- A general synthesis of 2′-deoxy-2′-[18F]fluoro-1-β-D- arabinofuranosyluracil and its 5-substituted nucleosides
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Several 2′-deoxy-2′-[18F]fluoro-1-β-D- arabinofuranosyluracil derivatives have been synthesized. Coupling of 1-bromo-2-deoxy-2-[18F]fluoro-3,5-di-O-benzoyl-α-D- arabinofuranose 2 with protected uracil derivatives 3a-e followed by hydrolysis and high-performance liquid chromatography purification produced the radiolabeled nucleosides 4a-e in 15-30% yield (d. c.), > 99% radiochemical purity and 55.5-103.6 GBq/μmol specific activities. Copyright
- Alauddin, Mian M.,Conti, Peter S.,Fissekis, John D.
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Read Online
- New concept for the separation of an anomeric mixture of α/β-D-nucleosides through regioselective enzymatic acylation or hydrolysis processes
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An efficient and high yield protocol for the synthesis and separation of 3′- and/or 5′-protected α-2′-deoxynucleosides has been developed through regioselective acylation/deacylation processes catalyzed by enzymes. Pseudomonas cepacia lipase (PSL-C) was f
- Garcia, Javier,Diaz-Rodriguez, Alba,Fernandez, Susana,Sanghvi, Yogesh S.,Ferrero, Miguel,Gotor, Vicente
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Read Online
- Regio- and stereoselective syntheses of L-pentose derivatives from L-arabinose
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Novel L-arabinose, L-ribose, 2-deoxy-L-ribose and 2-fluoro-2-deoxy-L-arabinose derivatives were synthesized from readily available L-arabinose. Different synthetic routes to methyl 3,5-di-O-acylated-L-arabino(ribo)furanosides as valued intermediates for t
- Sivets, Grigorii G.
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Read Online
- S-ANTIGEN TRANSPORT INHIBITING OLIGONUCLEOTIDE POLYMERS AND METHODS
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Various embodiments provide STOPS? polymers that are S-antigen transport inhibiting oligonucleotide polymers, processes for making them and methods of using them to treat diseases and conditions. In some embodiments the STOPS? modified oligonucleotides include an at least partially phosphorothioated sequence of alternating A and C units having modifications as described herein. The sequence independent antiviral activity against hepatitis B of embodiments of STOPS? modified oligonucleotides, as determined by HBsAg Secretion Assay, is an EC50 that is less than 100 nM.
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- MODIFIED OLIGOMERIC COMPOUNDS AND USES THEREOF
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The present disclosure provides oligomeric compounds comprising a modified oligonucleotide having at least one stereo-non-standard nucleoside. An oligomeric compound comprising a modified oligonucleotide consisting of 12-30 linked nucleosides, wherein at least one nucleoside of the modified oligonucleotide is a stereo-non-standard nucleoside; and wherein the oligomeric compound is selected from among an RNAi compound, a modified CRISPR compound, and an artificial mRNA compound.
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Page/Page column 83; 88
(2021/02/19)
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- MODIFIED OLIGOMERIC COMPOUNDS AND USES THEREOF
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The present disclosure provides oligomeric compounds comprising a modified oligonucleotide having at least one stereo-non-standard nucleoside.
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(2020/05/15)
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- A green synthetic clevudine pharmaceutical intermediates
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The invention relates to a green synthetic clevudine pharmaceutical intermediates method, comprises the following steps: The formula II compound is dissolved in the organic solvent, under ice bath by adding 40% of the hydrobromic, tetrabutyl ammonium fluo
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Paragraph 0021-0023
(2019/03/29)
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- Green synthetic process of clevudine
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The invention relates to a green synthetic process of clevudine. The green synthetic process comprises the following steps: dissolving a compound II as shown in the description in an organic solvent,adding 40% hydrobromic acid and tetrabutylammonium fluor
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Paragraph 0029; 0030; 0031; 0033
(2019/03/29)
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- Analysis of Configuration and Conformation of Furanose Ring in Carbohydrate and Nucleoside by Vibrational Circular Dichroism
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A reliable and convenient method for determining the configuration and conformation of the furanose ring in carbohydrates and nucleosides by vibrational circular dichroism (VCD) spectroscopy is described. Diastereomeric pairs of several furanose monosacch
- Taniguchi, Tohru,Nakano, Kie,Baba, Ryosuke,Monde, Kenji
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p. 404 - 407
(2017/04/21)
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- NEIL1 Binding to DNA Containing 2'-Fluorothymidine Glycol Stereoisomers and the Effect of Editing
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Thymine glycol (Tg), one of the oxidized bases formed in DNA by reactive oxygen species, is repaired by the DNA glycosylases such as NEIL1, NTH1 and Endo III. In our recent studies, we showed that NEIL1's catalytic efficiency and lesion specificity are regulated by an RNA-editing adenosine deamination reaction. In this study, we synthesized oligodeoxynucleotides containing 2'-fluorothymidine glycol with either ribo or arabino configuration and investigated the binding of these modified DNAs with the unedited and edited forms of human NEIL1 along with E. coli Endo III. For the two forms of hNEIL1, binding affinities to FTg-containing DNA were similar indicating that the editing effect is more subtle than to simply alter substrate affinity. While the NEIL1-binding to FTg-containing DNAs was largely insensitive to C5 and 2' stereochemistry, a preference was observed for the FTg-G pair over the FTg-A pair. In addition, we found that optimal binding is observed with Endo III and duplex DNA with riboFTg(5S) paired with dG. The modified DNAs reported here will provide useful tools for further characterizing the interaction between DNA repair glycosylases and thymine glycol containing DNA.
- Onizuka, Kazumitsu,Yeo, Jongchan,David, Sheila S.,Beal, Peter A.
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experimental part
p. 1338 - 1348
(2012/09/22)
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- Synthesis and Structural Characterization of 2'-Fluoro-α-L-RNA-Modified Oligonucleotides
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We describe the synthesis and binding properties of oligonucleotides that contain one or more 2'-fluoro-α-L-RNA thymine monomer(s). Incorporation of 2'-fluoro-α-L-RNA thymine into oligodeoxynucleotides decreased thermal binding stability slightly upon hybridization with complementary DNA and RNA with the smallest destabilization towards RNA. Thermodynamic data show that the duplex formation with 2'-fluoro-α-L-RNA nucleotides is enthalpically disfavored but entropically favored. 2'-Fluoro-α-L-RNA nucleotides exhibit very good base pairing specificity following Watson-Crick rules. The 2'-fluoro-α-L-RNA monomer was designed as a monocyclic mimic of the bicyclic α-L-LNA, and molecular modeling showed that this indeed is the case as the 2'-fluoro monomer adopts a C3'-endo/C2'-exo sugar pucker. Molecular modeling of modified duplexes show that the 2'-fluoro-α-L-RNA nucleotides partake in Watson-Crick base pairing and nucleobase stacking when incorporated in duplexes while the unnatural α-L-ribo configured geometry of the sugar is absorbed by changes in the sugar-phosphate backbone torsion angles. The duplex behavior of our new nucleotide follows that of α-L-LNA, by and large.
- Bundgaard Jensen, Troels,Pasternak, Anna,Stahl Madsen, Andreas,Petersen, Michael,Wengel, Jesper
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p. 1904 - 1911
(2012/05/04)
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- Synthesis and anti-HIV activity of 2′-deoxy-2′-fluoro-4′-C-ethynyl nucleoside analogs
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Based on the favorable antiviral profiles of 4′-substituted nucleosides, novel 1-(2′-deoxy-2′-fluoro-4′-C-ethynyl-β-d-arabinofuranosyl)-uracil (1a), -thymine (1b), and -cytosine (2) analogs were synthesized. Compounds 1b and 2 exhibited potent anti-HIV-1 activity with IC50 values of 86 and 1.34 nM, respectively, without significant cytotoxicity. Compound 2 was 35-fold more potent than AZT against wild-type virus, and also retained nanomolar antiviral activity against resistant strains, NL4-3 (K101E) and RTMDR. Thus, 2 merits further development as a novel NRTI drug.
- Wang, Qiang,Li, Yanfeng,Song, Chuanjun,Qian, Keduo,Chen, Chin-Ho,Lee, Kuo-Hsiung,Chang, Junbiao
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supporting information; experimental part
p. 4053 - 4056
(2010/08/19)
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- Antiviral activity of various 1-(2′-Deoxy-β- d -lyxofuranosyl), 1-(2′-Fluoro-β- d -xylofuranosyl), 1-(3′-Fluoro-β- d -arabinofuranosyl), and 2′-fluoro-2′,3′-didehydro-2′, 3′-dideoxyribose pyrimidine nucleoside analogues against duck hepatitis B virus (DHBV) and human hepatitis B virus (HBV) replication
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Despite the existence of successful vaccine and antiviral therapies, infection with hepatitis B virus (HBV) continues to be a major global cause of acute and chronic liver disease and high mortality. We synthesized and evaluated several lyxofuranosyl, 2′-fluoroxylofuranosyl, 3′- fluoroarabinofuranosyl, and 2′-fluoro-2′,3′-didehydro- 2′,3′-dideoxyribose pyrimidine nucleoside analogues for antiviral activities against hepatitis B virus. Among the compounds examined, 1-(2-deoxy-β-d-lyxofuranosyl)thymine (23), 1-(2-deoxy-β-d- lyxofuranosyl)-5-trifluoromethyluracil (25), 1-(2-deoxy-2-fluoro-β-d- xylofuranosyl)uracil (38), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)thymine (39), 2′,3′-dideoxy-2′,3′-didehydro-2′- fluorothymidine (48), and 2′,3′-dideoxy-2′,3′-didehydro- 2′-fluoro-5-ethyluridine (49) were found to possess significant anti-HBV activity against DHBV in primary duck hepatocytes with EC50 values of 4.1, 3.3, 40.6, 3.8, 0.2, and 39.0 μM, respectively. Compounds 23, 25, 39, 48, and 49 (EC50 = 41.3, 33.7, 19.2, 2.0-4.1, and 39.0 μM, respectively) exhibited significant activity against wild-type human HBV in 2.2.15 cells. Intriguingly, 25, 39, 48, and 49 retained sensitivity against lamivudine-resistant HBV containing a single mutation (M204I) and 48 emerged as an effective inhibitor of drug-resistant HBV with an EC50 of 4.1 μM. In contrast, 50% inhibition could not be achieved by lamivudine at 44 μM concentration in the drug-resistant strain. The compounds investigated did not show cytotoxicity to host cells up to the highest concentrations tested.
- Srivastav, Naveen C.,Shakya, Neeraj,Mak, Michelle,Agrawal, Babita,Tyrrell, D. Lorne,Kumar, Rakesh
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experimental part
p. 7156 - 7166
(2010/12/19)
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- IMPROVED PROCESS FOR THE PREPARATION OF CLEVUDINE AS ANTI-HBV AGENT
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Disclosed herein is an improved method for preparing l -(2'-deoxy-2'- fluoro-beta-L-arabinofuranosyl) thymine (clevudine) useful as an anti-HBV (hepatitis B vims) agent. The method comprises an improved purification process of 2-O-imidazolylsulfonyl-l,3,5
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(2008/12/06)
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- Synthesis and anti-viral activity of a series of D- and l-2′-deoxy-2′-fluororibonucleosides in the subgenomic HCV replicon system
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Based on the discovery of (2′R)-D-2′-deoxy-2′- fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of D- and L-2′-deoxy-2′-fluororibonucleosides with modifications at 5- and/or 4-positions were synthesized and evaluated for their in vitro activity against HCV and bovine viral diarrhea virus (BVDV). The key step in the synthesis, the introduction of 2′-fluoro group, was achieved by either fluorination of 2,2′-anhydronucleosides with hydrogen fluoride-pyridine or potassium fluoride, or a fluorination of arabinonucleosides with DAST. Among the 27 analogues synthesized, only the 5-fluoro compound, namely (2′R)-D-2′-deoxy-2′,5-difluorocytidine (13), demonstrated potent anti-HCV activity and toxicity to ribosomal RNA. The replacement of the 4-amino group with a thiol group resulted in the loss of activity, while the 4-methylthio substituted analogue (25) exhibited inhibition of ribosomal RNA. As N4-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, we combined the two functionalities of the N4-hydroxyl and the 2′-fluoro into one molecule, resulting (2′R)-D-2′-deoxy- 2′-fluoro-N4-hydroxycytidine (23). However, this nucleoside showed neither anti-HCV activity nor toxicity. All the L-forms of the analogues were devoid of anti-HCV activity. None of the compounds showed anti-BVDV activity, suggesting that the BVDV system cannot always predict anti-HCV activity.
- Shi, Junxing,Du, Jinfa,Ma, Tianwei,Pankiewicz, Krzysztof W.,Patterson, Steven E.,Tharnish, Phillip M.,McBrayer, Tamara R.,Stuyver, Lieven J.,Otto, Michael J.,Chu, Chung K.,Schinazi, Raymond F.,Watanabe, Kyoichi A.
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p. 1641 - 1652
(2007/10/03)
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- XNA ?(xylo nucleic acid): A summary and new derivatives
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Fully modified homopyrimidine 2′-deoxy-xylo nucleic acid (dXNA) form triple helixes with complementary DNA/RNA with thermal stabilities comparable to those of the corresponding DNA:DNA and DNA:RNA duplexes. However, a single or few insertions of dXNA monomers in a DNA strand significantly lower duplex stabilities. The dXNA monomers are known to adopt predominantly an N-type furanose conformation in solution. With a desire to increase the binding affinity, seven sugar-modified XNA monomers (H, F, N, M, K, P and Q) have been synthesised and their effect on hybridization towards DNA and RNA complements studied. The introduction of 2′-fluoro and 2′-hydroxy substituents was expected to induce conformational restriction towards C3′-endo-type furanose conformation of monomer F derived from 1-(2′-deoxy-2′-fluoro-β-D-xylofuranosyl)thymine and monomer H derived from 1-(β-D-xylofuranosyl)thymine. The presence of functionalites facing the minor groove as in 1-(2′-amino-2′-deoxy-2′-N, 4′-C-methylene-β-D-xylofuranosyl)thymine (monomer N), 1-[4-C-(N-methylpiperazinyl)methyl-β-D-xylofuranosyl]thymine (monomer P), 1-(4-C-piperazinylmethyl-β-D-xylofuranosyl)thymine (monomer Q), 1-(4-C-hydroxymethyl-β-D-xylofuranosyl)thymine (monomer M) and 9-(4-C-hydroxymethyl-β-D-xylofuranosyl)adenine (monomer K) was studied, with monomer N being locked in an N-type furanose conformation. Besides, an efficient synthesis of known xylo-LNA phosphoramidite 19, required for the incorporation of 1-(2′-O,4′-C-methylene-β-D-xylofuranosyl)thymine (monomer L) is described. For comparison, hydridization data of various XNAs reported in the literature are included in the discussion section. The thermal denaturation studies show that XNAs containing conformationally locked monomers (N and L) display improved binding affinity, and that partially modified DNA/XNA chimera, or fully modified XNA display preferential hybridization towards RNA complements. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.
- Babu, B. Ravindra,Raunak,Poopeiko, Nicolai E.,Juhl, Martin,Bond, Andrew D.,Parmar, Virinder S.,Wengel, Jesper
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p. 2297 - 2321
(2007/10/03)
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- Synthesis and in vitro anti-HCV activity of β-D- and L-2′-deoxy-2′-fluororibonucleosides
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Based on the discovery of β-D-2′-deoxy-2′-fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of β-D- and L-2′-deoxy-2′-fluororibonucleosides with modifications at 5 and/or 4 positions were synthesized and evaluated for their in vitro activity against HCV and bovine viral diarrhea virus (BVDV). The introduction of the 2′-fluoro group was achieved by either fluorination of 2,2′-anhydronucleosides with hydrogen fluoride-pyridine or potassium fluoride, or a fluorination of arabinonucleosides with DAST. Among the 27 analogues synthesized, only the 5-fluoro compounds, namely β-D-2′- deoxy-2′,5-difluorocytidine (5), had anti-HCV activity in the subgenomic HCV replicon cell line, and inhibitory activity against ribosomal RNA. As β-D-N4-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, the two functionalities of the N4-hydroxyl and the 2′-fluoro were combined into one molecule, yielding β-D-2′- deoxy-2′-fluoro-N4-hydroxycytidine (12). However, this nucleoside showed neither anti-HCV activity nor toxicity. All the L-forms of the analogues were devoid of anti-HCV activity. None of the compounds showed anti-BVDV activity, suggesting that the BVDV system cannot reliably predict anti-HCV activity in vitro. Copyright Taylor & Francis, Inc.
- Shi, Junxing,Du, Jinfa,Ma, Tianwei,Pankiewicz, Krzysztof W.,Patterson, Steven E.,Hassan, Abdalla E. A.,Tharnish, Phillip M.,McBrayer, Tamara R.,Lostia, Stefania,Stuyver, Lieven J.,Watanabe, Kyoichi A.,Chu, Chung K.,Schinazi, Raymond F.,Otto, Michael J.
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p. 875 - 879
(2007/10/03)
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- Antisense modulation of Notch (Drosophila) homolog 4 expression
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Antisense compounds, compositions and methods are provided for modulating the expression of Notch (Drosophila) homolog 4. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Notch (Drosophila) homolog 4. Methods of using these compounds for modulation of Notch (Drosophila) homolog 4 expression and for treatment of diseases associated with expression of Notch (Drosophila) homolog 4 are provided.
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(2010/02/06)
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- Xylo-configured oligonucleotides (XNA, xylo nucleic acid): Synthesis of conformationally restricted derivatives and hybridization towards DNA and RNA complements
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Xylo-Configured oligonucleotides (XNA) containing a novel conformationally restricted 2′-deoxy-2′-fluoro-β-D-xylofuranosyl nucleotide monomer, a novel conformationally locked 2′-amino-2′-deoxy-2′-N,4′-C-methylene-β-D- xylofuranosyl nucleotide monomer, and
- Poopeiko, Nicolai E.,Juhl, Martin,Vester, Birte,Sorensen, Mads D.,Wengel, Jesper
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p. 2285 - 2290
(2007/10/03)
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- xylo-configured oligonucleotides (XNA, xylo nucleic acids): Synthesis and hybridization studies
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We report synthesis and high-affinity hybridization of fully modified home-thymine 2′-deoxy and 2′-deoxy-2′-fluoro xylo nucleic acids.
- Poopeiko, Nicolai E.,Dahl, Britta M.,Wengel, Jesper
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p. 1147 - 1149
(2007/10/03)
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- Synthesis of 2',3'-dideoxy-2'-fluoro-3'-thioarabinothymidine and its 3'-phosphoramidite derivative.
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An efficient method for the synthesis of 5'-O-monomethoxytrityl-2',3'-dideoxy-2'-fluoro-3'-thioarabinothymidine [(5'MMT)araF-T(3'SH), (5)] and its 3'-phosphoramidite derivative (6) suitable for automated incorporation into oligonucleotides, is demonstrated. A key step in the synthesis involves reaction of 5'-O-MMT-2,3'-O-anhydrothymidine (4) (Eleuteri, A.; Reese, C.B.; Song, Q. J. Chem. Soc. Perkin Trans. 1 1996, 2237 pp.) with sodium thioacetate to give (5'-MMT)araF-T(3'SAc) (5) (Elzagheid, M.I.; Mattila, K.; Oivanen, M.; Jones, B.C.N.M.; Cosstick, Loennberg, H. Eur. J. Org. Chem. 2000, 1987-1991). This nucleoside was then converted to its corresponding phosphoramidite derivative, 6, as described previously ((a) Sun, S.; Yoshida, A.; Piccirilli, J.A. RNA, 1997, 3, 1352-1363; (b) Matulic-Adamic, J.; Beigelman, L. Helvetica Chemica Acta 1999, 82, 2141-2150: (c) Fettes, K.J.; O'Neil, I.; Roberts, S.M.; Cosstick, R. Nucleosides, Nucleotides and Nucl. Acids 2001, 20, 1351-1354).
- Elzagheid, Mohamed I,Tedeschi, Anna Lisa,Damha, Masad J
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p. 1343 - 1346
(2007/10/03)
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- New synthesis of L-FMAU from L-arabinose
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A new synthesis of 2′-deoxy-2′-fluoro-5-methyl-β-L-arabinofuranosyl uracil (13, L-FMAU) was achieved in 10 steps from L-arabinose.
- Sznaidman, Marcos L.,Almond, Merrick R.,Pesyan, Amir
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p. 155 - 163
(2007/10/03)
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- Synthesis and evaluation of thymidine-5′-O-monophosphate analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase
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A number of 2′- and 3′-modified thymidine 5′-O-monophosphate analogues were synthesized as potential leads for new anti-mycobacterial drugs. Evaluation of their affinity for Mycobacterium tuberculosis thymidine monophosphate kinase showed that a 2′-halogeno substituent and a 3′-azido function are the most favorable leads for further development of potent inhibitors of this enzyme.
- Vanheusden, Veerle,Munier-Lehmann, Helene,Pochet, Sylvie,Herdewijn, Piet,Van Calenbergh, Serge
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p. 2695 - 2698
(2007/10/03)
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- A practical synthesis of L-FMAU from L-arabinose
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A practical synthesis of 2'-deoxy-2'-fluoro-5-methyl-β-L- arabinofuranosyl uracil (14, L-FMAU) was developed from L-arabinose. L- Arabinose was convened to L-ribose 5, which was used for the synthesis of bromosugar 12 via 2,3,5-O-tribenzoyl-1-O-acetyl-β-L-ribofuranose 8, which was subjected to condensation with silylated thymine and the resulting protected L-FMAU 13 was deprotected to afford L-FMAU in 14 steps in 8% overall yield.
- Du, Jinfa,Choi, Yongseok,Lee, Kyeong,Chun, Byoung K.,Hong, Joon H.,Chu, Chung K.
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p. 187 - 195
(2007/10/03)
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- Antiviral Nucleosides. A Stereospecific, Total Synthesis of 2'-Fluoro-2'-deoxy-β-D-arabinofuranosyl Nucleosides
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A general, total synthesis of (2'-fluoro-2'-deoxy-β-D-arabinofuranosyl)uracils 1a-d is described.A study of the coupling reaction beetwen 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide (7) and silylated pyrimidines 11a-d has resulted in a high overall yield for the five-step stereospecific synthesis of β-nucleosides.
- Howell, Henry G.,Brodfuehrer, Paul R.,Brundidge, Steven P.,Benigni, Daniel A.,Sapino, Chester
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- Anti-herpes virus compositions containing 5-substituted 1-2'(deoxy-2-'-substituted-β-d-arabinofuranosyl)pyrimedene nucleosides
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Veterinarian composition for the treatment of herpes virus in animals comprising a pyrimidine nucleoside, or veterinarianically acceptable acid addition salte thereof, of the formula STR1 wherein A is OR3, SR3, NR3 R4
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- Nucleosides. 123. Synthesis of Antiviral Nucleosides: 5-Substituted 1-(2-Deoxy-2-halogeno-β-D-arabinofuranosyl)cytosines and -uracils. Some Structure-Activity Relationships
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The syntheses of several 2'-halogeno-5-substituted-arabinofuranosylcytosines and -uracils are described, and relationships of structure to anti herpes virus activity in vitro were examined.Those arabinonucleosides containing the 2'-fluoro function exhibit
- Watanabe, Kyoichi A.,Su, Tsann-Long,Klein, Robert S.,Chu, Chung K.,Matsuda, Akira,et al.
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p. 152 - 156
(2007/10/02)
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- 5-Substituted 1-(2'-Deoxy-2'-substituted-β-D-arabinofuranosyl)pyrimidine nucleosides
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Pyrimidine nucleosides exhibiting anti-viral and anti-tumor effects have the formula STR1 wherein A is OR3, SR3, NR3 R4 or NHacyl wherein R3 and R4 are the same or different and are hydroge
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