- A novel and economical synthesis of 2′-o-alkyl-uridines
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A highly efficient, two-step method to make 2′-O-methyluridine is described using only inexpensive reagents and no chromatography. The method is applicable for some other alkyls as well as some other pyrimidine derivatives. Copyright
- Ross, Bruce S.,Springer, Robert H.,Tortorici, Zeb,Dimock, Stuart
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- SYNTHESIS AND STRUCTURE OF HIGH POTENCY RNA THERAPEUTICS
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This invention provides expressible polynucleotides, which can express a target protein or polypeptide. Synthetic mRNA constructs for producing a protein or polypeptide can contain one or more 5′ UTRs, where a 5′ UTR may be expressed by a gene of a plant. In some embodiments, a 5′ UTR may be expressed by a gene of a member of Arabidopsis genus. The synthetic mRNA constructs can be used as pharmaceutical agents for expressing a target protein or polypeptide in vivo.
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- Noncanonical RNA Nucleosides as Molecular Fossils of an Early Earth—Generation by Prebiotic Methylations and Carbamoylations
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The RNA-world hypothesis assumes that life on Earth started with small RNA molecules that catalyzed their own formation. Vital to this hypothesis is the need for prebiotic routes towards RNA. Contemporary RNA, however, is not only constructed from the four canonical nucleobases (A, C, G, and U), it also contains many chemically modified (noncanonical) bases. A still open question is whether these noncanonical bases were formed in parallel to the canonical bases (chemical origin) or later, when life demanded higher functional diversity (biological origin). Here we show that isocyanates in combination with sodium nitrite establish methylating and carbamoylating reactivity compatible with early Earth conditions. These reactions lead to the formation of methylated and amino acid modified nucleosides that are still extant. Our data provide a plausible scenario for the chemical origin of certain noncanonical bases, which suggests that they are fossils of an early Earth.
- Schneider, Christina,Becker, Sidney,Okamura, Hidenori,Crisp, Antony,Amatov, Tynchtyk,Stadlmeier, Michael,Carell, Thomas
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supporting information
p. 5943 - 5946
(2018/04/30)
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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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- A reliable Pd-mediated hydrogenolytic deprotection of BOM group of uridine ureido nitrogen
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The benzyloxymethyl (BOM) group has been utilized widely in syntheses of a variety of natural and non-natural products. The BOM group is also one of few choices to protect uridine ureido nitrogen. However, hydrogenolytic cleavage of the BOM group of uridine derivatives has been unreliably performed via heterogeneous conditions using Pd catalysts. One of the undesirable by-products formed by Pd-mediated hydrogenation conditions is the over-reduced product in which the C5-C6 double bond of the uracil moiety was saturated. To date, we have generated a wide range of uridine-containing antibacterial agents, where the BOM group has been utilized in their syntheses. In screening of deprotection conditions of the BOM group of uridine ureido nitrogen under Pd-mediated hydrogenation conditions, we realized that the addition of water to the iPrOH-based hydrogenation conditions can suppress the formation of over-reduced uridine derivatives and the addition of HCO2H (0.5%) dramatically improve the reaction rate. An optimized hydrogenation condition described here can be applicable to the BOM-deprotections of a wide range of uridine derivatives.
- Aleiwi, Bilal A.,Kurosu, Michio
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experimental part
p. 3758 - 3762
(2012/09/25)
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- Synthesis and hybridization properties of 2′-O-methylated oligoribonucleotides incorporating 2′-O-naphthyluridines
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2′-O-(1-Naphthyl)uridine and 2′-O-(2-naphthyl)uridine were synthesized by a microwave-mediated reaction of 2,2′-anhydrouridine with naphthols. Using the 3′-phosphoramidite building blocks, these 2′-O-aryluridine derivatives were incorporated into 2′-O-methylated oligoribonucleotides. Incorporation of five 2′-O-(2-naphthyl)uridines into a 2′-O-methylated RNA sense strand significantly increased the thermostability of the duplex with a 2′-O-methylated RNA antisense strand. Circular dichroism spectroscopy and molecular dynamic simulation of the duplexes formed between the modified RNAs and 2′-O-methyl RNAs suggested that there are π-π interactions between two neighboring naphthyl groups in a sequence of the five consecutively modified nucleosides.
- Sekine, Mitsuo,Oeda, Yusuke,Iijima, Yoshihiro,Taguchi, Haruhiko,Ohkubo, Akihiro,Seio, Kohji
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experimental part
p. 210 - 218
(2011/02/23)
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- Convenient RNA synthesis using a phosphoramidite possessing a biotinylated photocleavable group
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A convenient RNA synthesis using a biotin-streptavidin interaction and a photocleavable protecting group is described. The biotinylated photocleavable group was introduced at the 2′-position of the uridine derivative. Using the phosphoramidite 12, we attempted the synthesis of a 21mer RNA, which is pure enough to show potent RNAi activity compared with a conventionally prepared and HPLC-purified 21mer RNA with the same sequence.
- Tomaya, Kota,Takahashi, Mayumi,Minakawa, Noriaki,Matsuda, Akira
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body text
p. 3836 - 3839
(2010/11/17)
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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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- Efficient large scale synthesis of 2′-O-alkyl pyrimidine ribonucleosides
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An efficient process to synthesize 2′-O-alkyl pyrimidine ribonucleosides in high yield has been described. The inexpensive method was used on a multikilogram-scale synthesis and optimized reaction conditions have been investigated.
- Roy, Saroj K.,Tang, Jin-Yan
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p. 170 - 171
(2013/09/07)
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- Chemical syntheses of 2'-O-methoxy purine nucleosides
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Several processes for the chemical synthesis of 2'-O-methoxy purine nucleosides are herein disclosed.
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- Introduction of 6-formylcytidine into a MYB binding sequence
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Single 6-formylcytidine was introduced into a oligonucleotide duplex (23 mers) as a substitute for thymidine in the Myb binding sequence of 3'-TTGAC- 5'. The modified duplex showed Tm of 67 °C, which was six degrees lower than the Tm of the native duplex. Binding affinity of the 23-mers to the Myb protein was estimated by electrophoretic mobility shift assays, and the binding was almost completely abolished.
- Kittaka, Atsushi,Kuze, Tetsuya,Amano, Midori,Tanaka, Hiromichi,Miyasaka, Tadashi,Hirose, Kunihiko,Yoshida, Tadao,Sarai, Akinori,Yasukawa, Takashi,Ishii, Shunsuke
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p. 2769 - 2783
(2007/10/03)
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- Method for synthesizing 2'-O-substituted pyrimidine nucleosides
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The present invention provides an improved method of synthesizing 2'-O--R substituted pyrimidine mononucleosides. The method comprises reacting an anhydropyrimidine with magnesium alkoxide in the corresponding alcohol at elevated temperatures to directly produce the 2'-O--R substituted pyrimidine nucleoside product. The method advantageously eliminates several steps from prior art methods, thereby reducing the time and cost of synthesis and increasing the yield of final product.
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- Process for the preparation of 2'-O-alkyl purine phosphoramidites
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2'-O-alkylated guanosine, uridine, cytidine, and 2,6-diaminopurine 3'-O-phosphoramidites are prepared by alkylating nucleoside precursors, adding suitable blocking groups and phosphitylating. Alkylation is effected on 2,6-diamino-9-(β-D-ribofuranosyl)purine followed by deamination to prepare guanosine 2'-O-alkylated 3'-O-phosphormidites. Alkylation is effected on a dialkyl stannylene derivative of uridine to prepare uridine 2'-O-alkylated 3'-O-phosphormidites. Alkylation is effected directly on cytidine to prepare cytidine 2'-O-alkylated 3'-O-phosphormidites. Alkylation is effected directly on 2,6-diaminopurine to prepare 2,6-diaminopurine 2'-O-alkylated 3'-O-phosphormidites.
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- 176. Nucleosides part LXI: A simple procedure for the monomethylation of protected and unprotected ribonucleosides in the 2′-O- and 3′-O-position using diazomethane and the catalyst stannous chloride
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Intensive studies on the diazomethane methylation of the common ribonucleosides uridine, cytidine, adenosine, and guanosine and its derivatives were performed to obtain preferentially the 2′-O-methyl isomers. Methylation of 5′-O-(monomethoxytrityl)-N 2-[2-(4-nitrophenyl)ethoxycarbonyl]-O 6-[2-(4-nitrophenyl)ethyl]-guanosine (1) with diazomethane resulted in an almost quantitative yield of the 2′-nd 3′-O-methyl isomers which could be separated by simple silica-gel flash chromatography (Scheme 1). Adenosine, cytidine, and uridine were methylated with diazomethane with and without protection of the 5′-O-position by a mono- or dimethoxytrityl group and the aglycone moiety of adenosine and cytidine by the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group (Schemes 2-4). Attempts to increase the formation of the 2′-O-methyl isomer as much as possible were based upon various solvents, temperatures, catalysts, and concentration of the catalysts during the methylation reaction.
- Cramer, Hagen,Pfleiderer, Wolfgang
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p. 2114 - 2136
(2007/10/03)
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- Alternate approaches to the synthesis of 2'-O-Me nucleosides
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Three different approaches to the synthesis of 2'-O-methyl nucleosides starting from the corresponding nucleoside or commercially available 1,2:5,6-di-O-isopropylidene-α-D-allofuranose 1 are described.
- Beigelman,Karpeisky,Matulic-Adamic,Usman
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p. 421 - 425
(2007/10/02)
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- Synthesis of 2'-substituted sulfide-linked dinucleotides
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3'-Deoxy-3'-(2-mesyloxyethyl)ribofuranosylthymine derivative 3, and its 2'-methoxy (16) and 2'-deoxy (38) analogs were condensed with 5'-deoxy-5'- thiothymidine 4 and 17 or 2'-O-methyl-5'-deoxy-5'-thiouridine 34 and 37 to provide, after standard functional group transformations, thymidine-thymidine and uridine-thymidine dimers 9, 21, 43 and 47. Oxidation of model sulfide dimer 48 with oxone gave sulfone 49. It was not stable to 27% ammonia.
- Wang,Meng,Damha,Just
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p. 1961 - 1984
(2007/10/02)
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- Apparatus and processes for the large scale generation and transfer of diazomethane
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For large scale preparation of pyrimidine ribonucleosides, the intermediate 2-O-methyl-(or ethyl)-1,3,5-tri-O-benzoyl-α-D-ribose can be prepared using a diazomethane (or diazoethane) reaction that is controlled via an inert solvent transferring system. This transfer system allows for large scale preparations of the pyrimidine ribonucleosides.
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- General preparative synthesis of 2'-O-methylpyrimidine ribonucleosides
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A convergent and general approach to synthesizing 2'-O-methylpyrimidine ribonucleosides 4a-e-, 6, 7 on a multigram scale is described which begins with an improved procedure for making larger quantities of 2-O-methyl-1,3,5-tri-O-benzoyl-α-D-ribose. The sugar was reacted with the desired silylated pyrimidines at room temperature under Vorbruggen conditions. The crude products contained less than 10% of the α anomers and the desired β anomers were isolated by crystallization. The blocked nucleosides were then deprotected and isolated by standard methods.
- Ross,Springer,Vasquez,Andrews,Cook,Acevedo
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p. 765 - 769
(2007/10/02)
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- A convergent synthesis of 2′-o-methyl uridine
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A convergent synthesis of 2′-O-methyl uridine (1) is described. The key steps in our synthesis are: (1) a facile obtention of the 2′-O-methyl sugar synthon using totally selective and efficient methylation conditions; (2) a stereoselective high-yield condensation with an uracil derivative, yielding the desired β-form.
- Parmentier, Gilles,Schmitt, Gaby,Dolle, Frederic,Luu, Bang
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p. 5361 - 5368
(2007/10/02)
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- Synthesis of O2'-methyluridine, O2'-methylcytidine, N4,O2'-dimethylcytidine and N4,N4,O2'-trimethylcytidine from a common intermediate.
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A facile synthesis of the title compounds from a readily accessible precursor, 3',5'-O-bis-protected O4-(2-nitrophenyl)uridine, is described.
- Nyilas,Chattopadhyaya
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p. 826 - 830
(2007/10/02)
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- Synthesis of C-5 and N-3 Arenesulfenyl Uridines. Preparation and Properties of a New Class of Uracil Protecting Group
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The nature and position of the ring substituent of an arenesulfenyl chloride control the regiospecific formation of either a C-5 substituted product, as in compounds 3a-3d, or a N-3 substituted product, as in compound 2a-2c.Arenesulfenyl groups have been subsequently found to successfully protect the urethane function of the residue as exemplified by teh synthesis of 2'-O-methyl uridine and oligoribonucleotide building blocks.
- Welch, C. J.,Bazin, H.,Heikkila, J.,Chattopadhyaya, J.
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p. 203 - 212
(2007/10/02)
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- Synthesis of 2',3'-Differentiated Ribonucleosides via Glycosylation. Reactions with 2-O-Me or 2-O-TBDMS Ribofuranose Derivatives. 1. Pyrimidine Series
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The synthesis of 2',3' asymmetrically substituted pyrimidine ribonucleosides in 70-95percent yields by using modified Vorbruggen conditions with "nonparticipating" 2-O-CH3 and 2-O-TBDMS ribofuranoses is described.Such compounds are useful synthons for oligoribonucleotide synthesis, including incorporation of "rare" bases.New and practically useful conditions for placement (using 1,2,4-triazole) and removal (KF/crown ether) of the tert-butyldimethylsilyl (TBDMS) protecting group are also reported.
- Chavis, C.,Dumont, F.,Wightman, R. H.,Ziegler, J. C.,Imbach, J. L.
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p. 202 - 206
(2007/10/02)
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- PROTECTION OF IMIDE GROUP OF URACIL MOIETY BY MEANS OF 2,2,2-TRICHLORO-TERT-BUTYLOXYCARBONYL CHLORIDE: A SELECTIVE SYNTHESIS OF 2'-O-METHYLURIDINE
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2,2,2-trichloro-tert-butyloxycarbonyl group (TCBOC) was useful protecting group for the protection of imide function of uracil moiety.Starting from N3-TCBOC uridine derivative, 2'-O-methyluridine was selectively synthesized without formation of N3-methyluridine derivatives.
- Kamimura, Takashi,Masegi, Tsukio,Hata, Tsujiaki
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p. 965 - 968
(2007/10/02)
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