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Bicyclonucleoside and oligonucleotide analogues

a technology of oligonucleotide and cyclonucleoside, which is applied in the field of new nucleotide analogues and novel nucleotide analogues, can solve the problems of insufficient in vivo stability of derivatives or analogues, insufficient sequence specificity, and inability to fully satisfy the requirements of in vivo stability

Inactive Publication Date: 2014-02-25
EXIQON AS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a new nucleic acid analog that can be used in antisense methods. This analog has a conformationally immobilized sugar portion in a nucleic acid and is a useful tool for inhibiting the expression of specific genes. The invention synthesizes a nucleoside analog that can be used to create antisense molecules, which have been found to be effective in reducing gene expression.

Problems solved by technology

When a naturally occurring oligonucleotide was applied to this method as an antisense molecule, however, it was decomposed with various nucleases in vivo, or its permeation through the cell membrane was not high.
Any resulting derivatives or analogues, however, have not been fully satisfactory in terms of In vivo stability, ease of synthesis, and sequence specificity (the property of selectively controlling the expression of a particular gene alone).

Method used

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  • Bicyclonucleoside and oligonucleotide analogues
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  • Bicyclonucleoside and oligonucleotide analogues

Examples

Experimental program
Comparison scheme
Effect test

example 2

Synthesis of Nucleoside Analogue

[0080](1) Synthesis of Methyl=5-O-(t-butyldiphenylsilyl)-4-hydroxymethyl-2,3-O-isopropylidene-β-D-ribofuranoside (Compound 14)

[0081]In a stream of nitrogen, Et3N (2.62 ml, 18.8 mmols) and t-butyldiphenylsilyl chloride (4.88 ml, 18.8 mmols) were added to an anhydrous CH2Cl2 solution (40 ml) of Compound 13 (2.00 g, 8.54 mmols) known in the literature under cooling with ice, and the mixture was stirred for 13 hours at room temperature. To the reaction mixture, a saturated sodium bicarbonate solution was added, whereafter the reaction system was extracted with AcOEt 3 times. The organic phase was washed once with a saturated sodium chloride solution, and then dried over anhydrous Na2SO4. The solvents were distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane:AcOEt=5:1) to obtain colorless oily matter (Compound 14) (2.82 g, 5.98 mmols, 70%).

[0082][α]D17−16.2° (c=0.52, CHCl3). IR ν (KB...

example 3

Synthesis of Nucleoside Analogue (Different Method)

[0115](1) Synthesis of 3-O-benzyl-5-O-t-butyldiphenylsilyl-4-(hydroxymethyl)-1,2-O-isopropylidene-α-D -erythropentofuranose (Compound 32)

[0116]In a stream of nitrogen, triethylamine (3.71 ml, 26.6 mmols) and t-butyldiphenylsilyl chloride (6.94 ml, 26.7 mmols) were added, under cooling with ice, to a methylene chloride solution (50 ml) of Compound 31 (2.50 g, 8.08 mmols) prepared in accordance with the aforementioned reference 5). The mixture was stirred for 10.5 hours at room temperature. After a saturated sodium bicarbonate solution was added to the reaction mixture, the system was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, and then dried over sodium sulfate. The solvents were distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (AcOEt-hexane:=1:4→4:3) to obtain a white solid, Compound 32 (2.97 g, 5.41 mmols,...

example 4

[0157](1) Synthesis of 2′-O-acetyl-3′-O-benzyl-5′-O-t-butyldiphenylsilyl-4′-p-toluenesulfonyloxymethyl-N6-benzoyladenosine (Compound 40)

[0158]In a stream of nitrogen, a 1,2-dichloroethane solution (5.0 ml) of Compound 34 (250 mg, 0.336 mmol) and trimethylsilyltrifluoromethane sulfonate (6.7 μl, 0.0336 mmols) were added, at room temperature, to 2TMS.ABz (128.7 mg, 0.336 mmol) prepared In accordance with a reference 6) (H. Vorbrggen, K. Krolikiewicz and B. Bennua, Chem., Ber., 114, 1234-1255 (1981)). The mixture was heated under reflux for 26 hours. After a saturated sodium bicarbonate solution was added to the reaction mixture, the system was extracted 3 times with methylene chloride. The organic phase was washed with a saturated sodium chloride solution, and then dried over sodium sulfate. The solvents were distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (CHCl3MeOH, 1:3) to obtain a white powder, Compound 40 (234...

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Abstract

An oligo- or polynucleotide analogue having one or more structures of the general formulawhere B is a pyrimidine or purine nucleic acid base, or an analogue thereof,is disclosed. The use of this analogue provides an oligonucleotide analogue antisense molecule, which is minimally hydrolyzable with an enzyme in vivo, has a high sense strand binding ability, and is easily synthesized.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]The present application is the national stage under 35 U.S.C. 371 of PCT / JP98 / 00945, filed Mar. 9, 1998.TECHNICAL FIELD[0002]This invention relates to a novel nucleoside analogue and a novel nucleotide analogue, and more particularly, to a nucleotide analogue suitable as an antisense molecule.BACKGROUND ART[0003]In 1978, it was reported for the first time that an antisense molecule inhibited influenza virus infection. Since then, reports have been issued that antisense molecules inhibited the expression of oncogenes and AIDS infection. In recent years, antisense oligonucleotides have become one of the most promising pharmaceuticals, because they specifically control the expression of undesirable genes.[0004]The antisense method is based on the idea of controlling a unidirectional flow called the central dogma, i.e., DNA→RNA→protein, by use of an antisense oligonucleotide.[0005]When a naturally occurring oligonucleotide was applied to this ...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07H19/06C07H19/16C07H21/00
CPCC07H19/16C07H19/06C07H1/00C07H19/067C07H19/167C07H21/02
Inventor IMANISHI, TAKESHIOBIKA, SATOSHI
Owner EXIQON AS
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