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Isonucleoside compound or ortho-phosphite derivative thereof and preparation method and application thereof

A technology of isonucleoside compounds and compounds, applied in the application field of modifying siRNA and deoxy oligonucleotides, can solve the problems of complex chemical modification and so on

Inactive Publication Date: 2012-10-24
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Similar to ASONs, siRNAs with natural structure cannot fully meet the needs of gene medicines, and necessary chemical modifications can improve their in vivo stability, membrane permeability, bioavailability and other characteristics, and enhance their silencing effect
The research on chemical modification methods of ASONs is of great help to the structural modification of siRNAs, but due to the complexity of the mechanism of action of siRNAs and their own structure, the chemical modification of siRNAs is more complicated than that of ASONs, and further research is still needed

Method used

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  • Isonucleoside compound or ortho-phosphite derivative thereof and preparation method and application thereof
  • Isonucleoside compound or ortho-phosphite derivative thereof and preparation method and application thereof
  • Isonucleoside compound or ortho-phosphite derivative thereof and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Example 1 Synthesis of 5-(S)-hydroxymethylene-4-(R)-hydroxyl-3-(S)-(adeninyl-9')-tetrahydrofuran (n=1 in formula I, B is adenine)

[0085] 1.5-(R)-dimethoxymethyl-4-(R)-hydroxyl-3-(S)-(adeninyl-9')-tetrahydrofuran[5-(R)-dimethoxy-methyl-4-( Synthesis of R)-hydroxy-3-(S)-(adenyl-9')-tetrahydrofuran] (formula III)

[0086]Adenine (958mg, 7.09mmol), DBU (1.76ml, 11.79mmol) was placed in a microwave reaction flask, and the compound 5-(R)-dimethoxymethyl-3-(R), 4-(R )-epoxy-tetrahydrofuran (formula II, 942 mg, 5.88 mmol) in 20 ml of anhydrous DMF, capped, and stirred at room temperature for 10 min; the reaction bottle was placed in a microwave reactor, catalyzed by medium-power microwaves, and reacted for 30 min at 180 ° C; After suction filtration, the solvent was evaporated to dryness with an oil pump, and the column was separated under normal pressure to obtain 1.45 g of the product as a white solid with a yield of 83.5%.

[0087] 1 H NMR (300MHz, DMSO-d 6 ) δ3.30-3....

Embodiment 2

[0093] Example 2 Synthesis of [5S-(2-hydroxyethyl)-4R-hydroxyl-3S-(adeninyl-9-yl)]-tetrahydrofuran, [5S-(2-hydroxyethyl)-4R-hydroxyl-3S- Synthesis of (adenin-9-yl)-tetrahydrofuran (n=2 in formula I, B is adenine)

[0094] 1.(2R-dimethoxymethyl-3S-O-p-toluenesulfonyl-4R-O-benzoyl)-tetrahydrofuran[(2R-dimethoxymethyl-3S-O-p-toluenesulfonyl-4R-O-benzoyl)- tetrahydrofuran] (Formula IV)

[0095] (2R-Dimethoxymethyl-3S-O-p-toluenesulfonyl-4R-hydroxy)-tetrahydrofuran (1.99g, 5.99mmol) was dissolved in anhydrous pyridine (40mL), and BzCl (1.05mL, 9.11mmol) was added ) and DMAP (77 mg, 0.63 mmol). The reaction solution was stirred at room temperature overnight, the solvent was evaporated to dryness, the residue was dissolved in ethyl acetate, saturated NaHCO 3 solution and saturated NaCl solution, anhydrous Na 2 SO 4 Dry, filter and concentrate. Atmospheric pressure silica gel column separation, eluting with petroleum ether-ethyl acetate, gave light yellow syrup (2.56g, 98.1%). ...

Embodiment 3

[0126] Example 3 Synthesis of [5S-(2-hydroxypropyl)-4R-hydroxyl-3S-(adeninyl-9'-yl)]-tetrahydrofuran (n=3 in formula I, B is adenine)

[0127] 1. {2S-[2-E(Z)-ethoxycarbonylvinyl]-3R-O-p-toluenesulfonyl-4R-O-benzoyl}-tetrahydrofuran, {2S-[2-E(Z) -ethoxycarboxyl-vinyl]-3R-O-p-toluenesulfonyl-4R-O-benzoxy}-tetrahydrofuran} (Formula XIV)

[0128] (2R-Dimethoxymethyl-3S-O-p-toluenesulfonyl-4R-O-benzoyl)-tetrahydrofuran (3.00 g, 6.78 mmol) was dissolved in 87.5% aqueous trifluoroacetic acid (8 mL), React at room temperature for 5 hours, evaporate most of the solvent, and dissolve the residue with dichloromethane, then wash with saturated NaHCO 3 Wash with aqueous solution and saturated NaCl aqueous solution, dry over anhydrous MgSO4, filter, and concentrate to obtain white sugar bubbles. A suspension of NaH (60%, 275mg, 6.88mmol) in anhydrous THF (19mL) was kept at -30°C, and (EtO) was added dropwise 2 P(O)CH 2 COOEt (1.43mL, 6.99mmol), after stirring for about 30 minutes, added...

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Abstract

The invention provides an isonucleoside compound or an ortho-phosphite derivative thereof. The compound can be used for effectively increasing the gene silencing efficiency of oligonucleotide modified by the compound and keeping the enzyme stability of the oligonucleotide. The invention further provides a preparation method of the isonucleoside compound or the ortho-phosphite derivative thereof, a solid-phase synthesis method of oligonucleotide 5' end phosphorylation and the application of the compound to the modification of the oligonucleotide.

Description

technical field [0001] The invention relates to a class of isonucleoside compounds or their phosphoramidite derivatives, a preparation method thereof and the application of the compounds in modifying siRNA and deoxyoligonucleotides. Background technique [0002] Antisense oligonucleotides (ASONs) are the most widely and deeply researched class of nucleic acid drugs, about 15-20bp in length, capable of hybridizing with homologous RNA sequences, inhibiting the transcription and translation of specific genes or destroying the structure of target RNA , so as to achieve the purpose of treating diseases. As drugs, oligonucleotides with natural structure cannot permeate the cell membrane and are easily degraded by internal endoenzyme, so their bioavailability is not high. Therefore, it is necessary to modify their structure to improve their biological properties. Phosphothiodiester Modified Oligonucleotide Vitravene TM , as an antisense drug to inhibit retinitis caused by cytomeg...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/34C07F9/6561C07H21/04C07H1/00C07F9/6558C07D405/04C07D473/18C07H21/02
Inventor 杨振军张俊王卓黄野关注张亮仁张礼和
Owner PEKING UNIV
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