- Synthesis of nucleoside-based antiviral drugs in ionic liquids
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Nucleoside-based antiviral drugs have been synthesized using imidazolium-based ionic liquids as reaction medium. The ionic liquids were proved to be better solvents for all the nucleoside in terms of solubility and reaction medium as compared to conventional molecular solvents.
- Kumar, Vineet,Malhotra, Sanjay V.
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- Photocycloaddition of deoxyuridines to 2,3-dimethyl-2-butene
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Direct and ketone (acetone or acetophenone)-sensitized photocycloaddition of 2,3-dimethyl-2-butene fo 2'-deoxyuridine (1a), thymidine (1b), 5-fluoro-2'-deoxyuridine (1c), and their 3',5'-di- O-acetyl derivatives 1d-1f by near-UV irradiation have been studied. The triplet excited state of the nucleosides was found to be the major intermediate by the triplet quenching technique. From the respective reactants, a pair of diastereomeric products having a cyclobutane ring were isolated. The absolute configuration of the bridgehead carbon atoms was identified by X-ray crystallographic analyses with two of them as (1R, 6R)-isomer 3a and (1S, 6S)-isomer 2b and by 1H NMH. The conformations of the glycosyl bond, the pyrimidine ring, and the sugar portion in solution were identified by 1H NMR and compared with the ones in the crystalline state.
- Haga,Ishikawa,Takayanagi,Ogura
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- An efficient and general synthesis of 5'-esters of 2',3'-didehydro-2',3'-dideoxynucleosides: A facile opening of 2',3'-orthoacetates of ribonucleosides followed by reductive elimination of the halogenoacetates
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A three-step reaction sequence from a ribonucleoside to give the corresponding 5'-O-acyl-2',3'-didehydro-2',3'-dideoxynucleoside is described. The key intermediate is the bromoacetate, made by reaction of the 2',3'-methoxyethylidine nucleoside with acetyl bromide. Reductive elimination of the bromoacetate using a zinc-copper couple furnishes the desired compounds in good overall yield.
- Talekar,Coe,Walker
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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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- Modified nucleotides as substrates of terminal deoxynucleotidyl transferase
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The synthesis of novel modified nucleotides and their incorporation into DNA sequences opens many possibilities to change the chemical properties of oligonucleotides (ONs), and, therefore, broaden the field of practical applications of modified DNA. The chemical synthesis of nucleotide derivatives, including ones bearing thio-, hydrazino-, cyano- and carboxy groups as well as 2-pyridone nucleobase-containing nucleotides was carried out. The prepared compounds were tested as substrates of terminal deoxynucleotidyl transferase (TdT). The nucleotides containing N4-aminocytosine, 4-thiouracil as well as 2-pyridone, 4-chloro- and 4-bromo-2-pyridone as a nucleobase were accepted by TdT, thus allowing enzymatic synthesis of 3′-terminally modified ONs. The successful UV-induced cross-linking of 4-thiouracil-containing ONs to TdT was carried out. Enzymatic post-synthetic 3′-modification of ONs with various photo- and chemically-reactive groups opens novel possibilities for future applications, especially in analysis of the mechanisms of polymerases and the development of photo-labels, sensors, and self-assembling structures.
- Tauraite, Daiva,Jakubovska, Jevgenija,Dabu?inskaite, Julija,Bratchikov, Maksim,Me?kys, Rolandas
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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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- 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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- A synergistic synthetic and computational insights towards anomerization of N-nitro pyrimidine nucleosides using fluorinating agents
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DAST and Deoxofluor are usually used for nucleophilic fluorination of nucleosides via SN1 or SN2 mechanism. DAST and Deoxo-fluor could enhance anomerization of N-substituted thymidine and 2′-deoxyuridine in dichloromethane into the more stable and favored α-anomers due to in-situ liberation of HF. This is strongly supported by computational calculations based on the density functional theory, that were performed to rationalize energy stability and electronic properties of both anomers in order to provide further insights into the proposed mechanism.
- Bayach, Imene,Khalil, Ahmed,Mathé, Christophe
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- 4 -thiouracil deoxynucleoside phosphate and application thereof in antiviral medicine
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The invention discloses 4 -thiouracil deoxynucleoside phosphate and a structural formula thereof. Q06, discovery of new drug molecules not only has a new choice for treating hepatitis B, but also has important significance for developing more ideal hepatitis B drugs for treating hepatitis B.
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Paragraph 0031-0034
(2021/10/16)
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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 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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- Phenyl-imidazolo-cytidine analogues: Structure-photophysical activity relationship and ability to detect single dna mismatch
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To expand the arsenal of fluorescent cytidine analogues for the detection of genetic material, we synthesized para-substituted phenyl-imidazolo-cytidine (PhImC) analogues 5a-g and established a relationship between their structure and fluoresce
- Kovaliov, Marina,Weitman, Michal,Major, Dan Thomas,Fischer, Bilha
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p. 7051 - 7062
(2014/08/18)
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- Sulfonic acid functionalized nano γ-Al2O3 catalyzed per-O-acetylated of carbohydrates
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A simple and clean synthesis of per-O-acetylation carbohydrate derivatives has been accomplished by treatment of sugars with a stoichiometric quantity of acetic anhydride under solvent-free conditions in the presence of sulfonic acid functionalized nano γ-Al2O3 as an efficient and environmentally benign catalyst.
- Wu, Liqiang,Yin, Zhikui
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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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- Oxidative damage of thymidines by the atmospheric free-radical oxidant NO3 ?
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Analysis of the products formed in the reaction of nitrate radicals, NO3 ?, with the N-and O-methylated and acetylated thymidines 1a and 1b revealed, for the first time, insight regarding how this important atmospheric free-radical oxidant can cause irreversible damage to DNA building blocks. Mechanistic studies indicated that the initial reaction step likely proceeds via NO3 ? induced electron transfer at the pyrimidine ring, followed by deprotonation of the methyl group at C5. The oxidation ultimately leads to formation of nitrates 2, aldehydes 4 and, in the case of high [NO3 ?], also to carboxylic acids 5. In addition to this, through a very minor pathway, loss of the methyl group at C5 also occurred to give the respective 2′-deoxyuridines 6. The nitrates 2 are highly labile compounds that undergo rapid hydrolysis during work-up and purification of the reaction mixtures, which could lead to serious misinterpretation of the experimental findings and reaction mechanism. Products resulting from NO3 ? addition to the C5≤C6 double bond in the pyrimidine ring were not observed. Also, no reaction of NO 3 ? with the 2′-deoxyribose moiety was detected.
- Wille, Uta,Goeschen, Catrin
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experimental part
p. 833 - 842
(2012/07/14)
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- Synthesis of novel nucleoside 5′-triphosphates and phosphoramidites containing alkyne or amino groups for the postsynthetic functionalization of nucleic acids
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A series of novel nucleoside 5′-triphosphates and phosphoramidites containing alkyne or amino groups for the postsynthetic functionalization of nucleic acids were designed and synthesized. For this purpose, the new 3-aminopropoxypropynyl linker group was used. It contains two alternative functional capabilities: an amino group for the reaction of amino-alkynyl- modified oligonucleotides with corresponding activated esters and an alkyne group for the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. It was shown that a variety of methods of the attachment of the new linker can be used to synthesize a diversity of modified pyrimidine nucleosides. Copyright Taylor and Francis Group, LLC.
- Vasilyeva, Svetlana V.,Budilkin, Boris I.,Konevetz, Dmitrii A.,Silnikov, Vladimir N.
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scheme or table
p. 753 - 767
(2012/07/28)
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- A versatile synthesis of 5'-fenctionalized nucleosides through regioselective enzymatic hydrolysis of their peracetylated precursors
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We describe a chemo-enzymatic synthesis of modified nucleosides through lipase-catalyzed hydrolysis of their peracetylated precursors. It was found from screening of a large number of substrates that these enzymesregioselectivities were affected by the sugar and the nucleobase structures. By selecting the best enzyme for each substrate in terms of activity and regioselectivity, we prepared a small library of differently monodeprotecled purine and pyrimidine nucleosides useful as intermediates for the synthesis of high-value nucleosides and mononucleotides. By this approach, the chemo-enzymatic preparation of doxifluridine (14) and uridine 5'-monophosphate (5'-UMP, 15) from peracetylated uridine 1 was carried out. Elimination of many of the processing stages associated with existing methods was achieved, and higher yields and products of increased purity were generated. Wiley-VCH Verlag GmbH & Co. KGaA.
- Bavaro, Teodora,Rocchietti, Silvia,Ubiali,Filice, Marco,Terreni, Marco,Pregnolato, Massimo
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experimental part
p. 1967 - 1975
(2009/09/08)
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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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- DNA-directed synthesis of aniline and 4-aminobiphenyl oligomers: Programmed transfer of sequence information to a conjoined polymer nanowire
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A new class of materials was prepared from aniline-containing oligomers that are covalently linked to the nucleobases of duplex DNA. Oligomers composed of repeating aniline (PANI) or 4-aminobiphenyl (PAB) units having the properties of conducting polymers conjoined to the DNA were prepared by the reaction of horseradish peroxidase and H2O2 with DNA having the appropriate monomers aligned within the major groove. These oligomers exhibit the spectral and chemical properties typical of para-linked polyanilines. This method of preparation enables utilization of the unique self-recognizing properties and sequence programmability of DNA to create tailored oligomers. This ability was demonstrated experimentally by preparation of PAB oligomers from alternating benzene and aniline monomers. Conjoined conducting polymers carrying the sequence information of DNA may have applicability as nanowires.
- Datta, Bhaskar,Schuster, Gary B.
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p. 2965 - 2973
(2008/09/18)
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- Fe2(SO4)3·xH2O-catalyzed per-O-acetylation of sugars compatible with acid-labile protecting groups adopted in carbohydrate chemistry
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Fully acetylated saccharides are inexpensive and very useful starting materials for the synthesis of many naturally occurring glycosides, oligosaccharides, and glycoconjugates. Ferric sulfate hydrate (Fe2(SO4)3·xH2O) was found to be a valuable Lewis acid promoter in the per-O-acetylation reaction of saccharides with acetic anhydride in 100% of conversion rate and 88-99% yields. Interestingly, the procedure is perfectly compatible with the presence of a variety of acid-labile protecting groups, such as isopropylidene, benzylidene, trityl, and TBDMS groups. The reactions were simply performed by stirring the mixture of a sugar with a slight excessive acetic anhydride in the presence of 2.0 mol % of Fe2(SO4)3·xH2O at rt and the pure products were obtained by a simple dilution of the reaction mixture with dichloromethane and washings with aqueous Na2CO3.
- Shi, Lei,Zhang, Guisheng,Pan, Feng
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p. 2572 - 2575
(2008/09/19)
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- A metallo base-pair incorporating a terpyridyl-like motif: Bipyridyl-pyrimidinone·Ag(I)·4-pyridine
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The design and characterization of a geometrically unique, metallo base-pair motif is reported. The Royal Society of Chemistry.
- Shin, Dongwon,Switzer, Christopher
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p. 4401 - 4403
(2008/04/01)
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- The synthesis of N4-(6-aminopyridin-2-yl)-2′-deoxycytidine for recognizing the CG base pair at neutral pH by oligodeoxyribonucleotide-directed triple helix formation
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The sequence-specific recognition of double-helical DNA by oligodeoxyribonucleotide-directed triple helix (triplex) formation is limited mostly to purine tracts. To interrupt the purine tract in a target sequence, a non-natural deoxyribonucleoside N4
- Chin
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p. 751 - 758
(2007/10/03)
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- Unexpected shift to a 4-imino tautomer upon N4-acylation of 5- methylcytosin-1-yl nucleoside analogues
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In contrast with the behaviour of 5-unsubstituted cytosine nucleoside analogues, 5-methylcytosine derivatives show upon N4-benzoylation, commonly used as base protection in oligonucleotide synthesis, a tautomeric change of the base moiety from a 4-amino- into a 4-imino isomer. In the latter form, which is easily diagnosticized by 13C NMR and confirmed by X-ray data, the compounds seem to be hydrolytically less stable.
- Busson,Kerremans,Van Aerschot,Peeters,Blaton,Herdewijn
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p. 1079 - 1082
(2007/10/03)
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- NMR studies on the self-association of uridine and uridine analogues
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Association constants for the dimerization of acylated uridine and two analogues, 4-thiouridine and 6-oxadihydrouridine, have been determined in chloroform solution. At 293 K, self-association constants K were found to decrease in the order uridine > 6-ox
- Dunger, Anita,Limbach, Hans-Heinrich,Weisz, Klaus
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p. 621 - 628
(2007/10/03)
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- An efficient method for the synthesis of [4-15N]cytidine, 2'-deoxy[4-15N]cytidine, [6-15N]adenosine, and 2'-deoxy[6-15N]adenosine derivatives
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Nucleophilic substitution reactions of 4-azolyl-1-β-D-ribofuranosylpyrimidin-2(1H)-one and 6-azolyl-9-β-D-ribofuranosyl-9H-purine derivatives, which were converted from uridine and inosine, with [15N]phthalimide in the presence of triethylamine
- Kamaike,Takahashi,Utsugi,Tomizuka,Okazaki,Tamada,Kinoshita,Masuda,Ishido
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p. 749 - 769
(2007/10/03)
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- A Practical Synthesis of 2'-Deoxyuridine from Uridine
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An efficient and improved synthetic method for 2'-deoxyuridine from uridine has been developed.
- Huang, Haoqlang,Chu, Chung K.
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p. 1039 - 1046
(2007/10/02)
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- Linear Free Energy Relationship Studies of 5-Substituted 2,4-Dioxopyrimidine Nucleosides
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The development of a direct and efficient palladium(0)-catalyzed biaryl coupling reaction permitted the synthesis of a series of N1-substituted 5-aryl-2,4-dioxopyrimidines.The physical and spectral properties of these compounds were determined and correlated by various linear free energy relationships.The relationships between the physical and spectral data with Hammett ? constants proved useful in analyzing the electron distribution of the heterocycle.Although a significant degree of orbital overlap and interaction between the substituents and the pyrimidine ring was observed, it is doubtful that the interactions are comparable to those of a benzene ring system.
- Chang, George,Mertes, Mathias P.
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p. 3625 - 3631
(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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