CN103787953A - Compound Aspochalasin V and preparation method and application thereof - Google Patents
Compound Aspochalasin V and preparation method and application thereof Download PDFInfo
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- CN103787953A CN103787953A CN201410021344.0A CN201410021344A CN103787953A CN 103787953 A CN103787953 A CN 103787953A CN 201410021344 A CN201410021344 A CN 201410021344A CN 103787953 A CN103787953 A CN 103787953A
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
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Abstract
The invention discloses a compound Aspochalasin V and a preparation method and application thereof. The structure of the compound Aspochalasin V is shown as a formula (I). The preparation method comprises the steps: inoculating aspergillus flavipes CCTCC NO:M 2013631 into a culture medium for performing fermentation cultivation; after fermentation cultivation, separating to obtain a fermentation liquor, and extracting the fermentation liquor by using an organic solvent to obtain an extraction solution; sequentially performing separation and purification by a normal phase silica gel chromatographic column and a high performance liquid chromatography after concentrating the extraction solution to obtain the compound Aspochalasin V. The invention further discloses application of the compound Aspochalasin V to preparation of antitumor medicines or tumor preventing health foods. The compound Aspochalasin V disclosed by the invention has an antitumor activity; the preparation method is simple and convenient, and is easy to operate, low in production cost and suitable for large-scale production.
Description
Technical field
The invention belongs to medical technical field, relate in particular to a kind of compd A spochalasin V and its preparation method and application.
Background technology
Cancer is common disease, the frequently-occurring disease of serious threat human life health, and mortality ratio is high, and what cancer was died from the whole world every year approximately has 4,300,000 people, and what China died from cancer every year approximately has 1,000,000 people, and this situation is also in aggravation.Therefore the medicine that, research and development have an anti-tumor activity has great importance.
The diversity of microorganism and the diversity of secondary metabolite thereof are to find the important foundation of lead compound.Ocean is the even environment of low temperature, high pressure of a high salt, oligotrophic, environment is very big compared with the difference on land, its special living environment has caused the metabolic rule of marine microorganism uniqueness, at present, from the secondary metabolite of numerous marine microorganisms, separate, purifying obtained novel structure and had the compound of remarkable activity.
Aspergillus fungi is the important bacterial classification of fermentation industry and food-processing industry, be utilized nearly 60 kinds.Before more than 2000 year, China is just for sauce processed, and aspergillus fungi is also the main bacteria seed of wine brewing, vinegar song processed.Aspergillus fungi is also one of main producer of bioactive natural product, and its meta-bolites almost comprises all structure types of having found.From aspergillus fungi, separate at present the multiple compound with anti-tumor activity, as: the Chinese patent that publication number is CN102311442A separation and purification from the solid fermentation thing of thalassiomycetes Aspergillus fumigatus (Aspergillus fumigatus) MF330 has obtained two snail lactam alkaloid compounds, these two compounds can be served as the inhibitor of NF К B, inducing apoptosis of tumour cell; Publication number is that Chinese patent separation and purification from the fermented product of microorganism Aspergillus aculeatus (Aspergillus aculeatus) IBPT-3 of CN103058846A has obtained a kind of quinone derivatives with anti-tumor activity; Etc..
Aspochalasin compounds is the one of cytochalasins, and this compounds is found to have antitumor or HIV (human immunodeficiency virus)-resistant activity.The Chinese patent separation and purification from the fermented product of the bright aspergillus of Huang (Aspergillus flavipes) ZHN1-09 that is CN102260271A as publication number goes out a cytochalasin compounds, and this compound can be used as inhibition of cell proliferation or antineoplastic agent; The discovery aspochalasin L such as Rochfort Simone have and suppress active HIV-1 intergrase, its half-inhibition concentration IC
50be 71.7 μ M(Journal of Antibiotics, 2005,58 (4), 279-283).But so far there are no the report that replaces Aspochalasin compounds and anti-tumor activity thereof about methylthio group.
Summary of the invention
The invention provides a kind of compd A spochalasin V, this compound, for extract the natural active matter obtaining from the fermenting culture of thalassiomycetes aspergillus flavipes (Aspergillus flavipes) Z-4, has anti-tumor activity.
A kind of compd A spochalasin V, its structure is as shown in formula I:
The preparation method who the invention provides described compd A spochalasin V, comprises the following steps:
(1) will in aspergillus flavipes CCTCC2013631 access substratum, carry out fermentation culture;
(2) after fermentation culture, separate and obtain fermented liquid, fermented liquid is extracted with organic solvent, be extracted liquid;
(3) after described extraction liquid is concentrated, successively through normal phase silica gel chromatography post and high performance liquid chromatography separation and purification, obtain described compd A spochalasin V.
Aspergillus flavipes CCTCC2013631, Classification And Nomenclature is aspergillus flavipes (Aspergillus flavipes), complete called after aspergillus flavipes (Aspergillus flavipes) Z-4, this bacterial strain has been preserved in the Chinese Typical Representative culture collection center (being called for short CCTCC) that is positioned at Wuhan, China Wuhan University, deposit number is CCTCC NO:M2013631, and preservation date is on December 4th, 2013.
Aspergillus flavipes CCTCC2013631 separates and obtains from the enteron aisle of extra large cockroach, and the colony growth rate of this bacterial strain is very fast, and quality is loose, and smooth, velvet is radial, neat in edge; Conidium is spherical, and it is radial that conidial head is.
Described substratum is 2216E liquid nutrient medium.This liquid nutrient medium is suitable for the growth of marine microorganism.
The temperature of described fermentation culture is 23～28 ℃, and the time is 25～35 days.Preferably, the temperature of described fermentation culture is 25 ℃, and the time is 28 days.
Described fermentation culture can adopt static cultivation mode, can not vibrate and shake training.
When extraction, organic solvent can be used ethyl acetate, methylene dichloride, chloroform etc., is preferably ethyl acetate; The volume ratio of described organic solvent and fermented liquid is 1:1.
In the time that normal phase silica gel chromatography post separates, eluting solvent is methylene chloride/methanol, when wash-out, adopting successively volume ratio is that the methylene chloride/methanol mixed solution of 100:1,98:2,95:5,90:10,80:20,50:50,0:100 carries out wash-out, the cut for the volume ratio methylene chloride/methanol mixed solution wash-out that is 90:10 of collection.
When high performance liquid chromatography carries out purifying, the acetonitrile solution of employing 58% carries out wash-out, can obtain compd A spochalasin V sterling.
Compd A spochalasin V described in the present invention also provides is in the application of preparing in antitumor drug or tumor prevention protective foods, and wherein, described tumour can be the rectum cancer, prostate cancer etc.
In vitro in anti-tumor activity test, compd A spochalasin V of the present invention has the effect of obvious inhibition tumor cell propagation, therefore, and can be using the compd A spochalasin V of effective dose as activeconstituents, add pharmaceutically acceptable auxiliary material, prepare antitumor drug.
Described pharmaceutically acceptable auxiliary material comprises the weighting agents such as starch, sucrose, Microcrystalline Cellulose, the tackiness agents such as starch slurry, hydroxypropylcellulose, gelatin, polyoxyethylene glycol, the wetting agents such as Magnesium Stearate, micropowder silica gel, polyethylene glycols, the absorption enhancers such as poly-sorb fat, Yelkin TTS, the tensio-active agents such as poloxamer, smooth, the poly-sorb fat of lipid acid sorb, can also add other assistant agent such as flavouring agent, sweeting agent, etc.
The formulation of medicine can be tablet, pill, pulvis, dispersible tablet, sachets, elixir, suspensoid, emulsion, solution, syrup, aerosol, capsule, injection liquid, liniment, suppository etc.Above-mentioned various formulation can adopt ordinary method to be prepared.
Route of administration is administration in administration or non-intestines in intestines, comprises oral, intramuscular injection, subcutaneous injection, intravenous injection etc.
Certainly, also can, take the compd A spochalasin V of effective dose as activeconstituents, add acceptable auxiliary material on food, prepare tumor prevention protective foods.
Compared with prior art, beneficial effect of the present invention is:
Compd A spochalasin V of the present invention is a kind of cytochalasin compounds of novel structure, its large loop section has methylthio group to replace, this compd A spochalasin V has anti-tumor activity, can be used in and prepare anti-tumor drug or tumor prevention protective foods, there is good development prospect.
Compound of the present invention extracts to separate and obtains from the fermenting culture of thalassiomycetes thalassiomycetes aspergillus flavipes (Aspergillus flavipes) Z-4, and extraction and separation method is easy, easy handling, and low production cost, is applicable to large-scale production.
Embodiment
Below in conjunction with specific embodiment, the present invention is further explained.
Collection, separation and the evaluation of embodiment 1 bacterial strain Z-4
1, the collection of bacterial strain Z-4, separation
Sea cockroach sample picks up from coastland, Zhoushan Of Zhejiang Province Dinghai, in aseptic working platform, use cockroach surface, sterilizing seawater flushing sea, taking out its enteron aisle cuts into pieces, be positioned on 2216E solid medium 25 ℃ leave standstill cultivate, according to bacterial plaque profile and color picking list bacterium colony, the method purifying that adopts plate streaking to separate obtains a strain filamentous fungus, called after Z-4, after move to 4 ℃, inclined-plane and save backup.
2, the evaluation of bacterial strain Z-4
On substratum, the colony growth rate of bacterial strain Z-4 is very fast, and quality is loose, and smooth, velvet is radial, neat in edge; Conidium is spherical, and it is radial that conidial head is.
Extract the DNA of bacterial strain Z-4, utilize primer NS1 and NS8 amplification 18S rDNA sequence, check order; Wherein, the base sequence of primer is:
NS：5`-GTAGTCATATGCTTGTCTC-3`；
NS8：5`-TCCGCAGGTTCACCTACGGA-3`。
The 18S rDNA of this bacterial strain is as shown in SEQ ID No.1, the sequence discovery of comparing in NCBI, homology degree (Max ident) the highest (reaching 99%) be Aspergillus (Aspergillus sp.) bacterial strain, and nearest with the genetic distance of aspergillus flavipes (Aspergillus flavipes), simultaneously in conjunction with its morphological specificity, identify that this bacterial strain Z-4 is aspergillus flavipes (Aspergillus flavipes), called after aspergillus flavipes (Aspergillus flavipes) Z-4.
This bacterial strain is delivered on December 4th, 2013 the Chinese Typical Representative culture collection center (be called for short CCTCC) that is positioned at Wuhan, China Wuhan University and is carried out preservation, and deposit number is CCTCC NO:M2013631.
The preparation of embodiment 2 compd A spochalasin V
(1) fermentation: add 200mL2216E liquid nutrient medium in 500mL triangular pyramidal bottle, bacterial strain Z-4 is implanted into liquid nutrient medium from slant medium, room temperature (25 ℃) leaves standstill cultivates 4 weeks.After cultivation completes, filter with filter paper, filtrate decompression is concentrated into 1L, and with equal-volume ethyl acetate extraction 3 times, combined ethyl acetate layer, obtains extract 10g after reclaim under reduced pressure organic solvent.
(2) separation and purifying: purification on normal-phase silica gel column chromatography (200～300 order silica gel for said extracted thing, 200g), with methylene chloride/methanol (100:1-0:100, successively take volume ratio as 100:1, 98:2, 95:5, 90:10, 80:20, 50:50, the methylene chloride/methanol of 0:100 is carried out wash-out, every concentration volume 1000ml) gradient elution, thin-layer chromatography detects, merge the cut (being that volume ratio is the cut of the methylene chloride/methanol wash-out of 90:10) that contains target compound, through preparative ODS-HPLC(acetonitrile/water (58%) wash-out, flow velocity is 10ml/min, retention time is 20min) purifying, obtain target compound sterling (35mg).
Target compound is white unformed solid, and HRTOFMS provides quasi-molecular ion peak m/z432.2572[M+H]
+, calculate that its molecular formula is C
25h
37nO
3s, infrared spectra (liquid film) (cm
-1): 3350(-NH), 1687(C=O).Hydrogen spectrum and carbon spectrum nuclear magnetic resonance data are in table 1.
The hydrogen spectrum of table 1Aspochalasin V and carbon spectrum nuclear magnetic resonance data
Through identifying, this target compound is the new A spochalasin compounds that a kind of methylthio group replaces, called after Aspochalasin V, and its structure is:
The determination of activity of embodiment 3 compd A spochalasin V
Adopt mtt assay to carry out anti tumor activity in vitro test to compd A spochalasin V.
Cell strain: prostate cancer PC3 cell, rectum cancer HCT116 cell.
Substratum: RPMI1640 substratum, containing 10% foetal calf serum.
Sample preparation: sample is dissolved in DMSO, and be diluted to 5 concentration according to certain ratio.
Active testing experiment: by the tumour cell in logarithmic phase, inoculate in 96 orifice plates with 20000/ml, every hole adds cell suspension 200 μ l, cultivates after 24h, adds respectively above-mentioned preparating liquid 1 μ l, and each concentration is established 3 multiple holes.Cell is hatched after 48h in 37 ℃, 5% CO2gas incubator, adding concentration is the MTT solution 20 μ l of 2.5mg/ml, continues to cultivate 4h, sucks supernatant liquor, add 100 μ lDMSO to shake up, under 570nm wavelength, measure the absorbance (OD value) in each hole by microplate reader and calculate cell inhibitory rate.
The anti-tumor activity of table 2Aspochalasin V
Test-results is in table 2, and in table, visible compd A spochalasin V has good restraining effect to the propagation of tumour cell, the wherein IC of compd A spochalasin V to PC3 cell
50be about 30 μ M, the IC50 of HCT116 cell is about to 39 μ M.
Claims (9)
1. a compd A spochalasin V, its structure is as shown in formula I:
2. the preparation method of compd A spochalasin V as claimed in claim 1, is characterized in that, comprising:
(1) will in aspergillus flavipes CCTCC2013631 access substratum, carry out fermentation culture;
(2) after fermentation culture, separate and obtain fermented liquid, fermented liquid is extracted with organic solvent, be extracted liquid;
(3) after described extraction liquid is concentrated, successively through normal phase silica gel chromatography post and high performance liquid chromatography separation and purification, obtain described compd A spochalasin V.
3. preparation method as claimed in claim 2, is characterized in that, described substratum is 2216E liquid nutrient medium.
4. preparation method as claimed in claim 2, is characterized in that, the temperature of described fermentation culture is 23～28 ℃, and the time is 25～35 days.
5. preparation method as claimed in claim 2, is characterized in that, described organic solvent is ethyl acetate, methylene dichloride or chloroform.
6. preparation method as claimed in claim 2, is characterized in that, described organic solvent and the volume ratio of fermented liquid are 1:1.
7. preparation method as claimed in claim 2, is characterized in that, in the time that normal phase silica gel chromatography post separates, eluting solvent is methylene chloride/methanol mixed solution.
8. compd A spochalasin V as claimed in claim 1 is in the application of preparing in antitumor drug or tumor prevention protective foods.
9. application as claimed in claim 8, is characterized in that, described tumour is the rectum cancer or prostate cancer.
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Cited By (4)
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|---|---|---|---|---|
| CN105085538A (en) * | 2015-08-21 | 2015-11-25 | 华中科技大学 | Compound with tumor cell G1-phase retardative effect, and preparation and application of compound |
| CN105267211A (en) * | 2015-10-27 | 2016-01-27 | 浙江大学 | Application of Aspochalasin compounds to preparation of anti-HIV (human immunodeficiency virus)-latency drugs and acquired immune deficiency syndrome treating drugs |
| CN107119087A (en) * | 2017-03-29 | 2017-09-01 | 浙江大学 | A kind of cytochalasins compound AspochalasinD preparation method and application |
| CN109750077A (en) * | 2019-01-15 | 2019-05-14 | 华南农业大学 | The Preparation method and use of Doby Asia cockroach symbiotic effects activity secondary metabolite |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085538A (en) * | 2015-08-21 | 2015-11-25 | 华中科技大学 | Compound with tumor cell G1-phase retardative effect, and preparation and application of compound |
| CN105267211A (en) * | 2015-10-27 | 2016-01-27 | 浙江大学 | Application of Aspochalasin compounds to preparation of anti-HIV (human immunodeficiency virus)-latency drugs and acquired immune deficiency syndrome treating drugs |
| CN105267211B (en) * | 2015-10-27 | 2018-06-19 | 浙江大学 | Aspochalasin classes compound prepare AntiHIV1 RT activity hide drug and treat AIDS-treating medicine in application |
| CN107119087A (en) * | 2017-03-29 | 2017-09-01 | 浙江大学 | A kind of cytochalasins compound AspochalasinD preparation method and application |
| CN107119087B (en) * | 2017-03-29 | 2020-05-12 | 浙江大学 | Preparation method and application of cytochalasin compound Aspochalasin D |
| CN109750077A (en) * | 2019-01-15 | 2019-05-14 | 华南农业大学 | The Preparation method and use of Doby Asia cockroach symbiotic effects activity secondary metabolite |
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