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Preparation of brominated flavanonollignan and application in medicine for treating viral hepatitis B

A dihydroflavonol lignan and dihydro technology, which is applied in the field of medicine, can solve problems such as not being effectively developed, and achieve the effects of convenient raw material sources, convenient synthesis, and easy-to-obtain raw material sources

Inactive Publication Date: 2011-01-26
DALI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Although flavonoid lignans represented by silibinin have the above-mentioned antioxidant effects, there are relatively few literatures on antiviral treatment. Flavonoids are especially effective in treating DNA virus infections Its application in anti-hepatitis B virus (including inhibition of HBsAg or HBeAg, inhibition of HBV DNA replication) has not been effectively developed. Therefore, active compounds in the field of anti-hepatitis B virus are searched from flavonoid lignans, that is, structural modification of flavonoid lignans Making it active against DNA-like viruses is a brand-new field; finding lead compounds that clear HBsAg or HBeAg and inhibit HBV DNA replication is a challenge that has never been tried before

Method used

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  • Preparation of brominated flavanonollignan and application in medicine for treating viral hepatitis B
  • Preparation of brominated flavanonollignan and application in medicine for treating viral hepatitis B
  • Preparation of brominated flavanonollignan and application in medicine for treating viral hepatitis B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Formula (1) (±)-2-[2,3-dihydro 3-(3-bromo-5-methoxy 4-hydroxyphenyl)-2-hydroxymethyl-1,4 benzodioxane Preparation of cyclo-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-benzopyran-4-one

[0032] Instruments and reagents:

[0033] The ultraviolet spectrum was measured with a Shimadzu UV-240 ultraviolet spectrophotometer; the hydrogen nuclear magnetic resonance spectrum 1 H-NMR is measured by INOVA type superconducting nuclear magnetic resonance spectrometer (VARIAN INOVA-400MHz) (tetramethylsilyl ether TMS is the internal standard); (100-200, 200-300 and 300-400 mesh) and silica gel GF254 (10-40 mesh) for thin layer chromatography are all produced by Qingdao Ocean Chemical Factory; all reagents used are analytically pure, and the boiling range of petroleum ether is 60 -90°C; thin-layer preparative chromatography (PTLC) uses aluminum foil silica gel plates from Merck; column chromatography uses dextran gel Sephadex LH-20 from Amersham Pharmacia Biotech AB in Sweden;...

Embodiment 2

[0051] Example 2: Inhibitory Effect of Compound (1) on Hepatitis B Surface Antigen (HBsAg) Secreted by HepG2.2.15 Cells

[0052] 2.1 Cell culture:

[0053] HepG2.2.15 cells were cultured in DMEM medium containing 10% inactivated fetal bovine serum, 100 U / ml penicillin and 100 U / ml streptomycin, 100 μg / ml G418 at 37°C, 5% CO 2 , cultured in an incubator with 100% relative humidity.

[0054] 2.2 The inhibitory effect of the compound of formula (1) on HepG2.2.15 cell growth was measured by MTT method:

[0055] Take the HepG2.2.15 cells in the logarithmic growth phase, and dilute the cells to 1×10 with medium 5 cells / ml, seeded in 96-well cell culture plate, 100 μl per well, at 37°C, 5% CO 2 After 24 hours in an incubator with 100% relative humidity, add compound (1) diluted with medium, the concentration is 1000 μg / ml, 200 μg / ml, 40 μg / ml and 8 μg / ml, 200 μg / ml in each well microliter, each concentration was set up in triplicate, placed at 37°C, 5% CO 2 , cultivated in an ...

Embodiment 3

[0064] Example 3: Inhibitory effect of compound (1) on hepatitis B e antigen (HBeAg) secreted by HepG2.2.15 cells.

[0065] 3.1 Cell culture: the method is the same as in Example 2.

[0066] 3.2 Determination of the inhibitory effect of the compound of formula (1) on the growth of HepG2.2.15 cells by MTT method: the method is the same as in Example 2.

[0067] 3.3 Determination of the inhibitory effect of the compound on hepatitis B e antigen (HBeAg): take the HepG2.2.15 cells in the logarithmic growth phase, and dilute the cells to 1 × 10 with the medium 5 / ml, seeded in 96-well cell culture plate, 100ml per well, at 37°C, 5% CO 2 After culturing in an incubator with 100% relative humidity for 24 hours, add samples diluted with culture medium at concentrations of 20 μg / ml, 4 μg / ml and 0.8 μg / ml, 200 μl per well, and set three concentrations for each Multiple wells were placed at 37°C, 5% CO 2 , cultivated in an incubator with 100% relative humidity, change the culture medi...

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Abstract

The invention relates to the preparation of brominated flavanonollignan and an application in medicines for treating viral hepatitis B, in particular to a B cyclo-dioxane flavanonollignan compound and a preparation method thereof as well as the application of the compound or pharmaceutically acceptable salts thereof in the preparation of medicines for eliminating hepatitis B surface antigens (HBsAg) and hepatitis B e antigens (HBeAg) and medicines for inhibiting HBV DNA replication. The compound has obvious activity of inhibiting HBsAg and HBeAg, and the intensities of the compound for eliminating HBsAg and HBeAg under the concentration of 20 microgram / millimeter are respectively 2.1 times and 1.2 times larger than the corresponding activity of a positive control medicine alpha-interferon; meanwhile, the compound displays high inhibition ratio more than 57% on HBV DNA at the concentration. The results show that the favonolignan or pharmaceutically acceptable salts thereof can be expected to be used for preparing non-nucleoside type medicines for eliminating HBsAg and HBeAg, inhibiting HBV DNA replication and treating HBV infected diseases.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular, the invention relates to a dihydroflavonol lignan compound of B-ring dioxane or a pharmaceutically acceptable salt thereof for the preparation of reducing hepatitis B virus surface antigen HBsAg and hepatitis B e antigen Use of HBeAg, inhibiting HBV DNA replication, or treating hepatitis B virus infection diseases. This flavonoid lignan has extremely significant inhibition of HBsAg and HBeAg activity, and its intensity of removing HBsAg and HBeAg is respectively 34.3% and 19.9% ​​under the concentration of 20 micrograms / milliliter, is positive control drug (10000 units / milliliter α- Interferon) 2.1 times and 1.2 times the corresponding activity; Simultaneously, at this concentration, it shows an inhibition rate greater than 57% to HBV DNA, which is 1.5 times the corresponding inhibition rate of alpha-interferon. The above pharmacodynamic results show that the flavonoid lignan or it...

Claims

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Application Information

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IPC IPC(8): C07D407/04A61K31/357A61P31/20
Inventor 杜一民阳应华杨哲龚景旭程伟巫秀美赵昱曾苏
Owner DALI UNIV
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