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Nucleic acid and application thereof

A nucleic acid and nucleotide technology, applied in the field of biomedicine, can solve problems such as low potency, short action time, and short half-life

Inactive Publication Date: 2019-08-20
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the aptamer also has the disadvantages of low potency and short action time (short half-life)

Method used

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  • Nucleic acid and application thereof
  • Nucleic acid and application thereof
  • Nucleic acid and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Example 1: 5-[N-(2-trifluoroacetamidoethylene)aminoacylmethylene]-2'-deoxyuridine (compound Synthesis of 1a)

[0101]According to the reaction formula in Scheme 1, 1.14g of 5-methoxycarbonylmethylene-2'-deoxyuridine (dU-EM, 3.8mol) was dissolved in 5mL of methanol, and it was added to 2.5mL of ethylenediamine (38mmol ) methanol solution, stirred for 4 hours, thin layer chromatography (TLC) showed that the reaction was complete. The reaction mixture was dissolved in 10mL of methanol, then 2.1mL of triethylamine and 5mL of ethyl trifluoroacetate were added to mix, the mixture was thoroughly mixed with silica gel and the solvent was evaporated under reduced pressure, and the product 1.1g (compound 1a), yield 68.3%, R f (dichloromethane:methanol, 9:1) 0.32.

[0102] 1 H NMR (400MHz, DMSO-d 6 ):δ2.08(m,2H,C2'-H),3.05(s,2H,CH 2 ),3.18(m,4H,CH 2 CH 2 ),3.56(m,2H,C5'-H),3.77(m,1H,C4'-H), 4.22(m,1H,C3'-H),4.96(t,J=5.5,C5'-OH ), 5.24(d, J=4.2, C3'-OH), 6.17(t, J=4.8, C...

Embodiment 2

[0105] Example 2: Synthesis of 5-(2-aminoethyl)-aminoacyl methylene-2'-deoxyuridine (compound 1-1)

[0106] According to the reaction formula in scheme 1, compound 1a (400mg, 0.94mmol) was added into concentrated ammonia water (40mL), stirred at room temperature for 4 hours, TLC showed that the reaction was complete. Column chromatography obtains product 286mg, yield 93%, R f (dichloromethane / ammonia methanol=1:1) 0.47.

[0107] 1 H NMR (400MHz, DMSO-d 6 ):2.09(m,2H,C2'-H),2.85(m,2H,CH 2 ),3.10(s,2H,CH 2 ),3.27(m,2H,CH 2 ),3.53(m,2H,C5'-H),3.78 (m,1H,C4'-H),4.24(m,1H,C3'-H),5.31(br,1H,C3'-OH), 6.18(m,1H,C1'-H),7.77(s,1H,C6-H),8.09(m,1H,NH),8.55(br,1H,NH).

[0108] 13 C NMR (100MHz, DMSO-d 6 ):33.9,37.1,61.9,70.9,84.5,87.9,109.0,139.0,150.9,163.8,170.8.

[0109] HRMS (C 13 h 20 N 4 o 6 +H + ,329.1456):329.1456; (C 13 h 20 N 4 o 6 +Na + , 351.1275):351.1276.

Embodiment 3

[0110] Example 3: 5'-(4,4'-dimethoxytriphenylmethyl)-5-[N-(2-trifluoroacetamidoethylene)amide Synthesis of Methylene]-2'-deoxyuridine (compound 1b)

[0111] According to the reaction formula in route 1, 1.20g of compound 1a (2.82mmol) was dissolved in 5mL of dry pyridine, 1.16g of DMTr-Cl (3.38mmol) was added thereto, and reacted at room temperature for 2 hours, when TLC showed that the reaction was complete , separated by column chromatography (5% pyridine treated silica gel) to obtain product 1.28g (compound 1b), yield 62.5%, R f (dichloromethane:methanol, 9:1) 0.56.

[0112] 1 H NMR (400MHz, DMSO-d 6 ):δ2.18(m,2H,C2'-H),2.70(s,2H,CH 2 ),3.17(m,6H,CH 2 CH 2 ,C5'-H),3.73(s,6H,2OCH 3 ), 3.87(m, 1H, C4'-H), 411.25(m, 1H, C3'-H), 5.32(d, J=4.5, C3'-OH), 6.20(t, J=4.8, C1' -H),6.86,7.19-7.40(2m,13H,arom.H),7.55(s,1H,C6-H),7.86(m,1H,CONH),9.33(s,1H,CONHCOCF 3 ),11.38(s,1H,3-NH).

[0113] 13 C NMR (400MHz, DMSO-d 6 ):δ33.1,37.5,55.0,63.9,70.5,84.0,85.4,85.8,108.8,113...

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Abstract

The invention belongs to the field of biological medicines, and relates to a nucleic acid and an application thereof. Specifically, the present invention relates to a nucleic acid which is formed by modifying 5'-d (GGT TGG TGT GGT TGG)-3' (SEQ ID NO:1) through at least one selected from nucleotide residues shown in a formula I to a formula III and salts thereof. On the basis, the invention also relates to the application of the nucleic acid. The nucleic acid can be used as a thrombin aptamer, has strong affinity with thrombin, and has an anticoagulant effect.

Description

technical field [0001] The invention belongs to the field of biomedicine, specifically relates to a nucleic acid, and also relates to the application of the nucleic acid. Background technique [0002] Aptamers refer to nucleic acids that are screened under certain conditions and have affinity for specific targets, including metal ions related to environmental pollution (such as Hg 2+ , Pb 2+ ), signaling molecules related to disease occurrence, abnormally expressed cells (tumor cells, etc.), diseased tissues, and foreign viruses and bacteria, etc. Therefore, aptamers with high specificity and high affinity can be used as probes for detecting metal ions or disease signaling molecules, and can also be used as therapeutic drugs to inhibit pathogenic protein molecules, viruses, bacteria, cells and tissues. [0003] Aptamers with higher affinity and specificity are currently a research hotspot. There are two main discovery strategies at present: the first one is to modify the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/115A61K31/7088A61P7/02G01N33/573
CPCC12N15/115C12N2310/16G01N33/573G01N2333/974
Inventor 何军林史卫国杜闪闪李阳郭磊李朋羽
Owner ACADEMY OF MILITARY MEDICAL SCI
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