CN107841466B - A method of by marine Penicillum category fungi large scale preparation penicillic acid - Google Patents
A method of by marine Penicillum category fungi large scale preparation penicillic acid Download PDFInfo
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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 belongs to Marine Microorganisms to utilize field, and in particular to a method of penicillic acid is prepared by marine Penicillum category fungi large scale fermentation.Include the following steps: that (1) first carries out Spawn incubation to marine fungi mould Penicillium sp.HK1-6 in bacterium culture medium；(2) fermented and cultured is carried out to the marine fungi mould Penicillium sp.HK1-6 in step (1) in the fermentation medium again；(3) fermentation liquid in the fermentation material for obtaining step (2) and thallus separation, fermentation liquid are extracted with organic solvent, and fermentation liquid medicinal extract is concentrated under reduced pressure to give after combining extraction liquid；Thallus is extracted with organic solvent, is concentrated under reduced pressure to give thallus medicinal extract after merging leaching liquor；Merge fermentation liquid medicinal extract and thallus medicinal extract, carries out chromatographic isolation and obtain crude product；(4) crude product that step (3) obtains obtains penicillic acid sterling, for purity 98.0% or more, yield is up to 500~650mg/L through recrystallization or chromatographic isolation.
Description
Technical field
The invention belongs to Marine Microorganisms to utilize field, and in particular to one kind is sent out on a large scale by marine Penicillum category fungi
The method that ferment prepares penicillic acid.
Background technique
Penicillic acid is a kind of mycotoxin, there are linear substitution two kinds of tautomeric forms of ketone acid and lactone, and molecular weight is
170.16, it is soluble in hot water, ethyl alcohol, ether and chloroform.
Report about penicillic acid pharmacological activity and its toxicity is more, it was reported that penicillic acid has antibacterium, antimycotic, anti-
Virus, anti-tumor activity, inhibit enzyme acetylcholine, inhibit NF- kB activation (" HETEROCYCLES ", 2008, volume 76 the 2nd
Phase, the 1561-1569 pages) etc. pharmacological activity mainly cause heart, liver in addition, penicillic acid all has toxicity to humans and animals
Dirty and kidney and other organs damages, and there is potential carcinogenicity.
Penicillic acid is mostly generated by grain or feed mold in the prior art, i.e., mostly land fungi generates；There is report in recent years
Road co-cultured by marine aspergillus category fungi and bacterium can produce penicillic acid (" microorganism journal ", 2014, volume 54 the 11st
Phase, the 1289-1295 pages), also have been reported that australene improves mould acid yield (" Zhongshan University's journal in marine aspergillus category fungi
(natural science edition) ", 2011, the 2nd phase of volume 50, the 66-69 pages).However there is no utilize marine Penicillum category fungi at present
Prepare the report of penicillic acid, the more report without utilizing marine Penicillum category fungi large scale preparation penicillic acid.In order to further grind
Study carefully the toxicity and its pharmacological activity of penicillic acid, while carrying out structure of modification to it, a large amount of mould acid starting material is required.Cause
This, develops a kind of easy to operate, and the method for the large scale preparation penicillic acid that raw material is easy to get is particularly important.
Summary of the invention
The purpose of the present invention is to provide one kind by marine fungi mould Penicillium sp.HK1-6 large scale preparation
The method of penicillic acid or its pharmaceutically acceptable salt.The strain of the marine fungi mould Penicillium sp.HK1-6 is protected
Hide information: depositary institution's title: China Committee for Culture Collection of Microorganisms's common micro-organisms center；Depositary institution address:
Yard 1, BeiChen xi Road, Chaoyang District, Beijing City 3, Institute of Microorganism, Academia Sinica；Preservation date: on July 5th, 2016；It protects
Hiding number: CGMCCNo.12762；Classification naming: mould Penicillium sp..
The present invention provide it is a kind of by marine fungi mould Penicillium sp.HK1-6 prepare penicillic acid or its pharmaceutically
The method of acceptable salt, includes the following steps:
(1) Spawn incubation first is carried out to marine fungi mould Penicillium sp.HK1-6 in bacterium culture medium；
(2) the marine fungi mould Penicillium sp.HK1-6 in step (1) is carried out in the fermentation medium again
Fermented and cultured；
(3) fermentation liquid in the fermentation material for obtaining step (2) and thallus separation, fermentation liquid with organic solvent A extract 2~
4 times, fermentation liquid medicinal extract is concentrated under reduced pressure to give after combining extraction liquid；Thallus is extracted 2~4 times with organic solvent B, after merging leaching liquor
It is concentrated under reduced pressure to give thallus medicinal extract；Merge fermentation liquid medicinal extract and thallus medicinal extract, carries out chromatographic isolation and obtain crude product；
(4) crude product that step (3) obtains obtains penicillic acid sterling through recrystallization or chromatographic isolation；
Wherein contain glucose, yeast extract, peptone, agar, coarse sea salt, water, fermented and cultured in the bacterium culture medium
Contain glucose, yeast extract, peptone, coarse sea salt, water in base.
In the above-mentioned preparation method of the present invention, organic solvent A ethyl acetate, methylene chloride, chloroform or the ether
One or more of；One or more of the preferred methanol of the organic solvent B, ethyl alcohol, THF or acetone；The color
Spectrum separates one or more of preferred normal phase silica gel column chromatography separation, reversed-phase silica gel column chromatography or gel column chromatography separation group
It closes；The preferred water of the recrystallization solvent, methanol, ethyl alcohol, ether, methylene chloride, chloroform, pentane, hexane, ethyl acetate or stone
One or more of oily ether.
Bacterium culture medium preferably comprises glucose 0.2% -5.0%, yeast extract 0.02%-in the above-mentioned preparation method of the present invention
2%, peptone 0.02% -2%, agar 0.2% -3.0%, coarse sea salt 0.05% -5%, suitable water；Above-mentioned percentage is
Weight percent；Cultivation temperature is preferably 15-25 DEG C；Incubation time is preferably 3-7 days.Fermentation medium preferably comprises glucose
0.2% -5.0%, yeast extract 0.02% -2%, peptone 0.02% -2%, coarse sea salt 0.05% -5%, suitable water；It is above-mentioned
Percentage is weight percentage；Cultivation temperature is preferably 15-25 DEG C；Incubation time was preferably 4-5 weeks；The purification on normal-phase silica gel
The silica gel mesh number of the stationary phase used in pillar layer separation is 100~200 mesh, 200~300 mesh or 300~400 mesh, and preferably 200
~300 mesh；Mobile phase is preferably the mixed solvent or methanol/dichloromethane that ethyl acetate/petroleum ether volume ratio is 1/10~3/5
The mixed solvent that alkane volume ratio is 1/30~1/8.
The purity of penicillic acid sterling is obtained in preparation method of the present invention 98.0% or more.
The marine fungi mould Penicillium sp.HK1-6 of the invention is preparing penicillic acid or it pharmaceutically may be used
Application in the salt of receiving.
Term " pharmaceutically acceptable salt " refers to the addition of atoxic inorganic or organic acid and/or alkali in the present invention
Salt, reference can be made to " Salt selection for basic drugs ", Int.J.Pharm. (1986), 33,201-217.
The advantage of the invention is that the marine fungi mould Penicillium sp.HK1-6 used in the present invention, can pass through
The artificial large scale fermentation that carries out ferments not by resource constraint by using above-mentioned culture medium and condition of culture, can largely obtain
Mould acid product or its pharmaceutically acceptable salt are obtained, yield (is i.e. separated up to 500~650mg/L in every liter of fermentation liquid
Obtaining penicillic acid sterling is 500~650mg), it is much better than fungi in the prior art and prepares the yield of penicillic acid (only more than ten to several
Ten milligrams per liter), have the condition of industrialization large-scale production.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and in below (eg embodiment) specifically
Each technical characteristic of description can be combined with each other, to form a new or preferred technical solution.As space is limited, not another herein
One tired states.
Specific embodiment
For the ease of a further understanding of the present invention, examples provided below has done more detailed description to it.But
It is that these embodiments are only not supposed to be a limitation to the present invention or implementation principle for better understanding invention, reality of the invention
The mode of applying is not limited to the following contents.
Embodiment 1
(1) culture of marine fungi mould Penicillium sp.HK1-6 strain
Culture medium used in the Spawn incubation of fungi mould Penicillium sp. (HK1-6) is to add in every 1000mL water
Enter: potato 200g, which boils, takes juice, glucose 20g, coarse sea salt 30g, agar 15g；It is poured into glass culture dish when use, training is made
Support base plate.Fungal bacterial strain is inoculated in culture medium flat plate, shaking table culture 3 days at 20 DEG C.
(2) fermentation of marine fungi mould Penicillium sp.HK1-6
Fermentation medium used in the fermented and cultured of fungi mould Penicillium sp.HK1-6 is, in every 1000mL water
Be added: potato 200g, which boils, takes juice, glucose 20g, coarse sea salt 30g；It is sub-packed in conical flask when use.Fungal bacterial strain is inoculated in
In the culture medium of conical flask, in 15~20 DEG C stationary culture 28 days.
(3) separation and Extraction of penicillic acid
The resulting fermentation material 30L of step (2) is taken, after fermentation liquid and thallus separation, fermentation liquid is extracted with ethyl acetate 2~
4 times, extract liquor is concentrated under reduced pressure to give fermentation liquid medicinal extract；Thallus is extracted 2~4 times with methanol, is concentrated under reduced pressure to give thallus medicinal extract；It closes
And fermentation liquid medicinal extract and thallus medicinal extract, normal phase silica gel column chromatography separation is first carried out, stationary phase: 200~300 mesh silica gel, mobile phase:
The ethyl acetate-light petrol mixed solvent of 10% -60% (percent by volume, similarly hereinafter), isolated mould acid crude (18g).
(4) purifying of penicillic acid
The mould acid crude (18g) that step (3) obtains is dissolved in suitable ethyl alcohol at 65 DEG C, Temperature fall is overnight,
Penicillic acid sterling (15.8g, purity 98.7%) is obtained by filtration.
Gained penicillic acid sterlingStructural identification data:
Colourless acicular crystal；1H NMR(CDCl3,600MHz)δ:5.47(1H,s,H-2),5.19(1H,brs,H-6a),
5.12(1H,brs,H-6b),3.92(3H,s,H-8),1.77(3H,s,H-7)；ESIMS m/z 171[M+H]+。
Embodiment 2
(1) culture of marine fungi mould Penicillium sp. (HK1-6) strain
Contain glucose 0.2% in culture medium used in the Spawn incubation of fungi mould Penicillium sp. (HK1-6)
(weight percent, similarly hereinafter), yeast extract 2%, peptone 0.02%, agar 0.2%, coarse sea salt 5%, remaining is water, when use
Test tube slant is made, fungal bacterial strain is cultivated 7 days at 25 DEG C.
(2) fermentation of marine fungi mould Penicillium sp. (HK1-6)
Fermentation medium used in the fermented and cultured of fungi mould Penicillium sp. (HK1-6) is to contain glucose
0.2% (weight percent, similarly hereinafter), yeast extract 0.02%, peptone 2%, coarse sea salt 0.05%, suitable water, fungal bacterial strain
It is cultivated 35 days in 15 DEG C.
(3) separation and Extraction of penicillic acid
The resulting fermentation material 50L of step (2) is taken, after fermentation liquid and thallus separation, fermentation liquid is extracted 4 times with ether, extraction
Liquid is taken to be concentrated under reduced pressure to give fermentation liquid medicinal extract；Thallus is concentrated under reduced pressure to give thallus medicinal extract with alcohol steep 2 times；Merge fermentation liquid
Medicinal extract and thallus medicinal extract first carry out normal phase silica gel column chromatography separation, stationary phase: 100~200 mesh silica gel, mobile phase: 10%-
The ethyl acetate-light petrol mixed solvent of 60% (percent by volume, similarly hereinafter), isolated mould acid crude (38g).
(4) purifying of penicillic acid
The mould acid crude (38g) that step (3) obtains is dissolved in suitable ethyl acetate in heating, addition is suitable just
Hexane is slowly dropped to room temperature to there is solid precipitation, stands 16~20 hours, penicillic acid sterling is obtained by filtration, and (33.0g, purity are
99.0%).
Embodiment 3
(1) culture of marine fungi mould Penicillium sp.HK1-6 strain
Contain (the weight of glucose 5% in culture medium used in the Spawn incubation of fungi mould Penicillium sp.HK1-6
Measure percentage, similarly hereinafter), yeast extract 0.02%, peptone 2%, agar 3%, coarse sea salt 1%, remaining is water, and examination is made in when use
Pipe inclined-plane, fungal bacterial strain are cultivated 4 days at 20 DEG C.
(2) fermentation of marine fungi mould Penicillium sp.HK1-6
Fermentation medium used in the fermented and cultured of fungi mould Penicillium sp.HK1-6 is to contain glucose 5%
(weight percent, similarly hereinafter), yeast extract 0.02%, peptone 2%, coarse sea salt 5%, remaining is water, and fungal bacterial strain is trained in 20 DEG C
It supports 30 days.
(3) separation and Extraction of penicillic acid
The resulting fermentation material 100L of step (2) is taken, after fermentation liquid and thallus separation, fermentation liquid is extracted with dichloromethane 2
Secondary, extract liquor is concentrated under reduced pressure to give fermentation liquid medicinal extract；Thallus is extracted 2 times with acetone, is concentrated under reduced pressure to give thallus medicinal extract；Merge hair
Zymotic fluid medicinal extract and thallus medicinal extract first carry out reversed-phase silica gel column chromatography separation, mobile phase: 80% -85% (percent by volume, similarly hereinafter)
Methanol+Water, isolated mould acid crude (51g).
(4) purifying of penicillic acid
The mould acid crude (51g) that step (3) obtains is separated through normal phase silica gel column chromatography, stationary phase: 200~300 mesh
Silica gel, mobile phase: ethanol/methylene volume ratio is 1/30~1/8 mixed solvent, and isolated penicillic acid sterling (47g, it is pure
98.3%) degree is.
Other Spawn incubations for not particularly pointed out in embodiment 1-3, fermentation condition and normal phase silica gel column chromatography separation,
Other experimental operating conditions such as reversed-phase silica gel column chromatography, recrystallization are the experimental operating conditions of this field routine, this field
Technical staff can reasonably be selected according to actual needs.
Claims (6)
1. one plant of marine fungi mouldPenicilliumSp.HK1-6, deposit number: CGMCC No.12762.
2. marine fungi mould described in claim 1PenicilliumSp.HK1-6 is preparing the application in penicillic acid.
3. a kind of marine fungi mould described in claim 1PenicilliumThe method that sp.HK1-6 prepares penicillic acid,
It is characterized in that including the following steps:
(1) first in bacterium culture medium to marine fungi mould described in claim 1PenicilliumSp.HK1-6 is carried out
Spawn incubation；Contain glucose 0.2% -5.0%, yeast extract 0.02% -2%, peptone 0.02%-in the bacterium culture medium
2%, agar 0.2% -3.0%, coarse sea salt 0.05% -5%, suitable water；Above-mentioned percentage is weight percentage；Culture temperature
Degree is 15-25 DEG C；Incubation time is 3-7 days；
(2) again in the fermentation medium to the marine fungi mould in step (1)PenicilliumSp.HK1-6 ferments
Culture；In the fermentation medium containing glucose 0.2% -5.0%, yeast extract 0.02% -2%, peptone 0.02% -2%,
Coarse sea salt 0.05% -5%, suitable water；Above-mentioned percentage is weight percentage；Cultivation temperature is 15-25 DEG C；Incubation time
For 4-5 weeks；
(3) fermentation liquid in the fermentation material for obtaining step (2) and thallus separation, fermentation liquid are extracted 2~4 times with organic solvent A,
Fermentation liquid medicinal extract is concentrated under reduced pressure to give after combining extraction liquid；Thallus is extracted 2~4 times with organic solvent B, is depressurized after merging leaching liquor
It is concentrated to get thallus medicinal extract；Merge fermentation liquid medicinal extract and thallus medicinal extract, carries out chromatographic isolation and obtain crude product；The organic solvent A
Selected from one or more of ethyl acetate, methylene chloride, chloroform or ether；The organic solvent B be selected from methanol, ethyl alcohol,
One or more of THF or acetone；
(4) crude product that step (3) obtains obtains penicillic acid sterling through recrystallization or chromatographic isolation.
4. according to the method described in claim 3, it is characterized in that the recrystallization uses water, methanol, ethyl alcohol, ether, two
One or more of chloromethanes, acetone, chloroform, pentane, hexane, ethyl acetate or petroleum ether are used as recrystallization solvent.
5. according to the method described in claim 3, it is characterized in that the chromatographic isolation is that normal phase silica gel column chromatography separates, is anti-
The combination of one or more of phase silica gel column chromatography or gel column chromatography separation.
6. according to the method described in claim 5, it is characterized in that the stationary phase used in normal phase silica gel column chromatography separation
Silica gel mesh number be 100~200 mesh, 200~300 mesh or 300~400 mesh；Mobile phase is that ethyl acetate/petroleum ether volume ratio is
The mixed solvent that 1/10~3/5 mixed solvent or ethanol/methylene volume ratio is 1/30~1/8.
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| CN108383813B (en) * | 2017-02-19 | 2022-03-01 | 扬州大学 | Penicic acid crystal form I and preparation method and application thereof |
| CN110527629B (en) * | 2018-05-27 | 2022-05-17 | 扬州蓝色生物医药科技有限公司 | Marine fungus-derived brefeldin A, preparation method and application thereof in resisting agricultural pathogenic bacteria |
| CN108715872A (en) * | 2018-06-06 | 2018-10-30 | 扬州工业职业技术学院 | A kind of microbial fermentation converts rheum emodin to the preparation process of Rhein |
| CN108715873A (en) * | 2018-06-06 | 2018-10-30 | 扬州工业职业技术学院 | A method of preparing Rhein using mutagenesis microbial fermentation technology |
| CN108660082B (en) * | 2018-06-15 | 2022-04-22 | 河北大学 | Marine aspergillus derived oxaanthraquinone compound, preparation method thereof and application thereof in preparation of antibacterial agent |
| CN109456899B (en) * | 2018-10-30 | 2021-10-22 | 云南大学 | Penicillium and method for producing penicillic acid by fermenting penicillium |
| CN109370919B (en) * | 2018-12-10 | 2020-06-05 | 青岛大学 | Bacterial strain for producing penicillic acid and application thereof |
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