CN101514143A - Method for preparing ginkgol - Google Patents
Method for preparing ginkgol Download PDFInfo
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- CN101514143A CN101514143A CNA2008102342826A CN200810234282A CN101514143A CN 101514143 A CN101514143 A CN 101514143A CN A2008102342826 A CNA2008102342826 A CN A2008102342826A CN 200810234282 A CN200810234282 A CN 200810234282A CN 101514143 A CN101514143 A CN 101514143A
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- bilobol
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- chloroform
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Abstract
The invention belongs to the field of biological medicines, and relates to a method for preparing ginkgol. The ginkgol is prepared by the following steps: preparing ginkgolic acid from gingko (leaves, fruits and testa); performing heat treatment on the ginkgolic acid for decarboxylation; and preparing the ginkgol after purification. The ginkgol prepared by the method can effectively inhibit proliferation of human tumor cells and has better effect of inhibiting the human tumor cells than the ginkgolic acid.
Description
Technical field
The invention belongs to biomedicine field, be specifically related to the preparation method of a kind of bilobol (ginkgols).
Background technology
Ginkgo (Ginkgo biloba L.) is the distinctive ancient seeds of China, the leaf of ginkgo, fruit all can be used as medicine, put down in writing according to " book on Chinese herbal medicine ", ginkgo is as medicinal existing more than 600 year history, since nineteen sixties, the pharmacological action of ginkgolic flavone glycoside, lactone two big composition uniquenesses and clinical effectiveness obtain certainly, ginkgo is produced at first to be widely accepted in Europe, be that (Extract of Ginkgo biloba EGb) is the prevention of generally acknowledging, the natural plant of treatment cardiovascular and cerebrovascular diseases for the Folium Ginkgo extract of effective component at present with ginkgolic flavone glycoside, lactone.
Ginkgolic acid is another the big active component that is present in the ginkgo, and the alkylphenol acid in the ginkgo comprises bilobol (ginkgols), ginkgoic acid (ginkgolic acids) and bilobol (bilobols), and three's structural formula is as follows:
Wherein the content of ginkgoic acid accounts for 1% of Ginkgo Leaf dry weight, 5% of exosper dry weight.Because the suspicious sensitization of ginkgoic acid, be considered to the toxic ingredient among the EGb for a long time, require its content in EGb761 must be below 5ppm; And the sensitization that bilobol does not have ginkgoic acid to have, therefore in Folium Ginkgo extract to its requirement of not limiting the quantity of.
Along with people go deep into gradually to the research of the phenolic acid in Ginkgo Leaf and the extract thereof, find that ginkgoic acid also has many biological activitys except suspicious sensitization: the existing ginkgoic acid that studies show that is to multiple G
+Bacterium has good inhibition effect, can suppress the growth of groups of people pathomycete and agriculture pathogeny bacterium.Ginkgoic acid has the good restraining effect to the growth of multiple lung cancer cell line, lymphoma cell strain, and less to Normocellular toxic action; The author has studied ginkgoic acid to lymphoma U
937The influence of cell, the discovery ginkgoic acid can be induced U
937Apoptosis illustrates that the antitumor action of ginkgoic acid is relevant with the induced tumor apoptosis.Ginkgoic acid also has the good oncomelania effect of killing, it is the main activity against snails composition in the gingko episperm, the related work author has applied for relevant patent (kind of plant agent for killing snails and preparation method thereof and using method), and obtain the authorization (patent No. ZL200510122657.6).
The extraction of relevant ginkgoic acid, preparation, analysis and active existing many pieces of reported in literature:
1. face upward pomegranate green grass or young crops, Wu Xiangyang, Chen Jun. the ginkgoic acid in the high effective liquid chromatography for measuring gingko episperm. analytical chemistry, 2002,30 (8): 901-905.
2.Van?Beek?T.A.Chemical?analysis?of?Ginkgo?biloba?leaves?and?extracts.J.ChromatographyA，2002，967：21-55.
3.H.Jaggy，E.Koch.Chemistry?and?Biology?of?Alkyphenols?from?Ginkgo?biloba?L..Pharmazie，1997，52：735-738.
4. poplar Xiao Ming, Zhu Wei, Chen Jun, etc. the monomeric anti-microbial activity research of ginkgoic acid. Chinese medicinal materials, 2004,27 (9): 661-663.
5. poplar Xiao Ming; The jade of money; Chen Jun. the anti tumor activity in vitro of ginkgoic acid research in the gingko episperm. Chinese medicinal materials, 2004,27 (1): 40-42.
6. Wu faces upward pomegranate green grass or young crops, Chen Jun on the sunny side. monomeric preparation of ginkgoic acid and anti-microbial effect research. and chemistry of forest product and industry, 2003,
The contriver is further finding in the research: the carboxyl in the ginkgoic acid structure has unstable to heat, decarboxylation and change into bilobol easily in the process of heating; The author passes through biological activity determination, the anti-tumor activity of finding bilobol is stronger than ginkgoic acid, therefore bilobol can be used as and a kind ofly has powerful antitumor effect more and the active substance that do not have a sensitization is developed research than ginkgoic acid, the research of relevant bilobol antitumor drug will produce huge social and economic benefit to research and development novel tumor medicine, to the abundant development and use of gingko resource.
Because the content of bilobol in Ginkgo Leaf, fruit and exosper significantly is lower than ginkgoic acid, therefore, except directly from ginkgo, the preparation bilobol, utilizing the characteristics of the easy decarboxylation of ginkgoic acid, prepare bilobol a kind of more economical bilobol preparation method that can yet be regarded as by the ginkgoic acid decarboxylation.
The relevant method of utilizing the ginkgoic acid decarboxylation to prepare bilobol, and the anti-tumor activity of bilobol does not all appear in the newspapers at present as yet.
Summary of the invention
The object of the present invention is to provide a kind of compound with anti-tumor activity---the preparation method and the anti-tumor application thereof of bilobol.
Bilobol involved in the present invention is the alkyl or alkenyl phenol compound, has the structure of general formula (I).Wherein, the R chain is an alkyl or alkenyl, is antineoplastic main active ingredient, mainly be present in leaf, fruit and the exosper of ginkgo (Ginkgo biloba L.), or in leaf, fruit and the bark of Anacardiaceae sumach plant.Carbonatoms on its R base is 10～19, double key number 0～3.Carbon atom can be replaced as O, S, N or halogen atom by other atom on its R base.
Bilobol of the present invention can prepare in the following ways:
With the ginkgoic acid is raw material, and the employing heating means remove the carboxyl on the ginkgoic acid phenyl ring, change into bilobol, and are specific as follows:
1, with ginkgoic acid with after basic metal, alkaline-earth metal or transition metal hydroxide mix in 100: 1～10: 1 ratio (g/g), under 80 ℃～100 ℃ heating, agitation condition, carried out 1～4 hour, decarboxylize obtains the bilobol crude product;
2, the organic solvent dissolution that adds 2～10 times of amounts (g/ml) in the bilobol crude product filters, and concentrates and obtains crude product;
3,, obtain purity and be not less than 96% bilobol homologue with the crude product purification by silica gel column chromatography.
Among the above-mentioned preparation method, alkali metal hydroxide is lithium hydroxide, sodium hydroxide or potassium hydroxide;
Among the above-mentioned preparation method, alkaline earth metal hydroxides is beryllium hydroxide, magnesium hydroxide or hydrated barta;
Among the above-mentioned preparation method, transition metal hydroxide is copper hydroxide, ironic hydroxide or zinc hydroxide, but is not limited to this three kinds of transition element oxyhydroxide;
Among the above-mentioned preparation method, organic solvent is acetone, methyl alcohol, ethanol, propyl carbinol, ethyl acetate or chloroform;
Among the above-mentioned preparation method, described purification by silica gel column chromatography is a gradient elution, and elutriant is chloroform and chloroform-methanol mixing solutions, and chloroform-methanol mixing solutions ratio gradually becomes 5: 5 (v/v) from 9: 1 (v/v), but is not limited to this eluent combined system.
Described ginkgoic acid is by the chemical separation method, from the leaf of ginkgo, really, obtain the extract of exosper; Or to Folium Ginkgo extract recovery again in the remaining fertilizer in extracting the course of processing; Or from containing the each several part extract of this compounds, other plant obtains.
The medicine that comprises The compounds of this invention can be the extract of the leaf, fruit and the exosper that derive from ginkgo, also can be to derive from the each several part extract that other plant contains this compounds.
Claimed this compound of the present invention and pharmacy acceptable salt thereof, ester, solvate, the material of crystal habit.
The medicine that comprises The compounds of this invention can use as antineoplastic agent separately, also can unite use with other antineoplastic agent, to reduce antitumous effect or to reduce its toxic side effect.
The drug regimen that comprises The compounds of this invention contains medicine acceptable carrier; Described composition can be injection liquid or oral drug preparation.
Seek antitumor drug from plant, be the emphasis of cancer therapy drug research at home and abroad, antineoplastic compound has important clinic value and DEVELOPMENT PROSPECT effectively.There is abundant gingko resource in China, annual production along with gingko, a large amount of gingko episperms is used as waste and slatterns, utilize the ginkgoic acid that content enriches in the gingko episperm to be raw material, preparation has the bilobol compound of remarkable anti-tumor activity, for the exploitation of new type antineoplastic medicine, all significant for making full use of of gingko resource.
Specific implementation method
Embodiment 1: the preparation of bilobol homologue
(1) extraction of ginkgoic acid:
With the gingko episperm of 100g drying, pulverizing, add sherwood oil (60～90 ℃ of boiling ranges) ultrasonic extraction 1h in 1: 5 ratio, filter, filter residue repeats to extract twice, and united extraction is flung to sherwood oil and is got exosper extraction medicinal extract.
With the medicinal extract gradation with a small amount of petroleum ether dissolution application of sample (silica gel 120g on silicagel column, silicagel column is the glass column of 32 * 400mm, wet method dress post), use sherwood oil: ether: formic acid=89: 11: 1 (V/V/V) wash-out, fluorescence occurring at the 254nm place with thin-layer chromatography is detection, collect the ginkgoic acid component, be concentrated into dried; Repeated post once, the ginkgoic acid component that obtains is washed to neutrality, is concentrated into driedly, or uses anhydrous Na SO
4After the drying, get the ginkgoic acid mixture.
(2) preparation of bilobol:
Get 1.0g ginkgoic acid and 0.02g NaOH and mix in single neck flask of a 50ml, immerse 100 ℃ water-bath, magnetic agitation 1 hour, mixture is cooled to room temperature, obtains the bilobol of 0.9g, uses the 3.0mL alcohol extraction then.Filter, concentrate and obtain a chocolate oily matter.
This product with dissolve with ethanol after, be splined on silicagel column (silica gel 120g, silicagel column is the glass column of 32 * 400mm, wet method dress post), adopt respectively chloroform, chloroform-methanol mixing solutions (ratio gradually became 5: 5 from 9: 1, V/V) wash-out, fluorescence occurring at the 254nm place with thin-layer chromatography is detection, collect the bilobol component, be concentrated into dried; Repeated post once, the bilobol homology mixture that obtains.
(3) evaluation of bilobol
The bilobol homologue for preparing is a light brown liquid, and its methanol solution ultraviolet absorption peak is respectively 201,275nm; Infrared spectra (KBr compressing tablet) is gone up 3340cm
-1There is wide ν at the place
O-HVibration, 1260cm
-1The ν of place
C-OAnd 1370cm
-1The δ at place
O-H(in the face) all susceptible of proof is alkyl substituted phenol.
LC-ESI-MS (Thermo electron Croporation) analyzes: Agilent TC18 post (150 * 4.6mm, 5 μ m), mobile phase methanol-3%HAc solution (90: 10, v/v), the quality that records 5 homologues of bilobol is respectively 276,304,302,330,328, correspond respectively to ginkgoic acid C13:0, C15:0, C15:1, C17:1 and C17:2.
Embodiment 2: the preparation of bilobol homologue
(4) extraction of ginkgoic acid:
With the gingko episperm of 100g drying, pulverizing, add sherwood oil (60～90 ℃ of boiling ranges) ultrasonic extraction 1h in 1: 5 ratio, filter, filter residue repeats to extract twice, and united extraction is flung to sherwood oil and is got exosper extraction medicinal extract.
With the medicinal extract gradation with a small amount of petroleum ether dissolution application of sample (silica gel 120g on silicagel column, silicagel column is the glass column of 32 * 400mm, wet method dress post), use sherwood oil: ether: formic acid=89: 11: 1 (V/V/V) wash-out, fluorescence occurring at the 254nm place with thin-layer chromatography is detection, collect the ginkgoic acid component, be concentrated into dried; Repeated post once, the ginkgoic acid component that obtains is washed to neutrality, is concentrated into driedly, or uses anhydrous Na SO
4After the drying, get the ginkgoic acid mixture.
(5) preparation of bilobol:
Get 1.0g ginkgoic acid and 0.01g Mg (OH)
2Mix in single neck flask of a 50ml, immerse 90 ℃ water-bath, magnetic agitation 1 hour, mixture is cooled to room temperature, obtains the bilobol of 0.9g, uses the 8.5mL ethyl acetate extraction then.Filter, concentrate and obtain a chocolate oily matter.
This product with dissolve with ethanol after, be splined on silicagel column (silica gel 120g, silicagel column is the glass column of 32 * 400mm, wet method dress post), adopt respectively chloroform, chloroform-methanol mixing solutions (ratio gradually became 5: 5 from 9: 1, V/V) wash-out, fluorescence occurring at the 254nm place with thin-layer chromatography is detection, collect the bilobol component, concentrate as for; Repeated post once, the bilobol homology mixture that obtains.
(6) evaluation of bilobol
The bilobol homologue for preparing is a light brown liquid, and its methanol solution ultraviolet absorption peak is respectively 201,275nm; Infrared spectra (KBr compressing tablet) is gone up 3340cm
-1There is wide ν at the place
O-HVibration, 1260cm
-1The ν of place
C-OAnd 1370cm
-1The δ at place
O-H(in the face) all susceptible of proof is alkyl substituted phenol.
LC-ESI-MS (Thermo electron Croporation) analyzes: Agilent TC18 post (150 * 4.6mm, 5 μ m), mobile phase methanol-3%HAc solution (90: 10, v/v), the quality that records 5 homologues of bilobol is respectively 276,304,302,330,328, correspond respectively to ginkgoic acid C13:0, C15:0, C15:1, C17:1 and C17:2.
Embodiment 3: the preparation of bilobol homologue and anti-tumor activity
(1) extraction of ginkgoic acid:
With the gingko episperm of 100g drying, pulverizing, add sherwood oil (60～90 ℃ of boiling ranges) ultrasonic extraction 1h in 1: 5 ratio, filter, filter residue repeats to extract twice, and united extraction is flung to sherwood oil and is got exosper extraction medicinal extract.
With the medicinal extract gradation with a small amount of petroleum ether dissolution application of sample (silica gel 120g on silicagel column, silicagel column is the glass column of 32 * 400mm, wet method dress post), use sherwood oil: ether: formic acid=89: 11: 1 (V/V/V) wash-out, fluorescence occurring at the 254nm place with thin-layer chromatography is detection, collect the ginkgoic acid component, be concentrated into dried; Repeated post once, the ginkgoic acid component that obtains is washed to neutrality, is concentrated into driedly, or uses anhydrous Na SO
4After the drying, get the ginkgoic acid mixture.
(2) preparation of bilobol:
Get 1.0g ginkgoic acid and 0.08g Cu (OH)
2Mix in single neck flask of a 50ml, immerse 80 ℃ water-bath, magnetic agitation 4 hours, mixture is cooled to room temperature, uses the 5.0mL acetone extract then.Filter, concentrate and obtain a chocolate oily matter.
After this product dissolves with chloroform, be splined on silicagel column (silica gel 120g, silicagel column is the glass column of 32 * 400mm, wet method dress post), adopt respectively chloroform, chloroform-methanol mixing solutions (ratio gradually became 5: 5 from 9: 1, V/V) wash-out, fluorescence occurring at the 254nm place with thin-layer chromatography is detection, collect the bilobol component, be concentrated into dried; Repeated post once, the bilobol homology mixture that obtains.
(3) evaluation of bilobol
The bilobol homologue for preparing is a light brown liquid, and its methanol solution ultraviolet absorption peak is respectively 201,275nm; Infrared spectra (KBr compressing tablet) is gone up 3340cm
-1There is wide ν at the place
O-HVibration, 1260cm
-1The ν of place
C-OAnd 1370cm
-1The δ at place
O-H(in the face) all susceptible of proof is alkyl substituted phenol.
LC-ESI-MS (Thermo electron Croporation) analyzes: Agilent TC18 post (150 * 4.6mm, 5 μ m), mobile phase methanol-3%HAc solution (90: 10, v/v), the quality that records 5 homologues of bilobol is respectively 276,304,302,330,328, correspond respectively to ginkgoic acid C13:0, C15:0, C15:1, C17:1 and C17:2.
(4) anti-tumor activity of bilobol homologue
Adopt mtt assay, bilobol dissolves with DMSO, and being diluted to the DMEM nutrient solution needs concentration again; With the tumour cell of logarithmic growth with tryptic digestion after, make 5 * 10 with the DMEM nutrient solution that contains 10% foetal calf serum
4Individual/the mL cell suspension, be seeded in 96 well culture plates, every hole 200 μ L are in 37 ℃, 5%CO
2Incubator in cultivate 24h after, the soup of different concns is added in the above-mentioned culture hole, establish 5 parallel holes, to contain the negative contrast of DMEM nutrient solution of 10% foetal calf serum, the positive contrast of cis-platinum, 48h is cultivated in continuation, and 4h adds 5mg/ml MTT solution 20 μ L, sucking-off nutrient solution behind the cultivation 4h before ending, add DMSO 200 μ L, concussion is evenly measured optical density(OD) (OD value) at the 490nm place, by formula calculates the growth of tumour cell inhibiting rate.Inhibiting rate (%)=1-(OD
Experiment-OD
Blank)/(OD
Contrast-OD
Blank) * 100%.Three repetitions are established in experiment.
Tested the cytotoxicity of bilobol, the results are shown in Table 1 human hepatoma cell strain SMMC7721, human leukemia cell line K562 and people's glioma cell line U251.
Table 1, ginkgoic acid, bilobol are to the restraining effect LD of human tumor cells
50(mg/L)
Claims (8)
1, a kind of preparation method of bilobol is characterized in that: be raw material with the ginkgoic acid, the employing heating means remove the carboxyl on the ginkgoic acid phenyl ring, change into bilobol.
2, the preparation method of a kind of bilobol as claimed in claim 1 is specially:
(1) with ginkgoic acid with after basic metal, alkaline-earth metal or transition metal hydroxide mix in 100: 1～10: 1 ratio (g/g), under 80 ℃～100 ℃ heating, agitation condition, carried out 1～4 hour, decarboxylize obtains the bilobol crude product;
(2) in the bilobol crude product, add the organic solvent dissolution of 2～10 times of amounts (g/ml), filter, concentrate and obtain crude product;
(3), obtain purity and be not less than 96% bilobol homologue with the crude product purification by silica gel column chromatography;
3, the preparation method of a kind of bilobol as claimed in claim 2 is characterized in that: alkali metal hydroxide is lithium hydroxide, sodium hydroxide or potassium hydroxide.
4, the preparation method of a kind of bilobol as claimed in claim 2 is characterized in that: alkaline earth metal hydroxides is beryllium hydroxide, magnesium hydroxide or hydrated barta.
5, the preparation method of a kind of bilobol as claimed in claim 2 is characterized in that: transition metal hydroxide is copper hydroxide, ironic hydroxide or zinc hydroxide.
6, the preparation method of a kind of bilobol as claimed in claim 2 is characterized in that: organic solvent is acetone, methyl alcohol, ethanol, propyl carbinol, ethyl acetate or chloroform.
7, the preparation method of a kind of bilobol as claimed in claim 2, it is characterized in that: described purification by silica gel column chromatography is a gradient elution, elutriant is chloroform and chloroform-methanol mixing solutions, and chloroform-methanol mixing solutions ratio gradually becomes 5: 5 (v/v) from 9: 1 (v/v).
8, the preparation method of a kind of bilobol as claimed in claim 1 or 2 is characterized in that: described ginkgoic acid is by the chemical separation method, from the leaf of ginkgo, really, obtain the extract of exosper; Or to Folium Ginkgo extract recovery again in the remaining fertilizer in extracting the course of processing; Or from containing the each several part extract of this compounds, other plant obtains.
Priority Applications (1)
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|---|---|---|---|
| CNA2008102342826A CN101514143A (en) | 2008-11-28 | 2008-11-28 | Method for preparing ginkgol |
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| CNA2008102342826A CN101514143A (en) | 2008-11-28 | 2008-11-28 | Method for preparing ginkgol |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709015A (en) * | 2013-12-25 | 2014-04-09 | 江苏大学 | Application of ginkgol C17:1 in treatment of liver cancer |
| CN103960555A (en) * | 2014-04-11 | 2014-08-06 | 天津科技大学 | Method for removing ginkgolic acid in gingko biloba seeds |
-
2008
- 2008-11-28 CN CNA2008102342826A patent/CN101514143A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709015A (en) * | 2013-12-25 | 2014-04-09 | 江苏大学 | Application of ginkgol C17:1 in treatment of liver cancer |
| CN103709015B (en) * | 2013-12-25 | 2016-08-31 | 江苏大学 | Ginkgol C17:1 purposes in liver cancer treatment |
| CN103960555A (en) * | 2014-04-11 | 2014-08-06 | 天津科技大学 | Method for removing ginkgolic acid in gingko biloba seeds |
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