CN106518643A - Cyclopentene ketone compound and preparation method and application thereof - Google Patents
Cyclopentene ketone compound and preparation method and application thereof Download PDFInfo
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- CN106518643A CN106518643A CN201610895077.9A CN201610895077A CN106518643A CN 106518643 A CN106518643 A CN 106518643A CN 201610895077 A CN201610895077 A CN 201610895077A CN 106518643 A CN106518643 A CN 106518643A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/707—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups a keto group being part of a three- to five-membered ring
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/24—Preparation of oxygen-containing organic compounds containing a carbonyl group
- C12P7/26—Ketones
- C12P7/38—Cyclopentanone- or cyclopentadione-containing products
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Abstract
The invention discloses a cyclopentene ketone compound and preparation method and application thereof, the method is being characterized by having a structural formula of cyclopentene ketone compound as indicated in I, the preparation method comprises the steps of obtaining a fermentation broth containing new cyclopentene ketone compound through the fermentation culture of aspergillus ustus with preservation number CCTCC No. M2014086, then extracting the fermentation broth using ethyl acetate, and obtaining the crude extract, after going through the process of decompression slica column chromatography, reverse phase medium pressure column chromatography, and finally the reverse phase semipreparation of high performance liquid chromatography, the extract is prepared by separation and purification, the cyclopentene ketone compound has the functions of supressing cell activity and being tumor resistant, the cyclopentene ketone compound has the advantages of the compound I being formulated with carrier, excipient or auxiliary materials acceptable by a variety of drugs, and being able to be prepared into anti-tumor drugs, the cyclopentene ketone compound can be used for treating tumors, the compound I can be used as a low molecular biological probe for inhibiting cell propagation and is used for studying life science.
Description
Technical field
The present invention relates to a kind of cyclopentenes ketone compounds, more particularly, to a kind of cyclopentenes ketone compounds and its preparation
The application of method and such compound in tumor cell proliferation inhibitor or antitumor agent is prepared.Background technology
The cyclopentenes ketone compounds generally compound with notable physiologically active, such as prostaglandin, pentenomycin etc..This
Inventor studies and learns, marine fungi Aspergillus ustus DJ003（It is preserved in China typical culture collection center,
Deposit number is：CCTCC No: M2014086）The ethyl acetate extract of liquid fermentation has preferable tumor cell proliferation suppression
System activity, is studied to its active component then.Have not yet to see chemical constitution and the tumor cell proliferation suppression of the compound
The report of system activity, therefore also there is not yet medicine related to this on market.
The content of the invention
The technical problem to be solved is to provide a kind of with suppression tumor cell proliferation and anti-tumor activity
Cyclopentenes ketone compounds and its production and use.
The present invention solve the technical scheme that adopted of above-mentioned technical problem for：A kind of cyclopentenes ketone compounds, the ring penta
The structural formula of ketene compounds is as shown in I：
（I）.
The preparation method of above-mentioned cyclopentenes ketone compounds, specifically includes following steps：
（1）Fermenting and producing
By the aspergillus ustus that preserving number is M2014086（Aspergillus ustus DJ003）Line brings back to life, and is inoculated into PDA solids
On slant medium, after cultivating 5 days in 28 DEG C of incubators；The bacterium colony that slant culture is obtained all is inoculated into equipped with 300mL
In PDB culture medium, in 28 DEG C, quiescent culture 45 days obtains fermentation liquid；
（2）The acquisition of extractum
Fermentation liquid is removed after thalline with filtered through gauze, fermentation liquid is repeated into extraction 3 times with isopyknic ethyl acetate, merge three
Extract concentrating under reduced pressure is removed ethyl acetate by extract obtained by secondary extraction, obtains crude extract；
（3）The separation and purification of compound
After by crude extract dichloromethane and methanol mixed solvent dissolving, plus 200-300 mesh silica gel mixed samples, using petroleum ether/second
Acetoacetic ester is with volume ratio 5:1 gradient carries out eluting for eluant, carries out decompression silica gel column chromatography to crude extract, collects eluting group
Point, by elution fraction through anti-phase middle compression leg chromatographic isolation, eluting ratio is adopted for 120 points of 10-100% methanol/water gradient elution
Clock, flow velocity are 20ml/min, collect the flow point that appearance time is 100 minutes, and finally the flow point is through partly preparing reversed phase high performance liquid
Phase chromatographic separation and purification obtains cyclopentenes ketone compounds, and its structure is shown in formula I：
（I）.
The formula of described PDB culture medium is as follows：200 g of Rhizoma Solani tuber osi, glucose 20 g and sea water 1L.
In described dichloromethane and methanol mixed solvent, dichloromethane is 1 with the volume ratio of methanol：1.
The described eluent for partly preparing reversed-phase high-performance liquid chromatography is methanol and water by volume 1:1 mixes.
The application of above-mentioned cyclopentenes ketone compounds, described cyclopentenes ketone compounds are preparing tumor cell proliferation suppression
Purposes in terms of preparation or antitumor drug.
Compared with prior art, it is an advantage of the current invention that：A kind of cyclopentenes ketone compounds of the present invention and its preparation side
Method and purposes, the present invention obtain the fermentation liquid containing new cyclopentenes ketone compounds by fermentable culture, then will send out
Zymotic fluid is extracted with ethyl acetate, obtains crude extract, and extract Jing is reduced pressure silica gel column chromatography, anti-phase medium pressure column chromatography, last anti-
Half preparative high-performance liquid chromatographic of phase is isolated and purified and is obtained, and the cyclopentenes ketone compounds have suppression cytoactive, and antitumor is made
With.Compound I and various pharmaceutically acceptable carriers, excipient or supplementary product compatibility, can be made into antitumor drug, for tumor
Treatment.Compound I is alternatively arranged as suppressing the low molecule bioprobe of cell propagation to be used for life science, used as probe application
When, compound I is dissolved in methanol, water or aqueous methanol, is applied in the aqueous solution for also dissolving in dimethyl sulfoxide.
Above-mentioned aspergillus ustus（Aspergillus ustus）, the bacterium is DJ003 bacterial strains, and deposit number is CCTCC No.
M2014086, was preserved in China typical culture collection center on 03 14th, 2014, and preservation address is China. Wuhan. it is military
Chinese university.
Specific embodiment
With reference to embodiments the present invention is described in further detail.
Embodiment 1
A kind of cyclopentenes ketone structural formula of compound is as shown in I：
（I）.
Embodiment 2
The preparation method of the cyclopentenes ketone compounds as shown in I formulas, specifically includes following steps：
（1）Fermenting and producing
By the aspergillus ustus that preserving number is M2014086（Aspergillus ustus DJ003）Line brings back to life, and is inoculated into PDA solids
On slant medium, after cultivating 5 days in 28 DEG C of incubators；The bacterium colony that slant culture is obtained all is inoculated into equipped with 300mL
In PDB culture medium (200 g of Rhizoma Solani tuber osi, 20 g of glucose, sea water 1L), in 28 DEG C, quiescent culture 45 days obtains fermentation liquid；
（2）The acquisition of extractum
Fermentation liquid is removed after thalline with filtered through gauze, fermentation liquid is repeated into extraction 3 times with isopyknic ethyl acetate, merge three
Extract concentrating under reduced pressure is removed ethyl acetate by extract obtained by secondary extraction, obtains crude extract；
（3）The separation and purification of compound
By crude extract dichloromethane and methanol（Dichloromethane is 1 with the volume ratio of methanol：1）After mixed solvent dissolving, plus
200-300 mesh silica gel mixed samples, adopt petrol ether/ethyl acetate with volume ratio 5:1 gradient carries out eluting for eluant, to crude extract
Decompression silica gel column chromatography is carried out, elution fraction is collected, by elution fraction through anti-phase middle compression leg chromatographic isolation, using eluting ratio
For 10-100% methanol/water gradient elution 120 minutes, flow velocity was 20ml/min, collected the flow point that appearance time is 100 minutes, most
The flow point obtains cyclopentenes ketone compounds through partly preparing reversed-phase high-performance liquid chromatography and isolating and purifying afterwards, its structure such as Formulas I institute
Show：
（I）.
The compounds I colorless oil, molecular formula C7H9O3Cl, anion HRESIMS m/z：175.0162,177.0149
[M – H]–,1H and13C-NMR data are shown in Table 1.
1 compounds I of table1H and13C NMR datas（500 and 125MHz, in DMSO-d 6）a
Note：a）Represent this table signals assignment based on DEPT,1H-1H COSY, HSQC and HMBC spectrum analysis results.Hydrogen signal is more
Severe uses s respectively（Singlet）、d（Doublet）、t（Triplet）And m（Multiplet）Table；B) represent numeral and the generation in this hurdle
Number represent respectively1H-1Coupling coherent signal is given with the 1H in corresponding line in H COSY spectrums1H cores；C) in representing this hurdle
Numeral and code name represent respectively HMBC compose in corresponding line in1H provides coupling coherent signal13C cores.
Embodiment 3
The test of anti tumor activity in vitro（Cell inhibitory effect active testing）
（1）Laboratory sample
The preparation of sample solution：Test sample is the compounds I sterling that isolates and purifies in above-described embodiment 1, and precision is weighed
Appropriate amount of sample, is configured to the solution of desired concn with methanol, for surveying activity.
The successive transfer culture of cell line and cell adopts Non-small cell lung carcinoma A549 cells and human hepatoma HepG2 cell,
10%BCS is used（OEG cell growth hormone）1640 culture medium, 37 DEG C in be passed through 0.5% carbon dioxide incubator relay
Culture.
（2）Experimental technique
Cell inhibitory effect activity test method：Tetramethyl azo azoles salt（MTT）Method is taken the logarithm people's non-small cell lung of trophophase
Cancer A549 cell and human hepatoma HepG2 cell, by cell with after pancreatin digestion, regulation density is 2～3 × 104Individual/hole, adds
It is added in 96 orifice plates, per 195 microlitres of hole, is placed in 37 DEG C, 0.5%CO2Cultivate 24 hours in incubator, be subsequently adding variable concentrations
To in 96 orifice plates, in 96 orifice plate of same, each concentration of sample is respectively provided with three holes to sample solution, right as feminine gender using methanol,
37 DEG C, 0.5%CO2Cultivate 48 hours in incubator；96 orifice plates are taken out, 20 microlitres of MTT (tetramethyl azo azoles salt) are added per hole
（5 mg/ml of concentration）, continue culture 4 hours；Culture fluid is abandoned, 150 microlitres of DMSO (dimethyl sulfoxide) are added per hole, 37 DEG C are shaken
6 min are swung, and are determined the light absorbs in each hole at 492 nm, three hole mean OD values are taken by IR（%）=（OD negative control-OD samples）/
OD negative control × 100% formulas calculate the cell proliferation inhibition rate under each concentration（IR%）.
（3）Experimental result
In mtt assay test, the compounds I of variable concentrations is thin to Non-small cell lung carcinoma A549 cells and human liver cancer HepG2
The Proliferation Ability result of born of the same parents is shown in Table 2 respectively.
Suppression ratio of the compounds I of 2 variable concentrations of table to cancer cell multiplication（%）
Compounds I has obvious Cytostatic to tumor cell effect as seen from the above table, can be used as inhibition of cell proliferation or anti-
Tumor agent is studied for antineoplastic.
Described above not limitation of the present invention, the present invention are also not limited to the example above.The art it is common
In the essential scope of the present invention, change, remodeling, addition or the replacement made should also belong to the protection of the present invention to technical staff
Scope.
Claims (6)
1. a kind of cyclopentenes ketone compounds, it is characterised in that：The structural formula of the cyclopentenes ketone compounds is as shown in I：
（I）.
2. a kind of preparation method of cyclopentenes ketone compounds according to claim 1, it is characterised in that specifically include as
Lower step：
（1）Fermenting and producing
By the aspergillus ustus that preserving number is M2014086（Aspergillus ustus）Line brings back to life, and is inoculated into the training of PDA solid slopes
On foster base, after cultivating 5 days in 28 DEG C of incubators；The bacterium colony that slant culture is obtained all is inoculated into and is trained equipped with 300mL PDB
In foster base, in 28 DEG C, quiescent culture 45 days obtains fermentation liquid；
（2）The acquisition of extractum
Fermentation liquid is removed after thalline with filtered through gauze, fermentation liquid is repeated into extraction 3 times with isopyknic ethyl acetate, merge three
Extract concentrating under reduced pressure is removed ethyl acetate by extract obtained by secondary extraction, obtains crude extract；
（3）The separation and purification of compound
After by crude extract dichloromethane and methanol mixed solvent dissolving, plus 200-300 mesh silica gel mixed samples, using petroleum ether/second
Acetoacetic ester is with volume ratio 5:1 gradient carries out eluting for eluant, carries out decompression silica gel column chromatography to crude extract, collects eluting group
Point, by elution fraction through anti-phase middle compression leg chromatographic isolation, eluting ratio is adopted for 120 points of 10-100% methanol/water gradient elution
Clock, flow velocity are 20ml/min, collect the flow point that appearance time is 100 minutes, and finally the flow point is through partly preparing reversed phase high performance liquid
Phase chromatographic separation and purification obtains cyclopentenes ketone compounds, and its structure is shown in formula I：
（I）.
3. a kind of preparation method of cyclopentenes ketone compounds according to claim 2, it is characterised in that described PDB trainings
The formula of foster base is as follows：200 g of Rhizoma Solani tuber osi, glucose 20 g and sea water 1L.
4. a kind of preparation method of cyclopentenes ketone compounds according to claim 2, it is characterised in that described dichloro
In methane and methanol mixed solvent, dichloromethane is 1 with the volume ratio of methanol：1.
5. the preparation method of a kind of cyclopentenes ketone compounds according to claim 2, it is characterised in that：Half described system
The eluent of standby reversed-phase high-performance liquid chromatography is methanol and water by volume 1:1 mixes.
6. a kind of application of cyclopentenes ketone compounds according to claim 1, it is characterised in that：Described cyclopentenone
Purposes of the class compound in terms of tumor cell proliferation inhibitor or antitumor drug is prepared.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107141335A (en) * | 2017-04-12 | 2017-09-08 | 宁波大学 | A kind of cyclic peptide compounds and its preparation method and application |
| CN108179114A (en) * | 2017-11-27 | 2018-06-19 | 南京晓庄学院 | Produce bacterial strain and fermentation process, the anaerobe resistant compound methods of extraction and preparation and application method of anaerobe resistant compound |
| CN112194572A (en) * | 2020-03-02 | 2021-01-08 | 福建省中科生物股份有限公司 | Phenolic compound ZKYY-037 and preparation method and application thereof |
| CN116874362A (en) * | 2023-06-27 | 2023-10-13 | 东海实验室 | Cyclopentenone compounds, and preparation method and application thereof |
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| CN1230165A (en) * | 1996-09-27 | 1999-09-29 | 宝酒造株式会社 | Cyclopentenones, process for preparing same, and use thereof |
| CN1247528A (en) * | 1997-03-11 | 2000-03-15 | 宝酒造株式会社 | Cyclopentenone derivatives |
| CN1409715A (en) * | 1999-12-16 | 2003-04-09 | 查特豪斯治疗有限公司 | Cyclopenteneone derivatives |
| CN101613264A (en) * | 2008-06-27 | 2009-12-30 | 中国科学院广州生物医药与健康研究院 | Annulenone compounds and the application in the preparation antitumour drug thereof |
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| CN1230165A (en) * | 1996-09-27 | 1999-09-29 | 宝酒造株式会社 | Cyclopentenones, process for preparing same, and use thereof |
| CN1247528A (en) * | 1997-03-11 | 2000-03-15 | 宝酒造株式会社 | Cyclopentenone derivatives |
| CN1409715A (en) * | 1999-12-16 | 2003-04-09 | 查特豪斯治疗有限公司 | Cyclopenteneone derivatives |
| CN101613264A (en) * | 2008-06-27 | 2009-12-30 | 中国科学院广州生物医药与健康研究院 | Annulenone compounds and the application in the preparation antitumour drug thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107141335A (en) * | 2017-04-12 | 2017-09-08 | 宁波大学 | A kind of cyclic peptide compounds and its preparation method and application |
| CN107141335B (en) * | 2017-04-12 | 2020-10-20 | 宁波大学 | Cyclopeptide compound and preparation method and application thereof |
| CN108179114A (en) * | 2017-11-27 | 2018-06-19 | 南京晓庄学院 | Produce bacterial strain and fermentation process, the anaerobe resistant compound methods of extraction and preparation and application method of anaerobe resistant compound |
| CN112194572A (en) * | 2020-03-02 | 2021-01-08 | 福建省中科生物股份有限公司 | Phenolic compound ZKYY-037 and preparation method and application thereof |
| CN112194572B (en) * | 2020-03-02 | 2023-01-10 | 福建省中科生物股份有限公司 | Phenolic compound ZKYY-037 and preparation method and application thereof |
| CN116874362A (en) * | 2023-06-27 | 2023-10-13 | 东海实验室 | Cyclopentenone compounds, and preparation method and application thereof |
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