemical imaging by isotopically edited alkyne vibrational palette
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Vibrational imaging such as Raman microscopy is a powerful technique for visualizing a variety of molecules in live cells and tissues with chemical contrast. Going beyond the conventional label-free modality, recent advance of coupling alkyne vibrational tags with stimulated Raman scattering microscopy paves the way for imaging a wide spectrum of alkyne-labeled small biomolecules with superb sensitivity, specificity, resolution, biocompatibility, and minimal perturbation. Unfortunately, the currently available alkyne tag only processes a single vibrational "color", which prohibits multiplex chemical imaging of small molecules in a way that is being routinely practiced in fluorescence microscopy. Herein we develop a three-color vibrational palette of alkyne tags using a 13C-based isotopic editing strategy. We first synthesized 13C isotopologues of EdU, a DNA metabolic reporter, by using the newly developed alkyne cross-metathesis reaction. Consistent with theoretical predictions, the mono-13C (13C≡ 12C) and bis-13C (13C≡13C) labeled alkyne isotopologues display Raman peaks that are red-shifted and spectrally resolved from the originally unlabeled (12C≡ 12C) alkynyl probe. We further demonstrated three-color chemical imaging of nascent DNA, RNA, and newly uptaken fatty-acid in live mammalian cells with a simultaneous treatment of three different isotopically edited alkynyl metabolic reporters. The alkyne vibrational palette presented here thus opens up multicolor imaging of small biomolecules, enlightening a new dimension of chemical imaging.
- Chen, Zhixing,Paley, Daniel W.,Wei, Lu,Weisman, Andrew L.,Friesner, Richard A.,Nuckolls, Colin,Min, Wei
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- Extension of furopyrimidine nucleosides with 5-alkynyl substituent: Synthesis, high fluorescence, and antiviral effect in the absence of free ribose hydroxyl groups
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A novel methodology to access alkynyl nucleoside analogues is elaborated. Highly fluorescent 5-alkynylfuropyrimidines were synthesized (97-46%) and their antiviral properties investigated in vitro. Regiochemistry of the functionalization was achieved with the aid of 5-endo-dig electrophilic halocyclization of acetyl 5-p-tolyl- or 5-p-pentylphenyl-2′-deoxyuridine. Structure of one of the resulting nucleosides, 6-p-tolyl-5-iodo-2′-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one, was confirmed by X-ray crystallography, and its conformation was compared to related nucleosides. Diverse alkynyl substituents were introduced at the heterobicyclic base C-5 position via Sonogashira coupling of 5-iodo-2′-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-ones. The resulting compounds had fluorescence emissions of 452–481 nm. High quantum yields of 0.53–0.60 were observed for 9-ethynyl-9-fluorenol and propargyl alcohol/methyl ether-modified furopyrimidines. These modified nucleosides, designed in the form of ribose acetyl esters, are potential tools for fluorescent tagging, studying nucleoside metabolism, 2′-deoxyribonucleoside kinase activity, and antiviral activity. Antiviral assays against a broad spectrum of DNA and RNA viruses showed that in human embryonic lung (HEL) cell cultures some of the compounds showed antiviral activity (EC50 1.3–13.2 μM) against varicella-zoster virus (VZV). The alkynyl furopyrimidine with two p-pentylphenyl substituents emerged as the best compound with reasonable and selective anti-VZV activity, confirming p-pentylphenyl potency as a pharmacophore.
- Kaczmarek, Renata,Twardy, Dylan J.,Olson, Trevor L.,Korczyński, Dariusz,Andrei, Graciela,Snoeck, Robert,Dolot, Rafa?,Wheeler, Kraig A.,Dembinski, Roman
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supporting information
(2020/10/13)
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- 5-iodo-4-thio-2′-deoxyuridine as a sensitizer of X-ray induced cancer cell killing
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Nucleosides, especially pyrimidines modified in the C5-position, can act as radiosensitizers via a mechanism that involves their enzymatic triphosphorylation, incorporation into DNA, and a subsequent dissociative electron attachment (DEA) process. In this paper, we report 5-iodo-4-thio-2′-deoxyuridine (ISdU) as a compound that can effectively lead to ionizing radiation (IR)-induced cellular death, which is proven by a clonogenic assay. The test revealed that the survival of cells, pre-treated with 10 or 100 μM solution of ISdU and exposed to 0.5 Gy of IR, was reduced from 78.4% (for non-treated culture) to 67.7% and to 59.8%, respectively. For a somewhat higher dose of 1 Gy, the surviving fraction was reduced from 68.2% to 54.9% and to 40.8% for incubation with 10 or 100 μM ISdU, respectively. The cytometric analysis of histone H2A.X phosphorylation showed that the radiosensitizing effect of ISdU was associated, at least in part, with the formation of double-strand breaks. Moreover, the cytotoxic test against the MCF-7 breast cancer cell line and human dermal fibroblasts (HDFa line) confirmed low cytotoxic activity of ISdU. Based on the results of steady state radiolysis of ISdU with a dose of 140 Gy and quantum chemical calculations explaining the origin of the MS detected radioproducts, the molecular mechanism of sensitization by ISdU was proposed. In conclusion, we found ISdU to be a potential radiosensitizer that could improve anticancer radiotherapy.
- Makurat, Samanta,Spisz, Paulina,Kozak, Witold,Rak, Janusz,Zdrowowicz, Magdalena
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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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- Development of ethynyl-2′-deoxyuridine chemical probes for cell proliferation
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A common method of evaluating cellular proliferation is to label DNA with chemical probes. 5-Ethynyl-2′-deoxyuridine (EdU) is a widely utilized chemical probe for labeling DNA, and upon incorporation, EdU treatment of cells is followed by a reaction with a small molecule fluorescent azide to allow detection. The limitations when using EdU include cytotoxicity and a reliance on nucleoside active transport mechanisms for entry into cells. Here we have developed six novel EdU pro-labels that consist of EdU modified with variable lipophilic acyl ester moieties. This pro-label:chemical probe relationship parallels the prodrug:drug relationship that is employed widely in medicinal chemistry. EdU and EdU pro-labels were evaluated for their labeling efficacy and cytotoxicity. Several EdU pro-label analogues incorporate into DNA at a similar level to EdU, suggesting that nucleoside transporters can be bypassed by the pro-labels. These EdU pro-labels also had reduced toxicity compared to EdU.
- Lovitt, Carrie J.,Hilko, David H.,Avery, Vicky M.,Poulsen, Sally-Ann
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p. 4272 - 4280
(2016/08/23)
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- Development of environmentally sensitive fluorescent and dual emissive deoxyuridine analogues
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Ratiometric and environment-sensitive fluorescent dyes present attractive advantages for sensing interactions in DNA research. Here, we report the rational design, synthesis, and photophysical characterization of 2-thienyl-, 2-furyl- and 2-phenyl-3-hydroxychromones bonded to the C-5 position of deoxyuridine. Since these two-color nucleosides were designed for incorporation into ODNs, we also investigated the sensitivity of the ratiometric response to hydration by using acetonitrile/water mixtures and neat solvents. The synthesized 2-thienyl and 2-furyl conjugates were found to exhibit more red-shifted absorption (by 31-36 nm) and emission (by 77-81 nm of the N? band), two-fold increased molar absorption coefficients, and dramatically enhanced (by 3-4.5 times) fluorescence quantum yields. Demonstrating a manifold increase in brightness, they preserve the ability of exquisite ratiometric responses to solvent polarity and hydration. This makes the new fluorescent nucleoside analogues highly relevant for subsequent labeling of the major groove in nucleic acids and sensing their interactions.
- Barthes,Karpenko,Dziuba,Spadafora,Auffret,Demchenko,Mély,Benhida,Michel,Burger
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p. 33536 - 33545
(2015/04/27)
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- DEVICES, COMPOSITIONS AND METHODS FOR IMAGING WITH RAMAN SCATTERING
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Methods, systems and computer-accessible medium for imaging a living cell or a living organism with bond-edited compounds using stimulated Raman scattering are disclosed. The method comprises the steps of introducing one or more bond-edited compounds into a live cell or a living organism, and detecting a vibrational tag in the cell or organism with stimulated Raman scattering. Also disclosed are methods for detecting a disease condition in a subject methods for monitoring treatment for a disease condition, methods for screening an agent, methods for tracing a cellular process in a live cell using bond-edited compounds in combination with stimulated Raman scattering. Also disclosed are a composition for labeling a target cell with at least one bond-edited compound and devices for imaging bond-edited compounds by stimulated Raman scattering.
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Paragraph 0203 - 0205
(2015/01/07)
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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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- Synthesis and antiviral evaluation of C5-substituted-(1,3-diyne)-2′- deoxyuridines
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Starting from acetylated 5-ethynyl-2′-deoxyuridine (3), 14 hitherto unknown C5-substituted-(1,3-diyne)-2′-deoxyuridines (with cyclopropyl, hydroxymethyl, methylcyclopentane, p-(substituted)phenyl and disubstituted-phenyl substituents) have been synthesized via a nickel-copper catalyzed C-H activation between two terminal alkynes, in yields ranging from 19% to 67%. Their antiviral activities were measured against a large number of DNA and RNA viruses including herpes simplex virus type 1 and type 2, varicella-zoster virus, human cytomegalovirus and vaccinia virus. The 5-[4-(4-trifluoromethoxyphenyl)buta-1,3-diynyl]-2′-deoxyuridine (26) is the most potent inhibitor of this series against VZV with an EC50 of ~1 μM and a CC50 of 55 μM. Their cytostatic activities were determined against murine leukemia cells, human T-lymphocyte cells and cervix carcinoma cells. Compounds were also evaluated on a wide panel of RNA viruses, including influenza virus A (H1N1 and H3N2) and B in MDCK cell cultures, parainfluenza-3 virus, reovirus-1, Sindbis virus and Punta Toro virus in Vero cell cultures and vesicular stomatitis, coxsackie B4 and respiratory syncytial virus in HeLa cell cultures and against human immunodeficiency virus type 1 and 2 in CEM cell cultures, with no specific antiviral effect. This class of compounds could be of further interest for lead optimization as anti-infectious (i.e. herpetic) agents.
- Sari, Ozkan,Roy, Vincent,Balzarini, Jan,Snoeck, Robert,Andrei, Graciela,Agrofoglio, Luigi A.
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experimental part
p. 220 - 228
(2012/08/28)
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- 5-Ethynyl-2′-deoxyuridine as a molecular probe of cell proliferation for high-content siRNA screening assay by "click" chemistry
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Labelling and identification of proliferating cells is important for the study of physiological or pathological processes in high-content screening (HCS) assays. Here we describe ethynyl deoxyuridine (EdU) as a biomarker for the assessment of cell proliferation and clearly demonstrate the feasibility of the EdU-labelling method for use in HCS assays. EdU detection is highly robust, reproducible, technically simple, and well suited for automated segmentation, which provides an excellent alternative for setting up multiplexed HCS assays of siRNA, miRNA and small-molecule libraries.
- Chen, Miaojuan,Qu, Dezhong,Chi, Weilin,Wang, Wei,Ren, Xiaoshuai,Cong, Shujie,Liang, Peizhou,Feng, Shipeng,Zhang, Biliang
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p. 1702 - 1710
(2012/05/19)
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- Synthesis and evaluation of 5-substituted 2′-deoxyuridine monophosphate analogues as inhibitors of flavin-dependent thymidylate synthase in mycobacterium tuberculosis
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A series of 5-substituted 2′-deoxyuridine monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC50 value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC50 > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.
- K?gler, Martin,Vanderhoydonck, Bart,De Jonghe, Steven,Rozenski, Jef,Van Belle, Kristien,Herman, Jean,Louat, Thierry,Parchina, Anastasia,Sibley, Carol,Lescrinier, Eveline,Herdewijn, Piet
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supporting information; experimental part
p. 4847 - 4862
(2011/09/19)
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- Synthesis of new C5-(1-substituted-1,2,3-triazol-4 or 5-yl)-2′- deoxyuridines and their antiviral evaluation
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The synthesis and antiviral evaluation of a series of C5-(1,4- and 1,5-disubstituted-1,2,3-triazolo)-nucleoside derivatives is described. The key steps of this synthesis are regioselective Huisgen's 1,3-dipolar cycloaddition, using either copper-catalyzed azide-alkyne cycloaddition (CuAAC) or ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) under microwave activation. Some compounds among the 5a-l series possess activity against herpes simplex viruses 1 and 2, varicella-zoster virus, human cytomegalovirus and vaccinia virus. Their cytostatic activities were determined against murine leukemia cells, human T-lymphocyte cells and cervix carcinoma cells. Compounds were also evaluated on a wide panel of RNA viruses, including Vesicular stomatitis virus, influenza viruses type A (H1N1 and H3N2) and B in MDCK cell cultures, parainfluenza-3 virus, reovirus-1, Sindbis virus and Punta Toro virus in Vero cell cultures and Vesicular stomatitis, Coxsackie B4 and respiratory syncytial virus, with no specific antiviral
- Montagu, Aurelien,Roy, Vincent,Balzarini, Jan,Snoeck, Robert,Andrei, Graciela,Agrofoglio, Luigi A.
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experimental part
p. 778 - 786
(2011/03/20)
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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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- Synthesis of 5-isoxazol-5-yl-2′-deoxyuridines exhibiting antiviral activity against HSV and several RNA viruses
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This paper describes a simple method for synthesizing a small library of 5-isoxazol-5-yl-2′-deoxyuridines from 5-iodo-2′-deoxyuridine. Nitrile oxides were generated in situ from oximes using a commercial bleaching agent; their cycloaddition with 5-ethynyl-2′-deoxyuridine yielded isoxazoles possessing activity against herpes simplex viruses 1 and 2, Encephalomyocarditis virus, Coxsackie B3, and vesicular stomatitis virus; these isoxazoles were, however, inactive against corona virus, influenza virus, and HIV.
- Lee, Yoon-Suk,Park, Sun Min,Kim, Byeang Hyean
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scheme or table
p. 1126 - 1128
(2009/08/07)
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- C5-Modified nucleosides exhibiting anticancer activity
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We describe (i) a simple method for the synthesis of C5-modified nucleosides from 5-iodo-2′-deoxyuridine and (ii) their activity against six types of human cancer cell lines (HCT15, MM231, NCI-H23, NUGC-3, PC-3, ACHN). We generated nitrile oxides in situ from oximes using a commercial bleaching agent; their cycloadditions with 5-ethynyl-2′-deoxyuridine yielded isoxazole derivatives possessing activity against the cancer cell lines. We synthesized several azides from benzylic bromides and their click reactions with 5-ethynyl-2′-deoxyuridine provided triazole derivatives.
- Lee, Yoon-Suk,Park, Sun Min,Kim, Hwan Mook,Park, Song-Kyu,Lee, Kiho,Lee, Chang Woo,Kim, Byeang Hyean
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scheme or table
p. 4688 - 4691
(2010/04/28)
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- Phosphine containing oligonucleotides for the development of metallodeoxyribozymes
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Novel transition metal catalysts based on oligonucleotides can be easily obtained by functionalization of 5-iodouridine with phosphine ligands, resulting in good asymmetric induction in palladium catalyzed allylic nucleophilic substitution. The Royal Society of Chemistry.
- Ropartz, Loic,Meeuwenoord, Nico J.,Van Der Marel, Gijsbert A.,Van Leeuwen, Piet W. N. M.,Slawin, Alexandra M. Z.,Kamer, Paul C. J.
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p. 1556 - 1558
(2008/02/02)
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- Selective fluorometric detection of guanosine-containing sequences by 6-phenylpyrrolocytidine in DNA
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The intrinsically fluorescent nucleoside 2′-deoxy-6- phenylpyrrolocytidine, when incorporated into an oligonucleotide, is selectively quenched by hybridization with match DNA vs. mismatched sequences. Georg Thieme Verlag Stuttgart.
- Hudson, Robert H. E.,Ghorbani-Choghamarani, Arash
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p. 870 - 873
(2008/02/03)
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- Oligodeoxynucleotides incorporating structurally simple 5-alkynyl-2′-deoxyuridines fluorometrically respond to hybridization
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Selected 5-ethynyl derivatives of 2′-deoxyuridine are shown to fluorometrically respond to hybridization and selectively base-pair to adenine whilst maintaining duplex stability. The Royal Society of Chemistry.
- Hudson, Robert H. E.,Ghorbani-Choghamarani, Arash
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p. 1845 - 1848
(2008/02/10)
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- Uridine derivatives as antiviral drugs against a flaviviridae, especially HCV
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The invention relates to the use of an uridine derivative of formula (I): wherein R1 represents monohalogenated alkynyl or dihalogenated alkenyl;R2 is chosen from among hydrogen, hydroxyl, -O-alkyl, -O-CO-alkyl and halogen;R3 is chosen from among hydrogen, hydroxyl, -O-alkyl, -O-CO-alkyl, halogen, -SH, -S-alkyl and N3; andR4 is chosen from among hydroxyl, -O-alkyl, -O-CO-alkyl, -O-phosphate, -O-diphosphate, -O-triphosphate and -O-phosphonate, as well as its possible tautomers, its possible pharmaceutically acceptable addition salts with an acid or a base, and its N-oxide forms, for the preparation of a drug having antiviral activity against a Flaviviridae.
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Page/Page column 7; 14
(2008/06/13)
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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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- Synthesis of dicobalt hexacarbonyl 5-p-tolylethynyl-2′-deoxyuridine
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Reactions of 5-p-tolylethynyl-2′-deoxyuridine and 3′,5′-diO-acetyl-5-p-tolylethynyl-2′-deoxyuridine with Co2(CO)8 in THF gave 5-p-tolC2[Co2(CO)6]-2′-deoxyuridine and 3′,5′-diO-acetyl-5-p-tolC2[Co2(CO) 6]-2′-deoxyuridine (92 and 66%).
- Esho, Noor,Davies, Brian,Lee, Janet,Dembinski, Roman
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p. 332 - 333
(2007/10/03)
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- Preparation of pyrenyl-modified nucleosides via Suzuki-Miyaura cross-coupling reactions
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The modified nucleosides 5-pyrenyl-2′-deoxyuridine (1) and 8-pyrenyl-2′-deoxyguanosine (2) were synthesized via palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of pyren-1-yl boronic acid (3) to either 5-iodo-2′-deoxyuridine (4), or 8-bromo-2′-deoxyguanosine (7), respectively. No protecting groups for the hydroxy and amino functions of the nucleoside are needed during the preparation. Both pyrene derivatives are suitable nucleoside models for the spectrosopic investigation of reductive electron transfer (in 1), or oxidative hole transfer (in 2).
- Amann, Nicole,Wagenknecht, Hans-Achim
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p. 687 - 691
(2007/10/03)
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- Base analogues
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Nucleotide or base analogues having structure (3) or (4) wherein X═O or NH or S and each R6is independently H or alkyl or alkenyl or alkoxy or aryl or a reporter moiety.
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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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- 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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- 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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- Synthesis and biological activity of 5-(trifluoromethyl)- and 5-(pentafluorethyl)pyrimidine nucleoside analogues
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Various 5-substituted perfluoroalkylpyrimidine nucleoside analogues have been synthesized, and their biological activity against L1210, S-180, Vero cells, and herpes simplex virus type 1 (HSV-1) was evaluated. The 5-trifluoromethyl derivatives, 7 and 9, showed significant antiviral activity against HSV-1 with ED50 values of 7 and 5 μM, respectively. In addition, the unblocked nucleoside 9 was found to be about 64-fold less toxic to the host Vero cells and gave a favorable therapeutic index of 64 against HSV-1 in vitro.
- Lin,Gao
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p. 598 - 601
(2007/10/02)
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- Nucleic Acid Related Compounds. 39. Efficient Conversion of 5-Iodo to 5-Alkynyl and Derived 5-Substituted Uracil Bases and Nuleosides
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Coupling of terminal alkynes with 5-iodo-1-methyl-uracil and 5-iodouracil nucleosides (protected as their p-toluyl esters) proceeded in high yields in the presence of bis(triphenylphosphine)palladium(II) chloride and copper(I)iodide in warm triethylamine.Several of the subsequently deprotected 5-alkynyl-2'-deoxyuridines, including the parent 5-ethynyl-2'-deoxyuridine, had antiviral activity, and their 5'-monophosphates inhibited thymidylate synthetase.Hydrogenation of the 5-alkynyl side chain can be controlled to give (Z)-5-alkenyl- or the saturated 5-alkyl-2'-deoxyuridines.This provides a stereocontrolled route to the known 5-ethyl-and 5-n-hexyl-2'-deoxyuridines as well as (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU).Hydration of the triple bond gave the corresponding uracil-5-alkanone products in favorable cases.
- Robins, Morris J.,Barr, Philip J.
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p. 1854 - 1862
(2007/10/02)
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