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Novel siRNA chemical modification monomer, preparation method thereof and use thereof

A chemical modification and monomer technology, applied in chemical instruments and methods, organic chemistry, pharmaceutical formulations, etc., can solve problems such as poor biological stability, short half-life, and limited development

Inactive Publication Date: 2010-12-22
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The results of in vivo and in vitro experiments show that Mdm2-siRNA has a significant inhibitory effect on the proliferation of breast cancer, but there are defects such as poor biological stability, short half-life and non-specific off-target effects, which limit its further development

Method used

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  • Novel siRNA chemical modification monomer, preparation method thereof and use thereof
  • Novel siRNA chemical modification monomer, preparation method thereof and use thereof
  • Novel siRNA chemical modification monomer, preparation method thereof and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] "Example 1" Preparation of 2-hydroxyl-3-(4,4'-dimethoxytrityloxy) propyl phenyl ether

[0038] Take phenol (90mmol), 150mL of methyl ethyl ketone, and potassium carbonate (180mmol), add them into a 500mL three-necked reaction flask, and add epichlorohydrin (630mmol) dropwise under stirring at 45°C. After about 30 minutes, the dropwise addition is completed, and the reaction solution becomes cloudy , heated up to 80°C, refluxed for 10h, cooled, filtered, evaporated most of the solvent under reduced pressure, added 100mL of water, extracted with dichloromethane (100mL×3), washed the organic layer with 20% NaOH (10mL×3) times, organic The layer was dried over anhydrous magnesium sulfate, filtered, and dichloromethane was distilled off under reduced pressure. 2,3-Epoxypropylphenyl ether was obtained as a yellow oil.

[0039] Take the crude product of 2,3-epoxypropylphenyl ether (90mmol), water (90mmol), DMF (9mmol) into the reaction flask, seal it, heat up to 110°C and sti...

Embodiment 2

[0042] "Example 2" Preparation of 2-hydroxyl-3-(4,4'-dimethoxytrityloxy) propyl (4-fluoro)phenyl ether

[0043] 4-fluorophenol was used instead of phenol, and the operation method was referred to in Example 1 to obtain a light yellow oil with a yield of 71.0%.

[0044] 1H NMR (DMSO-d6, 400MHz) δ: 3.09 (d, J = 4.8Hz, 2H, CH2), 3.73 (s, 6H; 2OCH3), 4.04-4.13 (m, 3H; CH2CH), 5.29 (d, J = 4.8 Hz, 1H; OH), 6.89-6.97 (m, 6H; ArH), 7.08-7.54 (m, 11H; ArH).

Embodiment 3

[0045] "Example 3" Preparation of 2-hydroxyl-3-(4,4'-dimethoxytrityloxy) propyl (4-methyl)phenyl ether

[0046] 4-methylphenol was used instead of phenol, and the operation method was referred to in Example 1 to obtain a light yellow oil with a yield of 55.4%.

[0047] 1H NMR (DMSO-d6, 400MHz) δ: 2.21 (s, 3H; CH3), 3.07 (m, 2H; CH2), 3.72 (s, 6H; 2OCH3), 3.90-3.99 (m, 3H; CH2CH), 5.11 (d, J=4.8Hz, 1H; OH), 6.77(d, J=8.4Hz, 2H; ArH), 6.84-6.86(m, 4H; ArH), 7.05(d, J=8.4Hz, 2H; ArH ), 7.19-7.29 (m, 7H; ArH), 7.38 (d, J=7.6Hz, 2H; ArH).

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Abstract

The invention relates to a novel siRNA chemical modification monomer, and the use of the monomer in the preparation of medicaments for genetic treatment of tumors. Experiments show that the chemically modified siRNAs has improved human breast cancer MCF-7 cell inhibiting activity and nuclease stability and is expected to be developed into medicaments used for the effective genetic treatment of tumors in clinic.

Description

Technical field: [0001] The invention relates to the design and synthesis of a novel chemically modified monomer; it provides the preparation of different chemically modified siRNAs and the application of chemically modified siRNAs in anti-tumor gene therapy. Background technique: [0002] In recent years, the newly developed RNA interference (RNA interference, RNAi) technology is that double-stranded RNA (dsRNA) specifically induces the degradation of mRNA molecules homologous to its sequence, resulting in the inhibition of corresponding gene expression. It is a special post-transcriptional gene silencing phenomenon. It has been confirmed that RNA interference is an effective gene silencing process that is ubiquitous in the biological world. It is widely found in eukaryotic cells such as plants and animals. Features such as mild side effects. The application of RNA interference technology to develop new targeted drugs has become one of the key development directions in th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/141C07H21/02A61K48/00A61P35/00
Inventor 王玉成李祎亮邵荣光任开环何红伟王菊仙白晓光许乐幸吴香玫李保卫
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI