CN102603522A - Phenol derivatives and application thereof to preparation of anti-HBV (hepatitis B virus) medicines - Google Patents
Phenol derivatives and application thereof to preparation of anti-HBV (hepatitis B virus) medicines Download PDFInfo
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- CN102603522A CN102603522A CN2011100243245A CN201110024324A CN102603522A CN 102603522 A CN102603522 A CN 102603522A CN 2011100243245 A CN2011100243245 A CN 2011100243245A CN 201110024324 A CN201110024324 A CN 201110024324A CN 102603522 A CN102603522 A CN 102603522A
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Abstract
The invention belongs to the field of traditional Chinese medicines and in particular relates to phenol derivatives from Houttuynia cordata thunb. and an application thereof to preparation of anti-virus medicines. The phenol derivatives include 1,4-dimethoxybenzene (1) and vanilline (2). The phenol derivatives 1,4-dimethoxybenzene and vanilline are extracted and obtained from the traditional Chinese medicine Houttuynia cordata thunb. and are proved to have obvious anti-HBV (hepatitis B virus) activities, and compared with the positive control lamivudine, the phenol derivatives have lower effective concentrations and lower cytotoxicity. The phenol derivatives can serve as active ingredients to prepare the medicines for treating hepatitis B. The formula (I) is shown in the specification.
Description
Technical field
The invention belongs to field of traditional Chinese medicine pharmacy, relate to the purposes of phenol analog derivative in the preparation antiviral that derives from the Herba Houttuyniae, be specifically related to wherein p-dimethyoxy benzene and the purposes of Vanillin in preparation treatment hepatitis B medicine.
Background technology
Show according to the relevent statistics, the whole world nearly more than 300,000,000 artificial chronic viral hepatitis B virus (HBV) carrier, China accounts for half.Have report to point out, hepatitis B virus infection has become global one of the principal disease of human health that influences, can cause chronic hepatitis, liver cirrhosis and primary hepatocarcinoma because HBV infects, and become one of nine big diseases that influence human longevity.The relative risk rate that liver cancer takes place the more non-carrier of chronic HBV infection person is 217; Annual nearly 2,000,000 people die from liver cirrhosis and the liver cancer that hepatitis B causes in the whole world; And China is the district occurred frequently of hepatitis B, and annual have 250,000 people to die from the chronic disease relevant with hepatitis B (liver cirrhosis and liver cancer) approximately.Above-mentioned disease brings massive losses for people ' s health and national economy, and therefore, the anti-HBV medicine of seeking high-efficiency low-toxicity has become instant problem.
Pharmaceutical chemists has been carried out unremitting effort in the process of screening anti-HBV medicaments for many years, but does not up to the present also see and can cure the specifics that HBV infects.The Interferon, rabbit and the nucleoside medicine NGPB-21 that have obtained FDA official approval use clinically can only obtain result of treatment to a certain extent, most patient are not also reached the purpose of healing.Simultaneously, " knock-on " phenomenon after stopping to treat is that medical worker feels stubborn problem most, so develop efficient, low toxicity, the anti-HBV new drug of " knock-on " has not proposed challenge to pharmaceutical chemists.In the process of screening anti-HBV new drug, increasing pharmaceutical chemists has turned to attention that plant origin is abundant, cheap and easy to get, toxic side effect is little, the complicated and diversified natural compounds of molecular structure.
Herba Houttuyniae is the whole herb with root of saururaceae plant houttuynia cordata (Houttuynia cordata Thunb.), is a kind of heat-clearing and detoxifying herb commonly used, is used for sick treatment such as pneumonia, upper respiratory tract infection, influenza, hepatitis clinically.Modern pharmacological research shows, pharmacological action such as that Herba Houttuyniae has is antibiotic, antiviral, anti-inflammatory, analgesia, antitumor, immunomodulatory, anti-oxidant, antianaphylaxis, diuresis, myocardial preservation.Herba Houttuyniae mainly contains chemical ingredientss such as volatile oil, flavones, vegeto-alkali, phenol analog derivative, amino acid, sterol and organic acid.
Herba Houttuyniae has clear superiority at anti-virus aspect; Research shows that main chemical compositions Quercitroside wherein can pass through to reduce cytopathic effect, suppress virus replication, thereby plays the effect of influenza A/WS/33 virus.Herba Houttuyniae fixed oil part mouse to influenza virus infection FM1 after abdominal injection, filling stomach prevention administration has the obvious treatment effect; And Herba Houttuyniae injectio has certain restraining effect to hemorrhagic fever virus (EHFV), in the cell in vitro experiment, also has the activity that suppresses influenza A virus and anti-target cell apoptosis; The Herba Houttuyniae aqueous extract can significantly suppress SARS-CoV 3C appearance proteolytic enzyme (3CL
Pro) activity.
The plaque inhibition test shows that Herba Houttuyniae injectio has significant anti-MHV 3 types (MHV-3) effect.Neo-houttuyninum can suppress the DNA of rat liver cancer ascites cells and synthesizing of RNA.The tradition traditional Chinese medical science thinks that as heat-clearing and detoxifying herb, Herba Houttuyniae has therapeutic action for the hepatobiliary damp-heat type hepatitis B, therefore, is necessary that particularly the anti-hepatitis b effect is studied for the anti-hepatitis of Herba Houttuyniae.
At present, flavones ingredient in the existing relevant Herba Houttuyniae is like active documents of anti-HBV such as Quercetin, Quercitrosides; But do not see the effect of the antagonism of phenol monomer in Herba Houttuyniae HBV as yet and be used to treat the report of hepatitis B.
Summary of the invention
The purpose of this invention is to provide new antiviral active substance, be specifically related to derive from phenol analog derivative and the purposes in the preparation antiviral thereof in the Herba Houttuyniae, relate in particular to the purposes of this phenol analog derivative in the preparation anti-hepatic-B virus medicine.
The phenol compound that derives from the Herba Houttuyniae of the present invention, comprise p-dimethyoxy benzene (
1) and Vanillin (
2).
The present invention uses the modern pharmacology screening method; Active substance to suppressing HBV in the plant amedica is studied, and ethyl acetate extract extracts phenol compound and confirms that it has resisting HBV virus active from Saururaceae heartleaf houttuynia platymiscium Herba Houttuyniae (Houttuynia cordata Thunb.).
Phenol compound of the present invention has the chemical structure of formula
:
（
）
Wherein, R
1=OH, R
2=H, R
3=COOH;
R
1=R
3=OCH
3,?R
2=H。
Among the present invention, work as R
1=OH, R
2=H, R
3During=COOH, compound be p-dimethyoxy benzene (
1); Work as R
1=R
3=OCH
3, R
2During=H, compound be Vanillin (
2).
Phenol compound of the present invention prepares through following method:
Get the dry herb of Herba Houttuyniae (Houttuynia cordata Thunb.), extract with 95% ethanol room temperature cold soaking, united extraction liquid is concentrated into does not have the alcohol flavor, and residue adds the water suspendible, respectively with sherwood oil, ETHYLE ACETATE and n-butanol extraction; Get acetic acid ethyl ester extract and carry out macroporous resin column chromatography, with different concentration ethanol solution gradient wash-out, gained stream part is carried out repeatedly silica gel column chromatography and preparation thin-layer chromatography again, separate obtain p-dimethyoxy benzene (
1) and Vanillin (
2).
Wherein, described compound (
1) p-dimethyoxy benzene (1,4-dimethoxybenzene,
1) C
8H
10O
2(138), white plates crystallization (sherwood oil-acetone), m.p. 55-56 ℃;
1H-NMR (CDCl
3, 400 MHz) and δ ppm:6.80 (4H, s, H-2,3,5,6), 3.75 (6H, s, OCH
3* 2);
13C-NMR (CDCl
3, 100 MHz) and δ ppm:155.5 (C-1,4), 127.8 (C-2,3,5,6), 57 (OCH
3* 2); ESI-MS (
M/z): 139 [M+H]
+
Wherein, described compound Vanillin (
2) (vanillin,
2) C
8H
8O
3(152), colourless acicular crystal (acetone), m.p. 170-172 ℃;
1H-NMR (CDCl
3, 400 MHz) δ ppm:9.83 (1H, s, CHO), 7.43 (2H, m, H-2,6), 7.04 (1H, d,
J=8.6 Hz, H-5), 6.27 (1H, s, OH), 3.96 (3H, s, 3-OCH
3);
13C-NMR (CDCl
3, 100 MHz) and δ ppm:190.8 (CHO), 151.7 (C-4), 147.2 (C-3), 129.9 (C-1), 127.5 (C-6), 114.4 (C-5), 108.8 (C-2), 56.1 (OCH
3); ESI-MS (
M/z): 153 [M+H]
+
Phenol derivation compound of the present invention is through pharmacological evaluation, and the result confirms that said compound has the significant anti-HBV effect, and has that effective concentration is lower, cytotoxicity features of smaller (as shown in table 1); Wherein, The compound p-dimethyoxy benzene all shows restraining effect to HBsAg and HBeAg; Inhibiting rate to HBsAg and HBeAg when 50 μ g/mL is respectively 63.7 and 39.9%, is significantly higher than positive control lamivudine (inhibiting rate is respectively 25.7% and 28.4% during 200 μ mol/mL); The compound Vanillin shows stronger restraining effect to HBsAg when 200 μ g/mL, inhibiting rate is 43.3%, and is suitable with the positive control lamivudine to the restraining effect of HBsAg when 100 μ g/mL.
Table 1 is compound p-dimethyoxy benzene and Vanillin to the toxicity situation of the 2.2.15 cell strain of Hep G2 and to the inhibition effect of HBsAg and HBeAg.
-: " not seeing overt toxicity " means with mtt assay and detects cell survival rate >=75%;
+: " demonstration toxicity " phalangeal cell survival rate < 75%;
/: do not carry out the inhibiting rate test.
Phenol compound of the present invention can be used as the medicine that the activeconstituents preparation is used to treat hepatitis B.
Description of drawings:
Fig. 1 is the extraction and separation process schema of compound p-dimethyoxy benzene and Vanillin.
Embodiment
Get the dry herb 20kg of Herba Houttuyniae (Houttuynia cordata Thunb.); With 95% ethanol room temperature cold soaking three times; United extraction liquid is concentrated into does not have the alcohol flavor; Extracting solution thin up suspendible is respectively with sherwood oil (1L * 3 time), ETHYLE ACETATE (1L * 3 time) and propyl carbinol (1L * 3 time) extraction.Obtain acetic acid ethyl ester extract 223g; Get acetic acid ethyl ester extract and carry out macroporous resin column chromatography, with different concentration ethanol solution gradient wash-out, stream part of 30% ethanol elution gained is carried out silica gel column chromatography repeatedly with chloroform-methanol again, and concrete steps are following:
1. get the wash-out position of chloroform-methanol (20:1) and carry out silica gel column chromatography repeatedly with chloroform-acetone, the part that chloroform-acetone (8:1) elutes is carried out chromatography with sherwood oil-acetone again, promptly the compound p-dimethyoxy benzene (
1).
2. get the wash-out position of chloroform-methanol (50:1) and carry out silica gel column chromatography repeatedly with sherwood oil-acetone, colourless needle, promptly the compound Vanillin (
2).
Use the 2.2.15 cell strain (Board of Education/medical molecular virology key lab of the Ministry of Health, Shanghai) of Hep G2, with every hole 10 * 10
5Individual cell inoculation is in 24 orifice plates, and substratum is DMEM, and growth media contains 10% foetal calf serum, 380 μ g/mlG418, and 0.03% glutamine, penicillium mould, each 100 μ g/ml of Streptomycin sulphate are at 5%CO
2Cultivate after 48 hours for 37 ℃ in the incubator; Change the nutrient solution of the drug of DMSO 99.8MIN. hydrotropy into; Every kind of medicine is established 3 ~ 5 concentration, and each concentration is established 4 parallel holes, continues to cultivate 9 days (changing liquid once in per 3 days); Collect supernatant and detect HBsAg and HBeAg content with ELISA, under the similarity condition with the nutrient solution supernatant of drug not as control group; Use above-mentioned cell strain simultaneously, measure the cytotoxicity of medicine with mtt assay.Positive control is lamivudine (3TC).The result confirms that The compounds of this invention has the significant anti-HBV effect, and effective concentration is low, and cytotoxicity is less.
Claims (7)
1. the phenol analog derivative of formula
（Ⅰ）
Wherein, R
1=OH, R
2=H, R
3=COOH;
R
1=R
3=OCH
3,?R
2=H。
2. by the described formula of claim 1
Phenol analog derivative, it is characterized in that, work as R
1=OH, R
2=H, R
3During=COOH, compound is p-dimethyoxy benzene (1); Work as R
1=R
3=OCH
3, R
2During=H, compound is Vanillin (2).
3. the preparation method of the phenol analog derivative of claim 1 is characterized in that, it comprises step:
Get the dry herb of Herba Houttuyniae, extract with 95% ethanol room temperature cold soaking, united extraction liquid is concentrated into does not have the alcohol flavor, and residue adds the water suspendible, respectively with sherwood oil, ETHYLE ACETATE and n-butanol extraction; Get acetic acid ethyl ester extract; Get acetic acid ethyl ester extract and carry out macroporous resin column chromatography; With different concentration ethanol solution gradient wash-out, stream part of gained is carried out silica gel column chromatography repeatedly with chloroform-methanol again, separates to obtain compound p-dimethyoxy benzene (1) and Vanillin (2).
4. press the preparation method of claim 3; It is characterized in that, in the said method, get the wash-out position of chloroform-methanol 20:1 and carry out silica gel column chromatography repeatedly with chloroform-acetone; The part that chloroform-acetone 8:1 elutes is carried out chromatography with sherwood oil-acetone again, gets compound p-dimethyoxy benzene (1).
5. by the preparation method of claim 3, it is characterized in that, in the said method, get the wash-out position of chloroform-methanol 50:1 and carry out silica gel column chromatography repeatedly, get colourless needle, i.e. compound Vanillin (2) with sherwood oil-acetone.
6. the phenol analog derivative of claim 1 is in the purposes of preparation in the anti-hepatic-B virus medicine.
7. the phenol analog derivative of claim 1 is treated the purposes in the hepatitis B medicament in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110024324.5A CN102603522B (en) | 2011-01-23 | 2011-01-23 | Phenol derivatives and application thereof in preparation of anti-HBV (hepatitis B virus) medicines |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110024324.5A CN102603522B (en) | 2011-01-23 | 2011-01-23 | Phenol derivatives and application thereof in preparation of anti-HBV (hepatitis B virus) medicines |
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| Publication Number | Publication Date |
|---|---|
| CN102603522A true CN102603522A (en) | 2012-07-25 |
| CN102603522B CN102603522B (en) | 2015-04-22 |
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103055006A (en) * | 2013-02-05 | 2013-04-24 | 河南省医药科学研究院 | Effective part of Houttuynia cordata as well as extracting method and application thereof |
| CN105198735A (en) * | 2014-06-01 | 2015-12-30 | 复旦大学 | Long-chain alkyl salicylic acid and application thereof in preparing oncomelania killing preparation |
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| JPH04234320A (en) * | 1990-12-28 | 1992-08-24 | Fujirebio Inc | Anti-hbv agent |
| CN1907276A (en) * | 2005-08-02 | 2007-02-07 | 盛华（广州）医药科技有限公司 | Application of hydroxybenzoate acid and its analogue in the preparing process of medicine for preventing and treating virus infection |
| CN101342166A (en) * | 2005-08-02 | 2009-01-14 | 盛华（广州）医药科技有限公司 | Application of hydroxyl benzoate and analogue in preparing medicament for preventing and treating hepatitis B virus |
| CN101721534A (en) * | 2010-01-15 | 2010-06-09 | 复旦大学 | Houttuynia cordata Thunb. polysaccharide, preparation method and pharmaceutical application thereof |
-
2011
- 2011-01-23 CN CN201110024324.5A patent/CN102603522B/en not_active Expired - Fee Related
Patent Citations (4)
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| JPH04234320A (en) * | 1990-12-28 | 1992-08-24 | Fujirebio Inc | Anti-hbv agent |
| CN1907276A (en) * | 2005-08-02 | 2007-02-07 | 盛华（广州）医药科技有限公司 | Application of hydroxybenzoate acid and its analogue in the preparing process of medicine for preventing and treating virus infection |
| CN101342166A (en) * | 2005-08-02 | 2009-01-14 | 盛华（广州）医药科技有限公司 | Application of hydroxyl benzoate and analogue in preparing medicament for preventing and treating hepatitis B virus |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103055006A (en) * | 2013-02-05 | 2013-04-24 | 河南省医药科学研究院 | Effective part of Houttuynia cordata as well as extracting method and application thereof |
| CN103055006B (en) * | 2013-02-05 | 2014-04-23 | 河南省医药科学研究院 | Effective part of Houttuynia cordata as well as extracting method and application thereof |
| CN105198735A (en) * | 2014-06-01 | 2015-12-30 | 复旦大学 | Long-chain alkyl salicylic acid and application thereof in preparing oncomelania killing preparation |
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| CN102603522B (en) | 2015-04-22 |
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