Nucleotide analogue and synthesis and application thereof

An analog and nucleotide technology, applied in the field of nucleotide analog synthesis, can solve the problems of unsuitable nucleotide analogs, increase selective protection and deprotection, etc., and achieve easy product separation and high yield , the effect of high substrate selectivity

Inactive Publication Date: 2012-07-11
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At the same time, if the substituent on the triazole ring contains functional groups such as amino and hydroxyl groups, it will also react with phosphorylation r...

Method used

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  • Nucleotide analogue and synthesis and application thereof
  • Nucleotide analogue and synthesis and application thereof
  • Nucleotide analogue and synthesis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 2,3,5-triacetyl-1-azido-ribose (2mmol) was dissolved in 44ml of phosphate buffer (pH 7.0) containing 10% (volume content) DMF, added lipase (derived from Candida rugosa) to a concentration of 5000U / ml, reacted at 37°C for 1.5 hours, ethyl acetate Extraction, concentrated silica gel column chromatography to get 5-hydroxy-2,3-diacetyl-1-azido ribose Yield 90%; The 5-hydroxyl-2,3-diacetyl-1-azido ribose (1mmol), dissolved in anhydrous 4ml tetrahydrofuran, added triethylamine (1.2mmol), added dropwise phosphorus oxychloride (1.2mmol) at 0°C, and stirred for 24h. Add 2ml of water, stir at room temperature, and concentrate to obtain 5-phospho-2,3-diacetyl-1-ribose azido

[0038] Synthetic 5-phospho-2,3-diacetyl-1-azido-ribose (1mmol), in 10ml containing the aqueous solution of 80% methanol, add phenylacetylene (1.1mmol), copper sulfate (0.1mmol) and sodium ascorbate (0.6mmol), stir reaction at 60 ℃ for 36 hours, through silica gel column chromatography, The product ...

Embodiment 2

[0046] The same method as in Example 1; the difference from Example 1 is that the alkyne used is 4-methoxyphenylacetylene, and in an aqueous solution containing 90% methanol, 5-phosphoric acid-2,3-diacetyl-1-alkyne The molar ratio of nitrogen ribose, phenylacetylene, copper sulfate and sodium ascorbate is 1:1.5:0.2:0.6, and the yield is 92%.

[0047]

[0048] 1 H NMR (D 2 O, 400MHz) δ (ppm) 8.17 (s, 1H), 7.39 (d, J = 8.4Hz, 2H), 6.96 (d, J = 8.4Hz, 2H), 5.95 (d, J = 4.6Hz, 1H) , 4.51 (dd, J 1 =J 2 = 4.6Hz, 1H), 4.34(dd, J 1 =J 2 =4.6Hz, 1H), 4.23(m, 1H), 3.99(m, 2H), 3.59(s, 3H). 13 C NMR (D 2 O, 100.6MHz) δ (ppm) 158.8, 147.3, 126.8, 121.9, 119.3, 114.1, 92.2, 84.2 (d, J=8.5Hz), 75.0, 70.5, 64.3, 55.2. 31 P NMR (D 2 O, 162MHz) δ (ppm) 4.11. HRMS (ESI) calcd for (C 14 h 18 N 3 o 8 P) - 386.0753, found 386.0763.

[0049] Inhibition of Escherichia coli growth assay

[0050] The method is the same as in Example 1, except that the difference from Example 1 is th...

Embodiment 3

[0054] The same method as in Example 1; the difference from Example 1 is that the concentration of lipase in the reaction system is 1000U / ml, and the yield of 5-hydroxyl-2,3-diacetyl-1-ribose azide is 50%. The alkyne used is 4-fluorophenylacetylene, in aqueous solution containing 50% ethanol, the reaction temperature is 40°C, the reaction time is 24h, and the yield is 98%.

[0055]

[0056] 1 H NMR (D 2 O, 400MHz) δ (ppm) 8.27 (s, 1H), 7.54 (m, 2H), 7.00 (m, 2H), 6.02 (d, J = 4.8Hz), 4.53 (dd, J 1 =J 2 = 4.8Hz, 1H), 4.37(dd, J 1 =J 2 =4.8Hz, 1H), 4.26(m, 1H), 4.11(m, 2H). 13 C NMR (D 2 O, 100.6MHz) δ(ppm) 163.7(d, J=245.6Hz), 146.9, 127.5(d, J=8.2Hz), 125.3, 119.8, 115.8(d, J=21.9Hz), 92.3, 84.3(d , J=8.3Hz), 75.2, 70.4, 64.3. 31 P NMR (D 2 O, 162MHz) δ (ppm) 4.13. 19 F NMR (D 2 O, 376.5MHz) δ (ppm)-114.2. HRMS (ESI) calcd for (C 13 h 15 N 3 o 7 FP) - 374.0553, found 374.0566.

[0057] Inhibition of Escherichia coli growth assay

[0058] The method is the ...

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Abstract

The invention discloses a nucleotide analogue and a synthesis and a application thereof. The constitutional formula of the nucleotide analogue is that: Tetra-O-Acetyl-D-Ribose is adopted as a raw material and generates the nucleotide analogue containing a triazole ring formwork through four steps of reaction, wherein R is C2-C15 saturated or unsaturated alkyl, or C2-C10 saturated or unsaturated alkyl containing hetero atoms; or R is R1 which is hydroxyl, alkoxy, amino or substituent amido; or R is R2 which is aryl or saturated or unsaturated alkyl; or R is R3 which is halogen, amono, methoxyl, methyl or other substituent. The nucleotide analogue can restrain the growth of microorganism such as escherichia coli, and can be used as an inhibitor of dehydrogenase such as malate dehydrogenase.

Description

technical field [0001] The invention relates to a synthesis method of a class of nucleotide analogs, in particular to a synthesis method and application of a class of nucleotide analogs with a triazole ring structure, belonging to the field of chemical synthesis of organic compounds. Background technique [0002] Nucleoside and nucleotide analogues are used for the treatment of AIDS, hepatitis B virus, cancer, etc. et al. Chemical Reviews 2010, 110, 1828-1856) important drug. Among them, the base is a five-membered heterocyclic nucleoside with a triazole ring skeleton, which has the characteristics of simple synthesis and high biological activity. People have carried out more chemical synthesis and activity research on it (C.Najera et al.Organic & Biomolecular Chemistry 2009, 7 , 4567-4581). [0003] Under physiological conditions, nucleoside analogs must be converted into corresponding nucleotides in the cell, and then nucleoside triphosphates can be generated by nucleoti...

Claims

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Application Information

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IPC IPC(8): C07H19/056C07H1/00A61K31/7056A61P31/04A61P35/00
CPCY02A50/30
Inventor 赵宗保侯淑华
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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