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5'-modified nucleoside and nucleotide using same

A nucleic acid and carbon number technology, applied in the field of nucleosides modified at the 5' position and nucleotides using the same, can solve problems such as complicated manufacturing processes, and achieve the effect of excellent industrial productivity

Inactive Publication Date: 2021-10-01
OSAKA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, since the synthesis of such an artificial nucleic acid having a substituent at the 5' position requires the separation of diastereoisomers (Non-Patent Documents 3 and 4), the overall production process becomes complicated, and further development is desired. for industrial production

Method used

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  • 5'-modified nucleoside and nucleotide using same
  • 5'-modified nucleoside and nucleotide using same
  • 5'-modified nucleoside and nucleotide using same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0435] (Example 1: Synthesis of 5' modified nucleosides (1))

[0436]

[0437] Reagents and conditions of each process: (a) TEMPO, PhI(OAc) 2 , CH 2 Cl 2 , room temperature, 5 hours, then H 2 O, MeCN, room temperature, 4 hours; (b) EDC·HCl, MeOH, CH 2 Cl 2 , 0°C, 4.5 hours, 84% (2 processes); (c) CH 2MgBr, THF, -20°C, 8 hours, 84%; (d) DMT-dT phosphoramidite, BTT, MeCN, room temperature, 3 hours; (e) TBHP, MeCN, room temperature, 1 hour, 76% (2 process); (f) TEA·3HF, THF, 0°C to room temperature, 41.5 hours, 95%; (g) i PR 2 NP(Cl)OC 2 h 4 CN, DIPEA, MeCN, room temperature, 4 hours, 67%.

[0438] (1-1) Synthesis of compound 2

[0439]

[0440] After dissolving compound 1 (4.26 g, 11.95 mmol) produced by the method described in Caruthers et al., Tetrahedron Lett., 1996, Vol. 37, No. 35, pages 6239-6242 in dichloromethane (60 mL), diacetic acid was added Iodobenzene (PhI(A)2; 8.47 g, 26.30 mmol). Then, 2,2,6,6-tetramethylpiperidin-1-oxyl radical (TEMPO; 430.4 m...

Embodiment 2

[0474] (Example 2: Synthesis of 5' modified nucleosides (2))

[0475]

[0476] Reagents and conditions of each process: (h) DMT-dG (ib) phosphoramidite, BTT, MeCN, room temperature, 2 hours; (i) TBHP, MeCN, room temperature, 2 hours, 94% (2 processes).

[0477] (2-1) Synthesis of Compound 9

[0478]

[0479] Compound 4 (494.7mg, 1.29mmol) obtained in (1-3) of Example 1 was azeotroped with anhydrous toluene, dissolved in anhydrous acetonitrile (13mL), and added 5′-(4, 4′-Dimethoxytrityl)-N-isobutyryl-2′-deoxyguanosine-3′-[(2-cyanoethyl)-(N,N-diisopropyl)] - Phosphoramidite (DMT-dG(ib) phosphoramidite; 1.66g, 1.98mmol), 5-(benzylthio)-1H-tetrazole (BTT; 372.6mg, 1.94mmol), stirred at room temperature for 2 hours . After completion of the reaction, water was added, followed by extraction with ethyl acetate. After washing with water and saturated brine, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained com...

Embodiment 3

[0489] (Example 3: Synthesis of 5' modified nucleosides (3))

[0490]

[0491] Reagents and conditions of each process: (j) BTT, MeCN, room temperature, 5.5 hours; (k) TBHP, MeCN, room temperature, 1.5 hours, 42% (2 processes)

[0492] (3-1) Synthesis of Compound 12

[0493]

[0494] Compound 8 (80.5mg, 0.071mmol) obtained in (1-7) of the above-mentioned Example 1 was azeotroped with anhydrous toluene, dissolved in anhydrous acetonitrile (0.5mL), and added sequentially under a nitrogen stream. (1-3) The obtained compound 4 (21.9 mg, 0.057 mmol) and 5-(benzylthio)-1H-tetrazole (BTT; 17.1 mg, 0.089 mmol) were stirred at room temperature for 5.5 hours. After completion of the reaction, water was added, followed by extraction with ethyl acetate. After washing with water and saturated brine, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained compound 12 (105.9 mg; crude product) was used for the subsequent rea...

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Abstract

Disclosed are a 5'-modified nucleoside and a nucleotide using the same. The nucleoside according to the present invention is represented by formula (I). The 5'-modified nucleoside according to the present invention can be a substitute for a phosphorothioate-modified nucleic acid that is a concern due to possible accumulation in a specific internal organ, and does not require a process for separating diastereomers in the production of the nucleoside, whereby the present invention has excellent industrial productivity.

Description

technical field [0001] The present invention relates to modified nucleosides at the 5' position and nucleotides using the same. More specifically, it relates to a 5'-modified nucleoside that has good nuclease resistance and can be efficiently produced, and a nucleotide using the same. Background technique [0002] There are antisense methods, antigene methods, nucleic acid aptamers, siRNA, and the like as therapeutic methods for diseases using nucleic acid drugs. Among them, the antisense method is to introduce an oligonucleotide (antisense strand) complementary to a disease-related mRNA from the outside to form a double strand, thereby hindering the translation process of the pathogenic RNA to treat or prevent the disease. Similarly, siRNA blocks the translation of mRNA into protein by administering double-stranded RNA to the living body. On the other hand, the antigene method inhibits the transcription from DNA to RNA by introducing from the outside a triplex-forming oli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H21/04C12N15/113
CPCC07H21/04
Inventor 小比贺聪山口卓男羽渕贵纪加藤刚井上贵雄吉田德幸M·A·伊斯兰
Owner OSAKA UNIV
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