- A minute amount of S-puckered sugars is sufficient for (6-4) photoproduct formation at the dinucleotide level
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The di-2′-α-fluoro analogue of thymidylyl(3′,5′)-thymidine, synthesized to probe the effect of a minimum amount of S conformer on the photoreactivity of dinucleotides, is endowed with only 3% and 8% of S sugar conformation at its 5′- and 3′-end, respectively. This analogue gives rise to the (6-4) photoproduct as efficiently as the dithymine dinucleotide (74% and 66% at the 5′- and 3′-end, respectively) under 254 nm. Our results suggest that the 5′-N, 3′-S conformer gives rise to the (6-4) photoproduct.
- Moriou, Ceìline,Denhez, Cleìment,Plashkevych, Oleksandr,Coantic-Castex, Steìphanie,Chattopadhyaya, Jyoti,Guillaume, Dominique,Clivio, Pascale
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- C2′-F Stereoconfiguration As a Puckering Switch for Base Stacking at the Dinucleotide Level
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Fluorine configuration at C2′ of the bis(2′-fluorothymidine) dinucleotide is demonstrated to drive intramolecular base stacking. 2′-β F-Configuration drastically reduces stacking compared to the 2′-α series. Hence, base stacking emerges as being tunable by the C2′-F stereoconfiguration through dramatic puckering variations scrutinized by NMR and natural bond orbital analysis. Accordingly, 2′-β F-isomer photoreactivity is significantly reduced compared to that of the 2′-α F-isomer.
- Moriou, Céline,Da Silva, Adilson D.,Vianelli Prado, Marcos Joel,Denhez, Clément,Plashkevych, Oleksandr,Chattopadhyaya, Jyoti,Guillaume, Dominique,Clivio, Pascale
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- 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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- 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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- 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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- 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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