CN1951378A - Medical usage of 2beta-hydroxyilicicacid in inhibiting hepatitis B - Google Patents
Medical usage of 2beta-hydroxyilicicacid in inhibiting hepatitis B Download PDFInfo
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Abstract
The invention relates to a hemiterpene derivant 2-Hydroxyilicic acid, as formula (1) 2beta-hydroxy-5alphaH-eudesmane-11(13)-allyl-12-acid and relative compounds which can be used to prepare the drug treating hepatitis B disease. The inventive compound can restrain the copy of hepatitis B surface antigen (HBsAg) and the hepatitis B deoxyribonucleic acid (HBV-DNA), while its HBsAg restrain ability is higher than positive contrast difuradin; in the density as 100mug/ml, 20mug/ml, and 4mug/ml, it can restrain the copy of hepatitis B virus HBV-DNA.
Description
Technical field
The present invention relates to eudesmane type sesquiterpene derivant 2 beta-hydroxy ilicic acids (2 β-Hydroxyilicic acid), i.e. the medical usage of 2 beta-hydroxies-5 α H-eucalyptus globulus alkane-11 (13)-alkene-12-acid in preparation treatment hepatitis B virus infection disease and anti-hepatic-B virus medicine.
Technical background
Hepatitis B is the infectious disease that is caused by hepatitis B virus.By blood and body fluid communication, has chronic carrier state.Primary disease is widely current in China, crowd infection rate's height, and infection rate reaches more than 35% in certain areas.According to interrelated data, hepatitis detects male patient and has reached 1.89 hundred million, and the number (carrier) nearly 400,000,000 of should not going to a doctor.It is one of the most serious infectious disease of current harm people ' s health.Hepatitis B clinical manifestation variation easily develops into chronic hepatitis and liver cirrhosis, and a few patients can change primary hepatocarcinoma into.The treatment of hepatitis B now mainly contains nucleoside medicine, protects the liver class medicine and immune formulation etc., but equal progress of disease controlling fully.At present the most frequently used in the nucleoside medicine also is lamivudine the most effectively, but its life-time service can cause drug resistance, easily knock-on after the drug withdrawal, and this has had a strong impact on the curative effect of medicine.
The present antiviral drugs of the using inhibitor of virus replication just in fact, directly kill virus and break virus body, otherwise will damage host cell.These antiviral drugs also exist toxic and side effects greatly, easily to cause after viral gene sudden change, the drug withdrawal shortcomings such as easily knock-on, so the development of new antiviral agents is the task of top priority in current medicament research and development field.
Eudesmane type sesquiterpenes acid is the terpenoid that 15 carbon constitute skeleton, it is characterized in that 12 oxidation of coals are carboxylic acid.Eudesmane-type sesquiterpenoids generally has multiple biological activity, and report focuses mostly in antitumor, antibiotic, malaria and antifungal direction.External recently such eudesmane type sesquiterpene alcohol of discovery has multiple antiviral activity.As (Journal of Antimicrobial Chemotherapy such as Hayashi in 1996,1996,37 (4), separate when 759-768) Tripterygium platymiscium Tripterygium wilfordii Hook fil.var.regelii Makino being studied and obtained one herpes simplex types 1 virus (herpes simplex virus type 1, HSV-1) (treatmentindex TI) surpasses 10 chemical compound Triptofordin C-2 (chemical compound 1) to the selective therapy index.
(Tennen Yuki Kagobutsu Toronkai Koen Yoshishu such as Duan in 1999,1999,41st, 535-540) ethyl acetate of the methanolic extract of the root position of plant Tripterygiumhypoglaucum (Levi.) Hutch that Tripterygium is belonged to has partly been carried out system's separation, obtain chemical compound 2, and find that it has the activity of certain anti HIV-1 virus, can promote the generation of cytokine simultaneously.At continuation further investigation (Duan etc. to this plant, Journalof Natural Products, 2000,63 (3), the new eudesmane type sesquiterpene alcaloid-derivatives Triptonine B (chemical compound 3) that is separated to 357-361) has embodied the activity of potential anti HIV-1 virus, its half virtual value (EC
50) less than 0.1 μ g/ml, and its external treatment index is greater than 1000, so there is very much exploitation to be worth.
(Phytochemistry such as Hoang Vu Dinh in 2002,2002,59 (3), 325-329) separate from LitseaverticillataHance (Lauraceae) and obtain new eudesmane type sesquiterpene verticillatol (chemical compound 4), it has certain AIDS resisting cytotoxic activity (its 503nhibiting concentration IC to use the test shows of being carried out as model by the osteosarcoma of HIV viral infection (human osteosarcoma) HOG.R5 cell
50Value is 34.5 μ g/ml), when 20 μ g/ml, detect toxicity simultaneously less than its pair cell, can be used as the lead compound of AIDS resisting.
(Journal of Natural Products such as Sun in 2004,2004,67 (12), 1975-1979) reported new eudesmane type sesquiterpene 4 (15)-eucalyptus globulus alkane-1 β that are separated to from Caragana intermedia, the minimum inhibitory concentration that 7 salmefamols (5) are gone into the HIV-IIIB virus of MT-2 cell to infection is 10 μ g/ml, and other three chemical compounds (6,7,8) then shown inhibitory action to rice blast virus, minimum inhibitory concentration is respectively 12,16 and 20 μ g/ml.
Make a general survey of above-mentioned discovery: existing eudesmane-type antiviral compound focuses mostly on eucalyptus globulus alkanols chemical compound, and eucalyptus globulus alkanoic acid compounds nobody set foot in.This points out us further forefathers not to be added the eudesmane type sesquiterpenes acid analog derivative of studying to carry out antiviral activity test.
During the inventor worked in the past once systematic study the chemical constituent and the pharmacological action of Yunnan treatment influenza among the people and parotitic medical herbs Compositae Laggera alata (Roxb.) Sch.-Bip. platymiscium LINGDANCAO (being tooth wing Laggera alata (Roxb.) Sch.-Bip. Laggera pterodonta (DC.) Benth) and Laggera alata (Roxb.) Sch.-Bip. (Laggera alata (D.Don) Sch.-Bip.ex Oliv), [girth is new to find wherein to contain a large amount of eudesmane type sesquiterpenes acid compounds, Zhao Yu etc., CHINA JOURNAL OF CHINESE MATERIA MEDICA, (summary) 2006,31 (14), 1133-1140, and the pertinent literature quoted of this article].The inventor also finds, show through experiment in vitro and zoopery, the extract of LINGDANCAO and Laggera alata (Roxb.) Sch.-Bip. has significant antiinflammatory action, can obviously suppress dimethylbenzene induced mice auricle edema, rat pleuritis due to rat toes swelling due to the chondrus ocellatus Holmes, the chondrus ocellatus Holmes had obvious suppression effect [Wu Yihang (Yihang Wu), Zhao Yu etc., Journal ofEthnopharmacology, 2006; Wu Yihang (Yihang Wu), Zhao Yu etc., Phytotherapy Research, 2006,20 (7), 585-590].The inventor has done further research on the basis of existing technology, being primarily aimed at this kind of plant chemical monomer composition antiviral activity screens, discovery belongs to a kind of eudesmane type sesquiterpenes acid that extracts the medicinal plants from Laggera alata (Roxb.) Sch.-Bip. and has the effect that significant anti-hepatitis virus reduces hepatitis B surface antigen simultaneously, and consult through document, up to the present, still not about the report of this compounds for treating hepatitis B virus infection disease with the preparation anti-hepatic-B virus medicine.Finish the present invention in view of the above.
Summary of the invention
The eudesmane type sesquiterpenes acid derivant and officinal salt or the solvate that the purpose of this invention is to provide a high-efficiency low-toxicity shown in the formula (1), the application of this eudesmane type sesquiterpenes acid in sick viral infectious diseases of treatment hepatitis B and preparation anti-hepatic-B virus medicine specifically.
Wherein:
Preferably separation and purification from plant of eudesmane type sesquiterpenes acid more preferably obtains from feverfew shown in the Chinese style of the present invention (1), most preferably obtains from Compositae Laggera alata (Roxb.) Sch.-Bip. platymiscium LINGDANCAO or Laggera alata (Roxb.) Sch.-Bip..
Formula (1) chemical compound is specially: 2 beta-hydroxy ilicic acids (2 β-Hydroxyilicic acid), i.e. 2 beta-hydroxies-5 α H-eucalyptus globulus alkane-11 (13)-alkene-12-acid;
Another purpose of the present invention has provided the purposes that formula (1) chemical compound is used to prevent and treat hepatitis B, reduces hepatitis B surface antigen;
Another object of the present invention has provided a kind of pharmaceutical composition of preventing and treating hepatitis B, reduction hepatitis B surface antigen that contains formula (1) chemical compound, it contains the formula as active component (1) chemical compound for the treatment of effective dose, perhaps its officinal salt and pharmaceutically acceptable auxiliaries.It can be that tablet, capsule, injection, aerosol, suppository, membrane, drop pill, paster agent, subcutaneous planting bury agent, externally-applied liniment, oral liquid or ointment, can also adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.
The specific embodiment
The preparation method of the eudesmane type sesquiterpenes acid shown in this formula (1), can be referring to researcheres such as inventor publish an article [Zheng Qunxiong, Zhang Qijun, Zhao Yu etc., journal of Zhejiang university (medicine), 2002,31 (6): 406: Zhao Yu Journal of Natural Products such as (Zhao Y), 1997,60 (6): 545].Prepare formula (1) chemical compound according to the method for describing in the document, its spectroscopic data of the formula that purification obtains (1) chemical compound conforms to reported values in the document.
Formula (1) chemical compound spectroscopic data: colourless needle, fusing point 198-199 ℃ (methanol); Mass spectrum EIMS m/z[M]
+268 (7), 250,217,204,167;
13C-NMR (100MHz, deuterated acetone) δ 170.04,148.39,121.52,70.86,67.82,55.56,50.23,47.82,45.92,41.39,34.75,27.63,27.36,25.63,20.84.
Adopt mtt assay to measure the inhibitory action of formula (1) chemical compound to the growth of HepG2.2.15 cell.The toxic experimental result of specimen pair cell shows that the formula of extracting (1) chemical compound does not have obvious inhibitory action to the growth of HepG2.2.15 cell under experimental concentration from LINGDANCAO or Laggera alata (Roxb.) Sch.-Bip..Measure the inhibitory action of eudesmane type sesquiterpene derivant to HBV: experimental result shows that the formula of extracting (1) chemical compound has the effect of significant inhibition HBV from LINGDANCAO or Laggera alata (Roxb.) Sch.-Bip.; Its growth to the HepG2.2.15 cell does not have obvious inhibitory action, hepatitis B surface antigen (HBsAg) and duplicating of hepatitis B virus DNA (deoxyribonucleic acid) (HBV-DNA) to HepG2.2.15 emiocytosis have significant inhibitory effect, and prompting type (1) chemical compound has the characteristics of drug safety and highly efficient anti-virus.Therefore, according to the inventor's research, the formula of extracting from LINGDANCAO or Laggera alata (Roxb.) Sch.-Bip. (1) chemical compound can be used for the treatment of the hepatitis B virus infection disease and be used to prepare the medicine of treatment hepatitis B virus infection disease.
In order to understand essence of the present invention better, use formula (1) chemical compound to the HepG2.2.15 cell growth inhibition and to the result of the inhibitory action of the duplicating test of the HBsAg of HepG2.2.15 emiocytosis and HBV-DNA below respectively, its new purposes in pharmaceutical field is described.Embodiment has provided the part activity data of formula (1) chemical compound.Mandatory declaration, embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.The simple modifications subordinate that essence according to the present invention is carried out the present invention is in the scope of protection of present invention.
Embodiment 1: formula (1) chemical compound is to the inhibitory action of the hbs antigen (HBsAg) of HepG2.2.15 emiocytosis
1) cell culture:
In containing 10% inactivated fetal bovine serum, 100U/ml penicillin and 100 μ g/ml streptomycins in the DMEM culture medium of 100 μ g/ml G418, are put 37 ℃, 5%CO with the HepG2.2.15 cell culture
2, cultivate in the incubator of 100% relative humidity.
2) adopt mtt assay to measure the inhibitory action of formula (1) chemical compound to the growth of HepG2.2.15 cell:
The take the logarithm HepG2.2.15 cell of trophophase becomes 1 * 10 with culture medium with cell dilution
5/ ml is inoculated in 96 porocyte culture plates, every hole 100 μ l, and at 37 ℃, 5%CO
2Cultivate formula (1) chemical compound that adds after 24 hours with the culture medium dilution in the incubator of 100% relative humidity, concentration is respectively 1000 μ g/ml, 200 μ g/ml, 40 μ g/ml and 8 μ g/ml, every hole 200 μ l, each concentration is established three multiple holes, place 37 ℃, 5%CO2 cultivates in the incubator of 100% relative humidity, cultivates after 72 hours, every hole adds 5mg/ml MTT reagent 10 μ l, continue to cultivate 4 hours, discard culture medium, every hole adds DMSO 200 μ l, with agitator vibration 20 minutes, under the 570nm wavelength, measure the OD value with microplate reader.With the culture hole that only adds culture medium is control wells.
Suppression ratio (%)=(control wells OD value-experimental group OD value)/control wells OD value * 100%.The experiment triplicate.
Mensuration formula (1) chemical compound is to the inhibitory action of hbs antigen (HBsAg).The take the logarithm HepG2.2.15 cell of trophophase becomes 1 * 10 with culture medium with cell dilution
5/ ml is inoculated in 96 porocyte culture plates, every hole 100 μ l, and at 37 ℃, 5%CO
2, cultivate formula (1) chemical compound that adds after 24 hours with the culture medium dilution in the incubator of 100% relative humidity, concentration is respectively 100 μ g/ml, 20 μ g/ml and 40 μ g/ml, every hole 200 μ l, each concentration is established three multiple holes, places 37 ℃, 5%CO
2, cultivate in the incubator of 100% relative humidity, changed the culture medium that contains the same concentrations sample in per 4 days, with the culture medium equal-volume mixing that swaps out of the same concentration of same sample, as testing sample.With hbs antigen (HBsAg) concentration in the ELISA kit measurement culture medium, represent with P/N; With the positive contrast of lamivudine (3-TC).
3) experimental result
Experimental result is as shown in table 1, and the formula of extracting from LINGDANCAO or Laggera alata (Roxb.) Sch.-Bip. (1) chemical compound has the effect of significant inhibition hbs antigen (HBsAg).It is to the no obvious inhibitory action of HepG2.2.15 cell growth, all is higher than lamivudine but the hbs antigen HBsAg of HepG2.2.15 emiocytosis is suppressed activity under high, medium and low dosage.
Table 1. formula (1) chemical compound is to the excretory hbs antigen of HepG2.2.15 (HBsAg) suppression ratio (%)
| Sample number into spectrum | Concentration (μ g/mL) | 4 days | 8 days |
| HBsAg | HBsAg | ||
| Formula (1) chemical compound | 100 20 4 | 36.68 14.89 18.77 | 50.45 28.73 21.43 |
| The 3TC lamivudine | 100 20 4 | 28.12 / / | 14.7 / / |
This embodiment presentation of results: the 8th day hbs antigen (HBsAg) to HepG2.2.15 emiocytosis of formula (1) chemical compound has significant inhibitory effect, can expect and develop into the medicine that reduces hbs antigen, control Type B viral hepatitis symptom.
Embodiment 2: the inhibitory action that formula (1) chemical compound duplicates the hepatitis B virus deoxyribose ribozyme (HBV-DNA) of HepG2.2.15 emiocytosis.
1) cell culture:
Method is with embodiment 1.
2) adopt mtt assay to measure the inhibitory action of formula (1) chemical compound to the growth of HepG2.2.15 cell:
Method is with embodiment 1.
3) mensuration formula (1) chemical compound inhibitory action that hepatitis B virus DNA (deoxyribonucleic acid) (HBV-DNA) is duplicated.
The take the logarithm HepG2.2.15 cell of trophophase becomes 1 * 10 with culture medium with cell dilution
5/ ml is inoculated in 96 porocyte culture plates, every hole 100 μ l, and at 37 ℃, 5%CO
2, cultivate formula (1) chemical compound that adds after 24 hours with the culture medium dilution in the incubator of 100% relative humidity, concentration is respectively 100 μ g/ml, 20 μ g/ml and 40 μ g/ml, every hole 200 μ l, each concentration is established three multiple holes, places 37 ℃, 5%CO
2, cultivate in the incubator of 100% relative humidity, changed the culture medium that contains the same concentrations sample in per 4 days, with the culture medium equal-volume mixing that swaps out of the same concentration of same sample, as testing sample.Measure HBV-DNA concentration in the culture medium with the HBV-DNA quantitative PCR kit in the time of the 8th day.With the positive contrast of lamivudine (3-TC).
4) experimental result
Experimental result is as shown in table 2, the effect that the formula of extracting from LINGDANCAO or Laggera alata (Roxb.) Sch.-Bip. (1) chemical compound has certain inhibition hepatitis B virus DNA (deoxyribonucleic acid) (HBV-DNA) to duplicate.High dose group (100 μ g/mL) has significant inhibition HBV-DNA replication activity.
The suppression ratio (%) that table 2. formula (1) chemical compound duplicated the HBV-DNA of HepG2.2.15 cell in the time of the 8th day
| Sample number into spectrum | Concentration (μ g/mL) | HBV-DNA |
| Formula (1) chemical compound | 100 20 4 | 56.52 19.45 3.61 |
| The 3TC lamivudine | 100 20 4 | 84.78 75.16 67.52 |
This embodiment presentation of results: formula (1) chemical compound had certain inhibitory action to duplicating of hepatitis B virus DNA (deoxyribonucleic acid) (HBV-DNA) in the time of the 8th day, thereby can expect that optimized development is to suppress the medicine that HBVDNA duplicates.
Claims (6)
1. 2 beta-hydroxy ilicic acids of the eudesmane type sesquiterpene derivant shown in the formula (1) (2 β-Hydroxy ilicicacid), promptly 2 beta-hydroxies-5 α H-eucalyptus globulus alkane-11 (13)-alkene-12-acid is to the inhibition activity of the hepatitis B surface antigen (HBsAg) of HepG2.2.15 emiocytosis.
2. described formula (1) chemical compound of claim 1 inhibition activity that the hepatitis B virus DNA (deoxyribonucleic acid) (HBV-DNA) of HepG2.2.15 emiocytosis is duplicated.
3. according to claim 1～2, formula (1) chemical compound is used to prevent and treat the medical usage of hepatitis B, reduction hepatitis B surface antigen.
4. be used to suppress the pharmaceutical composition that hepatitis B surface antigen was duplicated, reduced to hepatitis B virus DNA (deoxyribonucleic acid) (HBV-DNA) according to what claim 3 a kind of contained formula (1) chemical compound, it contains the formula as active component (1) chemical compound for the treatment of effective dose, perhaps its officinal salt and pharmaceutically acceptable auxiliaries.
5. require 4 pharmaceutical composition according to power, it can be that tablet, capsule, injection, aerosol, suppository, membrane, drop pill, paster agent, subcutaneous planting bury agent, externally-applied liniment, oral liquid or ointment, can also adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.
6. according to the preparation of formula (1) chemical compound of claim 1～5, it is characterized in that: separation and purification from plant, preferably from feverfew, obtain, most preferably from Compositae Laggera alata (Roxb.) Sch.-Bip. platymiscium, obtain.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103800321A (en) * | 2013-09-06 | 2014-05-21 | 青岛农业大学 | Application of 1,2-selinane type sesquiterpenes in Phellinus igniarius to avian influenza H5N1 virus resistance |
| CN113795258A (en) * | 2019-02-25 | 2021-12-14 | 吉亚生技控股股份有限公司 | Methods and compositions for inhibiting viral infection |
-
2006
- 2006-10-09 CN CNB2006100537498A patent/CN100482217C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103800321A (en) * | 2013-09-06 | 2014-05-21 | 青岛农业大学 | Application of 1,2-selinane type sesquiterpenes in Phellinus igniarius to avian influenza H5N1 virus resistance |
| CN103800321B (en) * | 2013-09-06 | 2016-05-18 | 青岛农业大学 | In phelliuns igniarius 1, the application of 2-eudesmane type sesquiterpene on anti-avian influenza H5N1 virus |
| CN113795258A (en) * | 2019-02-25 | 2021-12-14 | 吉亚生技控股股份有限公司 | Methods and compositions for inhibiting viral infection |
| CN113795258B (en) * | 2019-02-25 | 2024-04-16 | 吉亚生技控股股份有限公司 | Methods and compositions for inhibiting viral infection |
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