CN105030790B - Application of the Pananxadiol derivatives in prevention or treatment liver disease drug is prepared - Google Patents
Application of the Pananxadiol derivatives in prevention or treatment liver disease drug is prepared Download PDFInfo
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Abstract
The invention discloses a class Pananxadiol derivatives or its pharmaceutically can into salt prepare prevention or treatment liver disease drug in application.The present invention utilizes microbiological transformation technology, structural modification has successfully been carried out to panoxadiol, obtain various new compound, confirmed by Against Hepatic Fibrosis in Vitro test cell line, these compounds have preferable anti-hepatic fibrosis activity, can as anti-hepatic fibrosis medicines active component, tool has been widely used.
Description
Technical field
The present invention relates to field of medicaments, and in particular to Pananxadiol derivatives are in prevention or treatment liver disease drug is prepared
Using, more particularly relate to Pananxadiol derivatives prepare prevention and treatment hepatic fibrosis medicines in application.
Background technology
Liver fibrosis is to be caused by various pathogenic factors after hepatic injury, and HSCs is activated as with very strong life
Into the myofibroblastic-like cell of extracellular matrix ability, then collagen enzyme inhibitor generation increases, and collagenase activity also declines, and makes
Proportional imbalance between the generation and degraded of liver cell epimatrix, ultimately resulting in the over-deposit of Liver Collagen turns into liver fibrosis.
Liver fibrosis, which continues deterioration, causes hepatic sclerosis even liver cancer, so " hepatitis-liver fibrosis-hepatic sclerosis-liver cancer " this chain quilt
It is known as being that various chronic liver diseases cause the common pathway of serious consequence.Research so far has confirmed liver fibrosis by appropriate
Treatment can reverse, as long as can slow down or prevent the generation of liver fibrosis, it is possible to mitigate or cure hepar damnification
Pathogenesis.Therefore, the activation for suppressing HSCs is the most effective approach for treating liver fibrosis.
China has carried out the research of Liver Fibrosis with Traditional Chinese Medicine extensively in recent years.Autonomic drug, Chinese medicine compound prescription or animal drugs, exhibition
Show that natural drug is used for the great potential for the treatment of liver fibrosis.Therefore, continue to find and develop efficiently low from natural drug
The anti-hepatic fibrosis medicines of poison are still the important research direction of pharmacy worker.Panoxadiol (PD) is ginsenoside sour water
Primary product after solution, with preferable antitumor activity.But, panoxadiol belongs to tetracyclic triterpenoid, lacks and lives
Group is sprinkled, reaction site is few, be difficult to prepare the derivative for meeting and requiring using conventional chemical reaction method.
Microorganism conversion is the enzymic catalytic reaction of the enzyme system progress using organism autospecific, the type of reaction
It is many, and with High level of stereoselectivity and regioselectivity, become an important tool in organic synthesis.Use it for panoxadiol
Derivative prepare, great amount of samples can be provided for the follow-up study of the type compound.
The content of the invention
It is an object of the invention to provide Pananxadiol derivatives or its pharmaceutically can into salt prepare prevention or treat
Application in liver disease drug, the hepatopathy is the disease relevant with liver fibrosis, such as chronic hepatitis, hepatic sclerosis or liver cancer.It is described
Medicine is anti-hepatic fibrosis medicines.The Pananxadiol derivatives are the compound that structural formula is 1-8：
Compound 3,4,5,6,7 and 8 is the first public panoxadiol new derivative of the present invention.
Present invention also offers the preparation method of above-mentioned Pananxadiol derivatives, comprise the following steps：1) fermented and cultured is micro-
Biology, panoxadiol is added into culture medium, then carries out conversion culture, and zymotic fluid, micro- life are obtained after removing mycelium
Thing is that colter is mould (Absidia), Cunninghamella sp (Cunninghamella), Mucor (Mucor), rod method
(Alternaria), rhodotorula (Rhodotorula), mould (Syncephalastrum) or head mold (Rhizopus) belong to altogether
Bacterial strain；2) by the zymotic fluid after extraction, extract is evaporated, obtains converting crude extract；3) by the conversion crude extract with silicon
Plastic column chromatography, using dichloromethane-absolute ethyl alcohol system, collects and merges component；4) by component RP-HPLC color
Spectrum purifying, obtains product.
Wherein, microorganism is preferably colter mould (Absidia) or Mucor (Mucor) category bacterial strain, more preferably absidia corymbifera.
Above method step 1) in culture medium the concentration of panoxadiol be 2-2000 μ g/mL.
Above method step 2) in extractant be conventional type organic solvent, ethyl acetate.
Above method step 3) preferably RPLC preparation condition is half preparation chromatographic column Hedera C18A-
5 μm, 10.0I.D × 250mm (Jiangsu Chinese nation science and technology), acetonitrile-water (68:32, V/V), flow velocity 3.0mL/min, Detection wavelength
203nm。
Document Phytochemisty Letters 2009,2,63-66 and Bioorganic＆Medicinal
The method that Chemistry 2009,17 (8), 3003-3010 disclose prepare compound 1 and 2.
The present invention experiments prove that, Pananxadiol derivatives of the present invention have good anti-hepatic fibrosis activity,
Can as anti-hepatic fibrosis medicines active component.
During the active component of these anti-hepatic fibrosis medicines can be the compound selected from panoxadiol and structural formula 1-8
It is one or more of.
In using above-claimed cpd as the medicine of active component, it is necessary to when can also add it is one or more pharmaceutically
Acceptable carrier.The carrier includes the conventional diluent of pharmaceutical field, excipient, filler, adhesive, wetting agent, collapsed
Solve agent, sorbefacient, surfactant, absorption carrier, lubricant etc., can according to pharmaceutical field conventional method system
It is standby.
The present invention utilizes microbiological transformation technology, and structural modification has successfully been carried out to panoxadiol, obtains a class new
Pananxadiol derivatives, confirmed by interior animal experiment and Against Hepatic Fibrosis in Vitro test cell line, these compounds have
Preferable anti-hepatic fibrosis activity, can as anti-hepatic fibrosis medicines active component, tool has been widely used.
Brief description of the drawings
Fig. 1 is compound 3-8 of the present invention HPLC collection of illustrative plates.
Embodiment
Embodiment 1, structural formula are the preparation of 1-8 compound
Reference literature Phytochemisty Letters 2009,2,63-66 and Bioorganic＆Medicinal
Method prepare compound 1 and 2 disclosed in Chemistry 2009,17 (8), 3003-3010.
The present invention uses microbial conversion process, using panoxadiol as raw material, by fermentation, the step such as extracting and developing, comes
Prepare the compounds of this invention.Microorganism with conversion capability includes：Colter is mould (Absidia), Cunninghamella sp
(Cunninghamella), Mucor (Mucor), rod method (Alternaria), rhodotorula (Rhodotorula), common is mould
(Syncephalastrum) or head mold (Rhizopus) category microorganism；What wherein conversion capability was stronger is that colter is mould
(Absidia) and Mucor (Mucor) category bacterial strain.These bacterial strains can be purchased from Chinese Academy of Sciences's Microbiological Culture Collection management
Center (CGMCC) or Chinese Food Fermentation Research Institute Industrial Microorganism Preservation Administrative Center (CICC), in solid slope culture medium
On put preservation in 4 DEG C of refrigerators.Fungi culture medium selects potato culture, and bacteria culture media selects LB culture mediums.
The preparation (PDA culture medium) of potato culture：200g peeled potatoes are taken, are thinly sliced, are put into suitable quantity of water,
80 DEG C of insulation 1h after boiling.Filtrate is taken after being filtered with double gauze, 20g glucose is added, stirring is completely dissolved glucose, with
Water is settled to 1000mL.Prepare solid slope culture medium and add 3% agar in liquid medium within again.
The preparation (LB culture mediums) of bacteria culture media：5.0g yeast extracts, 10.0g are added per 1000mL fluid nutrient mediums
Peptone, 10.0g NaCl, is dissolved in water, and adjusts pH value to 7.0.Solid slope culture medium is prepared to add in liquid medium within again
1.5% agar.
By taking absidia corymbifera Absidia corymbiferaAS 3.3387 as an example, preparation structure formula is 3-8 compound
Process it is as follows：
1) ferment, convert and extract
Absidia corymbifera Absidia corymbiferaAS 3.3387 are accessed into 2 250mL triangular flasks and (100mL are housed
Potato culture) in, it is used as seed liquor.In after shaken cultivation at 160rpm on shaking table, 26 DEG C 1 day, treat that mycelial growth is in
Animated period, 1mL seed liquor is drawn with Sterile pipette, is added to 20 1000mL shaking flasks (equipped with the culture of 400mL potatos
Base) in.After shaken cultivation 1 day, 25mg panoxadiols (0.2mL, 125mg/mL ethanol solution) are added in each shaking flask, altogether
Use 500mg substrates.Continue to convert 7 days under the same terms, by filtering fermentation liquor, filter out mycelium, filtrate is with isometric acetic acid
Ethyl ester is extracted 3 times, and extract is concentrated under reduced pressure into dry, obtains conversion product crude extract about 1.5g.
2) silicagel column is purified
Gained crude extract is dissolved in a small amount of methanol, mixes with 1.5g column chromatography silica gels (200-300 mesh) and mixes sample, is done naturally
It is dry, the chromatogram capital equipped with 45g silica gel (200-300 mesh) is added to, with dichloromethane-absolute ethyl alcohol system gradient elution (50:1-
1:8) elution fraction, is collected, using TLC analysis methods (silica gel g thin-layer plate, dichloromethane-absolute ethyl alcohol (15:1) deploy,
10% ethanol solution of sulfuric acid is sprayed, heating colour developing) resulting similar elution fraction is merged.
3) RPLC is purified
Merge component with RPLC to be purified.Preparation condition is half preparation chromatographic column Hedera C18A-5μ
M, 10.0I.D × 250mm (Jiangsu Chinese nation science and technology), acetonitrile-water (68:32, V/V), flow velocity 3.0mL/min, Detection wavelength
203nm.6 converted products of compound that structural formula is 3-8 are obtained, as shown in Figure 1.Its13C-NMR data are as shown in table 1.
The compound 1-8 of table 1. carbon modal data (CDCl3)
| No. | Compound 1 | Compound 2 | Compound 3 | Compound 4 | Compound 5 | Compound 6 | Compound 7 | Compound 8 |
| 1 | 39.6 | 39.7 | 39.3 | 39.3 | 39.8 | 39.8 | 38.9 | 38.5 |
| 2 | 28.3 | 34.0 | 33.9 | 33.9 | 34.1 | 34.1 | 33.9 | 34.0 |
| 3 | 78.0 | 217.6 | 217.2 | 217.3 | 217.8 | 217.7 | 217.0 | 217.0 |
| 4 | 39.4 | 47.2 | 45.2 | 45.2 | 47.3 | 47.3 | 47.0 | 47.0 |
| 5 | 56.4 | 55.2 | 52.7 | 52.7 | 55.0 | 55.0 | 53.1 | 52.8 |
| 6 | 18.8 | 19.6 | 29.4 | 29.4 | 19.6 | 19.6 | 29.5 | 29.7 |
| 7 | 35.3 | 34.1 | 74.3 | 74.3 | 34.9 | 34.9 | 74.6 | 74.6 |
| 8 | 40.1 | 39.6 | 47.0 | 47.0 | 40.2 | 40.2 | 43.7 | 40.8 |
| 9 | 50.3 | 49.2 | 50.0 | 50.0 | 49.2 | 49.3 | 49.0 | 53.3 |
| 10 | 37.4 | 36.7 | 36.6 | 36.6 | 36.8 | 36.8 | 36.8 | 36.7 |
| 11 | 31.3 | 30.9 | 30.7 | 30.7 | 30.8 | 30.8 | 31.8 | 30.8 |
| 12 | 70.2 | 69.7 | 69.4 | 69.4 | 69.4 | 69.4 | 67.8 | 72.2 |
| 13 | 49.9 | 49.1 | 48.7 | 48.7 | 47.5 | 47.4 | 52.3 | 46.5 |
| 14 | 51.3 | 51.1 | 50.9 | 50.9 | 51.9 | 51.9 | 56.8 | 40.7 |
| 15 | 31.3 | 31.1 | 34.4 | 34.4 | 72.9 | 72.9 | 129.4 | 19.4 |
| 16 | 25.4 | 25.1 | 25.5 | 25.8 | 35.0 | 25.1 | 144.8 | 31.5 |
| 17 | 55.0 | 54.6 | 53.3 | 53.3 | 52.0 | 52.0 | 59.2 | 51.0 |
| 18 | 15.9 | 15.9 | 9.5 | 9.5 | 15.4 | 15.4 | 13.6 | 15.5 |
| 19 | 16.5 | 16.9 | 15.9 | 15.9 | 16.1 | 16.1 | 15.5 | 15.3 |
| 20 | 76.9 | 76.6 | 75.7 | 76.7 | 76.0 | 76.1 | 75.3 | 75.9 |
| 21 | 19.6 | 20.9 | 19.8 | 19.2 | 20.0 | 19.3 | 20.9 | 19.7 |
| 22 | 35.8 | 35.7 | 28.7 | 36.4 | 28.6 | 36.3 | 36.9 | 36.2 |
| 23 | 16.5 | 16.2 | 23.2 | 25.2 | 23.1 | 25.1 | 25.2 | 25.3 |
| 24 | 36.5 | 36.4 | 69.6 | 74.6 | 69.5 | 74.6 | 74.8 | 74.7 |
| 25 | 73.0 | 73.0 | 76.9 | 77.2 | 76.5 | 77.2 | 77.2 | 77.2 |
| 26 | 33.2 | 32.9 | 27.3 | 29.6 | 27.1 | 29.5 | 29.5 | 29.7 |
| 27 | 27.6 | 26.7 | 27.4 | 21.2 | 27.3 | 21.1 | 21.0 | 21.3 |
| 28 | 28.7 | 27.1 | 26.8 | 26.8 | 26.7 | 26.6 | 26.7 | 26.7 |
| 29 | 16.3 | 19.4 | 21.0 | 21.0 | 21.0 | 21.0 | 21.1 | 21.1 |
| 30 | 17.3 | 15.3 | 16.8 | 16.8 | 10.0 | 10.0 | 15.5 | 6.99 |
Result above shows that gained compound structure is correct.
It is specific such as mucor spinosus Mucor spinosus AS 3.3450, Mucor racemosus using the microorganism of other category
Mucor racemosus AS 3.205, Rhizopus arrhizus Rhzopus arrhizus AS 3.3457, top spore Acremonium
Strictum AS 3.2059, aspergillus niger Aspergillus flavus Link AS 3.3950, can use with it is upper identical
Process carry out prepare compound.
The compounds of this invention 1-8 of embodiment 2 anti-hepatic fibrosis activity
1) experiment material
Instrument and reagent：CO2Incubator (Jouan IGO150)；ELIASA (Bio-TEK ELx800)；Fluorescence is inverted aobvious
Micro mirror (Olympus IX51)；MTT cells are bred and citotoxicity detection kit (green skies biotechnology research institute), RPM
I1640 culture mediums (Gibcol BRL), Rnase A, hyclone, dimethyl sulfoxide (DMSO) (DMSO), trypsase (upper marine growth work
Journey Co., Ltd).
Test cell line：HSC-T6 cell lines, are the SD cultured rat hepatic stellate cells of SV40 transfections, are purchased from Chinese medicine section
Institute of oncology of institute.
Test sample：Compound 1-8, purity is more than 90%, positive reference substance colchicin, and each compound is with DMSO
Diluted after dissolving.
2) experimental method
Half inhibiting rate IC of each test-compound to HSC-T6 cell lines is determined using mtt assay50Value：Take the logarithm growth period
HSC-T6 cells, with nutrient solution containing 1%DMEM adjustment cell concentration be 5 × 105/ mL, is inoculated at 96 well culture plates, medicine
Reason group and cell controls group are added per the μ L cell suspensions of hole 100, and every group sets 3 multiple holes, and blank control group only adds full culture medium,
Per the μ L of hole 100, if 3 multiple holes.96 well culture plates are placed in 37 DEG C, 5%CO2After incubator culture 24h, various concentrations are added
Given the test agent, makes final concentration of 0..1-100 μM, continues to cultivate 72h.By mtt assay in ELIASA, 450nm absorbance is determined
(A) value, calculates inhibiting rate [inhibiting rate=(1- experimental groups A values/control group A value) × 100%].Experiment is repeated 3 times.Using SPSS
11.5 softwares make regression equation, calculate half-inhibition concentration (IC of each given the test agent to HSC-T6 cytosiies 72h50)。
3) experimental result
According to mtt assay test result, ICs of the compounds of this invention 1-8 to above-mentioned cell is calculated50Value, as a result as shown in table 2.
The inhibitory action that the test sample of table 2. is bred to HSC cells
| Compound | HSC-T6IC50value(mM) |
| Colchicin | 0.15 |
| Compound 1 | 11.3 |
| Compound 2 | 3.4 |
| Compound 3 | 5.2 |
| Compound 4 | 2.3 |
| Compound 5 | 13.2 |
| Compound 6 | 24.6 |
| Compound 7 | 15.4 |
| Compound 8 | 19.1 |
As a result show, there is good anti-hepatic fibrosis to live by panoxadiol (PD) of the invention and the compounds of this invention 1-8
Property, can as anti-hepatic fibrosis medicines active component.
Claims (2)
1. with following structural Pananxadiol derivatives or its pharmaceutically can into salt prepare prevention or treatment liver fiber
Application in chemical drug thing,
。
2. application as claimed in claim 1, it is characterised in that the medicine contains panoxadiol as claimed in claim 1 and derived
Thing or its pharmaceutically can into salt in one or more and pharmaceutically acceptable carrier.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05170657A (en) * | 1991-09-25 | 1993-07-09 | Toshio Yamada | Restrainer for hepatropathy |
| CN104352505A (en) * | 2014-11-14 | 2015-02-18 | 南通大学 | Applications of protopanaxatriol and derivatives thereof in preparation of medicines for treating hepatic disease |
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2015
- 2015-06-26 CN CN201510362096.0A patent/CN105030790B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05170657A (en) * | 1991-09-25 | 1993-07-09 | Toshio Yamada | Restrainer for hepatropathy |
| CN104352505A (en) * | 2014-11-14 | 2015-02-18 | 南通大学 | Applications of protopanaxatriol and derivatives thereof in preparation of medicines for treating hepatic disease |
Non-Patent Citations (1)
| Title |
|---|
| Biotransformation of 20(R)-panaxadiol by the fungus Rhizopus chinensis;Xiong-Hao Lin等;《phytochemistry》;20140630;第105卷;摘要，图1，结论，试验部分 * |
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