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Bi-and tri-cyclic nucleoside, nucleotide and oligonucleotide analoguse

A technology of nucleoside analogs and analogs, which is applied in the field of bis- and tricyclic nucleoside analogs, and can solve problems such as hybridization specificity and complex methods, complex synthesis, and lack of

Inactive Publication Date: 2006-09-06
EXIQON AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The evaluation of most of the reported analogs is complicated by the lack of data on analogs with G, A, and C nucleotide bases and the lack of data indicating the specificity and mode of hybridization
In many cases, the synthesis of reported monomer analogs is very complex, while in others, the synthesis of fully modified oligonucleotides is incompatible with the widely used chemical standards of phosphoramidites.

Method used

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  • Bi-and tri-cyclic nucleoside, nucleotide and oligonucleotide analoguse
  • Bi-and tri-cyclic nucleoside, nucleotide and oligonucleotide analoguse
  • Bi-and tri-cyclic nucleoside, nucleotide and oligonucleotide analoguse

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0291] 3-C-allyl-1,2-O-isopropylidene-α-D-ribofuranose (0A)

[0292] Method 1: 5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-α-D-nucleofuran-3-ketose (Y.Yoshimura, T.Sano , A.Matsuda and T.Ueda, Chem.Pharm.Bull., 1988,36,162) (17.8g, 58.9mmol) of anhydrous THF (980cm 3 ) solution and added dropwise in anhydrous ether (130cm 3 , 130 mmol) of 1M allylmagnesium bromide. After stirring for 2 hours, add a saturated aqueous solution of ammonium chloride (800cm 3 ) and dichloromethane (3×400cm 3 ) to extract the mixture. With salt water (3×450cm 3 ) to wash the organic phase and dry (sodium sulfate). The solvent was removed under reduced pressure and the residue was dissolved in anhydrous THF (700 cm 3 )middle. Add 1.1M tetrabutylammonium fluoride in THF (54.4cm 3 , 59.8 mmol) solution, the mixture was stirred at room temperature for 1 hour and evaporated to dryness. The residue was dissolved in dichloromethane (1700cm 3 ) and saturated aqueous solution of sodium bicarb...

Embodiment 2

[0295] 3-C-allyl-3,5-di-O-benzyl-1,2-O-isopropylidene-α-D-ribofuranose (0B)

[0296] Sodium hydride (4.9g, 123mmol) in anhydrous DMF (100cm 3 ) and added dropwise furanose OA (9.42g, 40.9mmol) in anhydrous DMF (65cm 3 ) solution. The solution was stirred at 50°C for 1 hour and cooled to 0°C. Benzyl bromide (14.5cm 3 , 121mmol) and anhydrous DMF (14.5cm 3 ) and stirred at room temperature for 18 hours. The reaction mixture was evaporated to dryness, washed with saturated aqueous sodium bicarbonate (2×450cm 3 ) Dichloromethane (700cm 3 ) solution and dried (sodium sulfate). The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (9:1, v / v) as eluent to obtain compound OB (14.5 g, 86%) as an oil. δ H (CDCl 3 )7.39-7.21 (10H, m, Bn), 5.92 (1H, m, 2′-H), 5.71 (1H, d, J3.8, 1-H), 5.17-5.09 (2H, m, 3′- h a , 3′-H b ), 4.67(2H, m, Bn), 4.60(1H, d, J12.2, Bn), 4.52(1H, d, J12.1, Bn...

Embodiment 3

[0298] 3-C-allyl-1,2-di-O-acetyl-3,5-di-O-benzyl-D-ribofuranose (OC)

[0299] Stirring ribofuranose OB (12.42g, 30.3mmol) in 80% acetic acid (150cm 3 ) solution in aqueous solution for 3 hours. The solvent was removed under reduced pressure, and ethanol (3×75cm 3 ), toluene (3×75cm 3 ) of anhydrous pyridine (2×75cm 3 ) was co-evaporated with the residue and redissolved in anhydrous pyridine (60cm 3 ). Add acetic anhydride (46cm 3 ) and the solution was stirred at room temperature for 48 hours. Add ice and water (300cm 3 ) mixture, with diazomethane (2×300cm 3 ) to extract the resulting mixture. Sodium bicarbonate saturated aqueous solution (3 × 200cm 3 ) to wash the combined organic phases and dry (sodium sulfate). The solvent was evaporated, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (4:1, v / v) as eluent to obtain the oily anomeric mixture OC (β:α~2:1)( 13.3 g, 97%). δ C (CDCl 3 ) 169.7, 169.6 (C=O), 138...

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Abstract

The present invention relates to novel bicyclic and tricyclic nucleoside and nucleotide analogues as well as to oligonucleotides comprising such elements. The nucleotide analogues, LNAs (Locked Nucleoside Analogues), are able to provide valuable improvements to oligonucleotides with respect to affinity and specificity towards complementary RNA and DNA oligomers. The novel type of LNA modified oligonucleotides, as well as the LNAs as such, are useful in a wide range of diagnostic applications as well as therapeutic applications. Among these can be mentionned antisense applications, PCR applications, strand displacement oligomers, as substrates for nucleic acid polymerases, as nucleotide based drugs, etc. The present invention also relates to such applications.

Description

field of invention [0001] The present invention relates to the field of bi- and tricyclic nucleoside analogs and to the synthesis of such nucleoside analogs for the formation of nucleotide bases capable of forming nucleotide bases (necleobases) with single- and double-stranded nucleic acids. ) specific synthetic oligonucleotides of duplexes and triplexes. These complexes display higher thermotolerance than corresponding complexes formed from normal nucleic acids. The invention also relates to the field of bis- and tricyclic nucleoside analogs and the synthesis of such nucleosides which can be used as therapeutic agents and which can be conjugated to oligonucleotides by template-dependent nucleic acid polymerases. Background of the invention [0002] Synthetic oligonucleotides are widely used compounds in intersecting fields such as molecular biology and DNA-based diagnostics and therapeutics. [0003] Therapeutics [0004] In therapeutics, for example, oligonucleotides ha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/04C07H21/00A61K31/70C12Q1/68A61P35/00C12N15/09A61K31/7042A61K31/7052A61K31/7064A61K31/7072A61K31/7076A61K31/7088A61K31/712A61K48/00A61P31/12C07D491/08C07D493/04C07D493/08C07F7/18C07F9/6558C07H19/06C07H19/16C12N15/11
CPCC07H19/04C07H21/00A61P31/12A61P35/00
Inventor J·温格尔P·尼尔森
Owner EXIQON AS
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