CN103865808A - Novel anti-tumor application of penicillium enol A1 from penicillium citrinum - Google Patents
Novel anti-tumor application of penicillium enol A1 from penicillium citrinum Download PDFInfo
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- CN103865808A CN103865808A CN201410085085.8A CN201410085085A CN103865808A CN 103865808 A CN103865808 A CN 103865808A CN 201410085085 A CN201410085085 A CN 201410085085A CN 103865808 A CN103865808 A CN 103865808A
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Abstract
The invention relates to novel anti-tumor application of an alkaloid compound penicillium enol A1 from penicillium citrinum. The penicillium citrinum IBPT-5 is collected in the China Center for Type Culture Collection (CCTCC), which is located in Wuhan University and has the collection number of CCTCC NO:M2013713, on December 25, 2013. Experiments prove that the compound has better anti-tumor activity on various tumor cells, and can be used for preparing cell proliferation inhibition medicines or anti-tumor medicines for anti-tumor study, wherein tumor cells comprise human colon cancer cells SW620, human hepatoma cells Huh7, human gastric carcinoma cells BGC-823, human colon cancer cells SW480, human esophageal squamous carcinoma cells KYSE450, human esophageal cancer cells EC9706, human highly metastatic lung carcinoma cells 95-D, human hepatoma cells PLC and human gastric carcinoma cells HGC-27.
Description
Technical field
The present invention relates to the antineoplastic new usage of a kind of alkaloid compound mould enol A1 that comes from Penicillium citrinum.
Background technology
Alkaloid is the organic compounds containing nitrogen that a class is produced by biological secondary metabolism, and the alkaloid kind of occurring in nature is more, mostly derives from plant, therefore has again the title of vegeto-alkali.Alkaloid has important physiological action to humans and animals, comprises the antibechic of relievining asthma, hypoglycemic, reducing blood-fat, antibacterial, antitumor, analgesia etc., wherein with antibacterial, anti-tumor activity is the most outstanding.Natural structure alkaloid is the important sources of finding lead compound in original new drug research, is applied at present nearly hundred kinds of clinical alkaloidal drugs.Research discovery, some thalassiomycetess can produce novel structure, active good alkaloid in secondary metabolism process, have well medicinal and industrialization prospect.
The inventor studies and learns, Penicillium citrinum (
penicillium citrinum) IBPT-5 (has been deposited in Chinese Typical Representative culture collection center on December 25th, 2013, address: Wuhan Wuhan University, deposit number is: CCTCC NO:M 2013713) the crude extract of tunning have good cell inhibitory effect activity, then its activeconstituents is studied.Shown in research discovery, alkaloid compound has anti-tumor activity, have not yet to see the report of this compound to human colon cancer cell SW620, human liver cancer cell Huh7, human gastric cancer cells BGC-823, human colon cancer cell SW480, Human esophageal squamous cell cancer cell KYSE450, human esophagus cancer cell EC9706, the high proliferation inhibition activity that shifts lung carcinoma cell 95-D, human liver cancer cell PLC, gastric carcinoma cells HGC-27 of people, therefore on market, also there is not yet medicine related to this.
Summary of the invention
The object of the present invention is to provide the new purposes of anti-tumor aspect of a kind of alkaloid compound mould enol A1 that comes from Penicillium citrinum.
The present invention first relate to a strain Penicillium citrinum (
penicillium citrinum) IBPT-5, this bacterial strain has been deposited in Chinese Typical Representative culture collection center, address on December 25th, 2013: Wuhan Wuhan University, deposit number is: CCTCC NO:M 2013713.
The purposes of described bacterial strain is, by Penicillium citrinum (
penicillium citrinum) IBPT-5 carries out fermentation culture, fermentation broth extract is isolated to the compound with tumor cell proliferation inhibition activity.
This structural formula of compound is:
The preparation method of this compound, concrete steps are as follows:
(1) fermentative production
The ordinary method of culturing micro-organisms, get Penicillium citrinum (
penicillium citrinum) IBPT-5 is inoculated on PDA solid slant culture base and cultivates 4 days in 28 DEG C of incubators, is then inoculated in nutrient solution, 28 DEG C of static cultivations, after 30 days, obtain mycelium and fermented liquid; Described nutrient solution composition: every premium on currency is containing N.F,USP MANNITOL 20.0g, yeast extract paste 3.0 g, maltose 20.0 g, monosodium glutamate 10.0 g, glucose 10.0 g, KH
2pO
40.5 g, MgSO
40.3 g, NaCl 30.0 g;
(2) acquisition of medicinal extract
With gauze by mycelium and separation of fermentative broth, the ethyl acetate extracting twice by fermented liquid with 2 times of volumes, extraction liquid underpressure distillation, to dry, obtains the ethyl acetate extract of fermented liquid;
(3) separation and purification of compound
Ethyl acetate extract is by after 100-200 order silica gel mixed sample, with sherwood oil, methylene dichloride, methyl alcohol is elutriant decompression silica gel chromatographic column gradient elution, get methylene dichloride: the eluate of methyl alcohol v/v=100:1, further with methylene dichloride, methyl alcohol is elutriant, by pressurized silica gel column chromatography gradient elution, obtain methylene dichloride: the eluate of methyl alcohol v/v=50:1, continue taking methyl alcohol: water v/v=3:2 removes impurity as solvent carries out reversed-phase silica gel column chromatography, finally by half preparative liquid chromatography 1010 type ODS-A, 10 × 250 mm, 5 μ m: separating flow velocity is 5 mL/min, moving phase is that 80% methyl alcohol is containing 0.1% TFA, obtain
t rthe described compound of 5.9 min.
The present invention has also protected described compound in the purposes of preparing in Cytostatic to tumor cell medicine, and this compound is in the purposes of preparing in antitumor drug.Tumour cell comprises: human colon cancer cell SW620, human liver cancer cell Huh7, human gastric cancer cells BGC-823, human colon cancer cell SW480, Human esophageal squamous cell cancer cell KYSE450, human esophagus cancer cell EC9706, high lung carcinoma cell 95-D, human liver cancer cell PLC, the gastric carcinoma cells HGC-27 of shifting of people.
Remarkable advantage of the present invention: shown in research, this alkaloid compound is comparatively rare, described alkaloid compound has significant anti-tumor activity, have not yet to see this compound to human colon cancer cell SW620, human liver cancer cell Huh7, human gastric cancer cells BGC-823, human colon cancer cell SW480, Human esophageal squamous cell cancer cell KYSE450, human esophagus cancer cell EC9706, the high report that shifts lung carcinoma cell 95-D, human liver cancer cell PLC, gastric carcinoma cells HGC-27 cell inhibitory effect activity of people, therefore on market, also there is not yet medicine related to this.
Embodiment
The chemical structure of the compound of indication in following embodiment:
Fermentative production and the separation and purification of embodiment 1 this compound
1 fermentative production
Produce the fermentation culture of bacterium: by the ordinary method of culturing micro-organisms, get Penicillium citrinum (
penicillium citrinum) IBPT-5 (has been deposited in Chinese Typical Representative culture collection center on December 25th, 2013, address: Wuhan Wuhan University, deposit number is: CCTCC NO:M 2013713) appropriate, be inoculated on PDA solid slant culture base and cultivate 4 days in 28 DEG C of incubators.
Get the slant culture Penicillium citrinum of 4 days (
penicillium citrinum) IBPT-5 is appropriate, be inoculated into 400mL nutrient solution [nutrient solution composition (grams per liter): N.F,USP MANNITOL 20.0, yeast extract paste 3.0, maltose 20.0, monosodium glutamate 10.0, glucose 10.0, KH is housed
2pO
40.5, MgSO
40.3, NaCl, 30.0 constant volumes] 1000mL Erlenmeyer flask in, 28 DEG C of static cultivations are after 30 days, obtain mycelium and fermented liquid.
The acquisition of 2 medicinal extract
With gauze by mycelium and separation of fermentative broth.By fermented liquid ethyl acetate 1:2(v/v) extracting twice, extraction liquid underpressure distillation, to dry, obtains the ethyl acetate extract 32g of fermented liquid.
The separation and purification of 3 compounds
This medicinal extract is by after 100-200 order silica gel mixed sample, taking sherwood oil: methylene dichloride: methyl alcohol, as decompression silica gel chromatographic column gradient elution for elutriant, obtains 11 components.Component 7(4.2g) (methylene dichloride: the eluate of methyl alcohol v/v=100:1) taking methylene dichloride: methyl alcohol is as elutriant, further by pressurized silica gel column chromatography gradient elution, the subfraction 7-3(methylene dichloride obtaining: the eluate of methyl alcohol v/v=50:1) as carrying out reversed-phase silica gel column chromatography, solvent removes impurity taking methanol-water (v/v3:2), finally by half preparative liquid chromatography (1010 type ODS-A, 10 × 250 mm, 5 μ are m): separating flow velocity is 5 mL/min, moving phase is that 80% methyl alcohol is containing 0.1% TFA, (81.6 mg of compound shown in obtaining
t r5.9 min).
The faint yellow oily matter of compound, high resolution mass spectrum HRESI-MS exists
m/z296.1868 places provide molecular ion peak [M – H]
–, (Calcd for C
16h
26nO
4, 296.1862), prompting molecular weight is 297, infers that in conjunction with spectral information molecular formula is C
16h
27nO
4.
1h and
13the NMR data such as C-NMR are in table 1.
Table 1 compound
1h and
13c-NMR data (500 MHz, in CDCl
3)
a)
The test of embodiment 2 anti tumor activity in vitro
1 laboratory sample and experimental technique
The preparation test sample of sample solution is the pure compounds of separation and purification in above-mentioned enforcement 1.Precision takes appropriate sample, is mixed with the solution of desired concn with methyl alcohol, active for surveying.
The succeeding transfer culture of clone and cell adopts tumor cell line, and the DMEM substratum containing 10% FBS for tumour cell, at 37 DEG C of succeeding transfer culture in the incubator that passes into 5% carbonic acid gas.
Cell inhibitory effect activity test method
The tumour cell that tetrazolium (MTT) method is taken the logarithm vegetative period, is adjusted to every milliliter 2 × 10 by cell density
5individual cell, is inoculated in 96 porocyte culture plates by every hole 200 microlitres, passes into 5% CO in 37 DEG C
2incubator in cultivate 4 hours.Every hole adds 2 microlitre sample liquid or blank solutions, cultivates after 24 hours, and every hole adds MTT liquid (every milliliter of 5 milligrams of normal saline solutions of MTT) 10 microlitres, continue cultivate 4 hours, 37 DEG C, 2000 revs/min centrifugal 8 minutes, suck supernatant.Every hole adds each 100 microlitres of DMSO, vibrates 15 minutes on micro oscillator, after dissolving completely, utilizes MD company to produce SPECTRAMAX Plus type microplate reader and measures light absorption value (OD) value of every hole at 570nm place to crystallization.In same 96 orifice plates, each concentration of sample all arranges three holes, separately establishes three hole blanks and acellular zeroing hole (if medicine has color will do the acellular zeroing of relative medicine concentration).Each hole OD value is first done corresponding acellular zeroing, then gets the three average OD values in hole by IR (%)=(OD
blank-OD
sample)/OD
blank× 100% formula is calculated cell proliferation inhibition rate under each concentration (IR%).
2. experimental result
Cell inhibitory effect active testing result
In mtt assay test, according to the Cytostatic to tumor cell rate of this compound of different concns, application SPSS16.0 software carries out data processing calculation of half inhibitory concentration IC
50value.The results are shown in Table 2.
The inhibition activity of table 2 compound to human tumor cells propagation
3. conclusion
Compound has obvious inhibited proliferation to kinds of tumor cells, can be used as and prepares inhibition of cell proliferation or antineoplastic agent for antineoplastic research.Tumour cell comprises human colon cancer cell SW620, human liver cancer cell Huh7, human gastric cancer cells BGC-823, human colon cancer cell SW480, Human esophageal squamous cell cancer cell KYSE450, human esophagus cancer cell EC9706, high lung carcinoma cell 95-D, human liver cancer cell PLC, the gastric carcinoma cells HGC-27 of shifting of people.
Claims (6)
- One strain Penicillium citrinum ( penicillium citrinum) IBPT-5, this bacterial strain has been deposited in Chinese Typical Representative culture collection center, address on December 25th, 2013: Wuhan Wuhan University, deposit number is: CCTCC NO:M 2013713.
- 2. compound, come from Penicillium citrinum described in claim 1 ( penicillium citrinum) IBPT-5.
- 3. the preparation method of compound claimed in claim 2, is characterized in that: described preparation method's concrete steps are as follows:(1) fermentative productionThe ordinary method of culturing micro-organisms, get Penicillium citrinum ( penicillium citrinum) IBPT-5 is inoculated on PDA solid slant culture base and cultivates 4 days in 28 DEG C of incubators, is then inoculated in nutrient solution, 28 DEG C of static cultivations, after 30 days, obtain mycelium and fermented liquid; Described nutrient solution composition: every premium on currency is containing N.F,USP MANNITOL 20.0g, yeast extract paste 3.0 g, maltose 20.0 g, monosodium glutamate 10.0 g, glucose 10.0 g, KH 2pO 40.5 g, MgSO 40.3 g, NaCl 30.0 g;(2) acquisition of medicinal extractWith gauze by mycelium and separation of fermentative broth, the ethyl acetate extracting twice by fermented liquid with 2 times of volumes, extraction liquid underpressure distillation, to dry, obtains the ethyl acetate extract of fermented liquid;(3) separation and purification of compoundEthyl acetate extract is by after 100-200 order silica gel mixed sample, with sherwood oil, methylene dichloride, methyl alcohol is elutriant decompression silica gel chromatographic column gradient elution, get methylene dichloride: the eluate of methyl alcohol v/v=100:1, further with methylene dichloride, methyl alcohol is elutriant, by pressurized silica gel column chromatography gradient elution, obtain methylene dichloride: the eluate of methyl alcohol v/v=50:1, continue taking methyl alcohol: water v/v=3:2 removes impurity as solvent carries out reversed-phase silica gel column chromatography, finally by half preparative liquid chromatography 1010 type ODS-A, 10 × 250 mm, 5 μ m: separating flow velocity is 5 mL/min, moving phase is that 80% methyl alcohol is containing 0.1% TFA, obtain t rthe described compound of 5.9 min.
- 4. compound claimed in claim 2 is in the purposes of preparing in Cytostatic to tumor cell medicine.
- 5. compound claimed in claim 2 is in the purposes of preparing in antitumor drug.
- 6. purposes according to claim 4, is characterized in that: described tumour cell comprises human colon cancer cell SW620, human liver cancer cell Huh7, human gastric cancer cells BGC-823, human colon cancer cell SW480, Human esophageal squamous cell cancer cell KYSE450, human esophagus cancer cell EC9706, high lung carcinoma cell 95-D, human liver cancer cell PLC, the gastric carcinoma cells HGC-27 of shifting of people.
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|---|---|---|---|
| CN201410085085.8A CN103865808B (en) | 2014-03-10 | 2014-03-10 | A kind of anticancer usage of the penicillium sp enol A1 coming from Aspergillus citrimum |
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| CN201410085085.8A CN103865808B (en) | 2014-03-10 | 2014-03-10 | A kind of anticancer usage of the penicillium sp enol A1 coming from Aspergillus citrimum |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592082A (en) * | 2014-12-18 | 2015-05-06 | 福州大学 | Method for preparing penicillium enol D2 derived from Penicillium citrinum and application of penicillium enol D2 |
| CN106389417A (en) * | 2016-09-13 | 2017-02-15 | 福州大学 | Application of penem alcohol E1 derived from trichoderma citrinoviride in aspect of gastric cancer |
| CN106389418A (en) * | 2016-09-13 | 2017-02-15 | 福州大学 | Application of trichoderma citrinoviride-derived penicillium enol E1 to liver cancer aspect |
| CN106432035A (en) * | 2016-09-13 | 2017-02-22 | 福州大学 | Application of penem enol E1 derived from trichoderma citrinoviride on the aspect of malignant melanoma |
| CN106420716A (en) * | 2016-09-13 | 2017-02-22 | 福州大学 | Application of penemenol E1 derived from trichoderma citrinoviride in aspect of resisting intestinal cancer |
| CN106420717A (en) * | 2016-09-13 | 2017-02-22 | 福州大学 | Application of penemenol E1 derived from trichoderma citrinoviride in an aspect of resisting nasopharynx cancer |
| CN106432034A (en) * | 2016-09-13 | 2017-02-22 | 福州大学 | Application of penicilliumenol E1 from trichoderma citrinoviride in preparation of anti-breast cancer drugs |
| CN106432036A (en) * | 2016-09-13 | 2017-02-22 | 福州大学 | Penem enol E1 derived from trichoderma citrinoviride and application in preparation of anti-oral epidermoid carcinoma drug |
| CN106491597A (en) * | 2016-09-13 | 2017-03-15 | 福州大学 | Come from applications of the mould enol E1 of tangerine green trichoderma in terms of the cancer of the esophagus |
| CN106491596A (en) * | 2016-09-13 | 2017-03-15 | 福州大学 | Come from applications of the mould enol E1 of tangerine green trichoderma in terms of lung cancer |
| CN113801032A (en) * | 2021-09-30 | 2021-12-17 | 贵州大学 | Long-chain fatty acid glycerol alcohol compound Rubracin B, preparation method and application thereof |
| CN116173013A (en) * | 2023-01-17 | 2023-05-30 | 福州大学 | New use of penicillium enol A2 derived from penicillium citrinum for resisting vincristine drug resistance |
-
2014
- 2014-03-10 CN CN201410085085.8A patent/CN103865808B/en not_active Expired - Fee Related
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Cited By (21)
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| CN104592082A (en) * | 2014-12-18 | 2015-05-06 | 福州大学 | Method for preparing penicillium enol D2 derived from Penicillium citrinum and application of penicillium enol D2 |
| CN106389417A (en) * | 2016-09-13 | 2017-02-15 | 福州大学 | Application of penem alcohol E1 derived from trichoderma citrinoviride in aspect of gastric cancer |
| CN106389418A (en) * | 2016-09-13 | 2017-02-15 | 福州大学 | Application of trichoderma citrinoviride-derived penicillium enol E1 to liver cancer aspect |
| CN106432035A (en) * | 2016-09-13 | 2017-02-22 | 福州大学 | Application of penem enol E1 derived from trichoderma citrinoviride on the aspect of malignant melanoma |
| CN106420716A (en) * | 2016-09-13 | 2017-02-22 | 福州大学 | Application of penemenol E1 derived from trichoderma citrinoviride in aspect of resisting intestinal cancer |
| CN106420717A (en) * | 2016-09-13 | 2017-02-22 | 福州大学 | Application of penemenol E1 derived from trichoderma citrinoviride in an aspect of resisting nasopharynx cancer |
| CN106432034A (en) * | 2016-09-13 | 2017-02-22 | 福州大学 | Application of penicilliumenol E1 from trichoderma citrinoviride in preparation of anti-breast cancer drugs |
| CN106432036A (en) * | 2016-09-13 | 2017-02-22 | 福州大学 | Penem enol E1 derived from trichoderma citrinoviride and application in preparation of anti-oral epidermoid carcinoma drug |
| CN106491597A (en) * | 2016-09-13 | 2017-03-15 | 福州大学 | Come from applications of the mould enol E1 of tangerine green trichoderma in terms of the cancer of the esophagus |
| CN106491596A (en) * | 2016-09-13 | 2017-03-15 | 福州大学 | Come from applications of the mould enol E1 of tangerine green trichoderma in terms of lung cancer |
| CN106491596B (en) * | 2016-09-13 | 2019-01-22 | 福州大学 | Derived from application of the mould enol E1 in terms of lung cancer of tangerine green trichoderma |
| CN106420717B (en) * | 2016-09-13 | 2019-03-12 | 福州大学 | Derived from application of the mould enol E1 in terms of nasopharyngeal carcinoma of tangerine green trichoderma |
| CN106491597B (en) * | 2016-09-13 | 2019-03-12 | 福州大学 | Derived from application of the mould enol E1 in terms of the cancer of the esophagus of tangerine green trichoderma |
| CN106432036B (en) * | 2016-09-13 | 2019-05-10 | 福州大学 | Derived from tangerine green trichoderma mould enol E1 and prepare anti-oral cavity epidermal carcinoma medicinal application |
| CN106432034B (en) * | 2016-09-13 | 2019-05-10 | 福州大学 | Mould enol E1 derived from tangerine green trichoderma is in the application for preparing anti-breast cancer medicines |
| CN106389417B (en) * | 2016-09-13 | 2019-06-07 | 福州大学 | Derived from application of the mould enol E1 in terms of gastric cancer of tangerine green trichoderma |
| CN106389418B (en) * | 2016-09-13 | 2019-06-07 | 福州大学 | Derived from tangerine green trichoderma mould enol E1 liver cancer application |
| CN106420716B (en) * | 2016-09-13 | 2019-06-07 | 福州大学 | Derived from application of the mould enol E1 in terms of intestinal cancer of tangerine green trichoderma |
| CN113801032A (en) * | 2021-09-30 | 2021-12-17 | 贵州大学 | Long-chain fatty acid glycerol alcohol compound Rubracin B, preparation method and application thereof |
| CN113801032B (en) * | 2021-09-30 | 2023-03-07 | 贵州大学 | Long-chain fatty acid glycerol alcohol compound Rubracin B, preparation method and application thereof |
| CN116173013A (en) * | 2023-01-17 | 2023-05-30 | 福州大学 | New use of penicillium enol A2 derived from penicillium citrinum for resisting vincristine drug resistance |
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