CN106631803B - A kind of chloroanthraquinone compound in mangrove fungi source and its application as antibacterial agent - Google Patents
A kind of chloroanthraquinone compound in mangrove fungi source and its application as antibacterial agent Download PDFInfo
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- CN106631803B CN106631803B CN201611010857.7A CN201611010857A CN106631803B CN 106631803 B CN106631803 B CN 106631803B CN 201611010857 A CN201611010857 A CN 201611010857A CN 106631803 B CN106631803 B CN 106631803B
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- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
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Abstract
The invention belongs to marine fungi secondary species fields, and in particular to a kind of chloroanthraquinone compound in mangrove fungi source and its application as antibacterial agent.Chloroanthraquinone compound of the present invention has the following structure:
Description
Technical field
The invention belongs to marine fungi secondary species fields, and in particular to a kind of chloroanthraquinone in mangrove fungi source
Close object and its application as antibacterial agent.
Background technique
Mangrove is grown on tropical and subtropical zone intertidal zone, and living environment has the characteristics that high pressure, with high salt, hypoxemia, so that
Its endogenetic fungus has unique metabolic pathway, and then the ability with the compound for generating structure novel, diverse biological activities,
Its metabolite has a variety of medical values such as antibacterial, antitumor, immunological regulation, enzyme inhibition, is that potential microbial medicine is opened
Resource is sent out, therefore, mangrove endophytic fungus will become one of the valuable source of new drug development.
Using the method for artificial cultivation and fermentation, the cometabolism of important antibacterial activity is obtained from mangrove endophytic fungus
Product has the characteristics that environmental-friendly, sustainable development, can effectively solve that medicine source in drug discovery process etc. is key to ask
Topic, therefore there is unique advantage.
Summary of the invention
The present invention is after Chinese patent application 201610829377.7 and 201610829579.1, to mangrove fungi
The another invention achievement that Penicillium citrinum HL-5126 is further studied.Chinese patent application
201610829377.7 being fully incorporated in the present invention with the content in 201610829579.1.
The present invention provides the chloroanthraquinone compound or its pharmaceutically acceptable salt in a kind of mangrove fungi source, special
Sign is that the chloroanthraquinone compound has the following structure:
The present invention provides a kind of preparation method for preparing chloroanthraquinone compound or its pharmaceutically acceptable salt, feature
It is to include the following steps:
(1) seed culture medium is prepared, fungi Penicillium citrinum HL-5126 bacterial strain is accessed into seed culture
Base, obtains seed culture fluid in culture 3~4 days by 26~28 DEG C；
(2) in the seed culture fluid access fermentation medium obtained step (1), 26~28 DEG C stationary culture 21~24 days
Obtain fermentation material；
(3) fermentation liquid in the fermentation material for obtaining step (2) and thallus separation, fermentation liquid and thallus are used in equal volume respectively
Ethyl acetate extract 3~5 times, medicinal extract is concentrated under reduced pressure to give after combining extraction liquid；
(4) medicinal extract that step (3) obtains presses 100:0 to 0 by decompression silica gel column chromatography, using petroleum ether-ethyl acetate:
100 gradient elutions, wherein 20% ethyl acetate-light petrol elution fraction is through Sephadex LH-20 gel filtration chromatography, eluant, eluent
For CHCl3: MeOH=1: 1, then prepared through high-efficient liquid phase chromatogram HPLC, chromatographic column is the μ of Agilent C18,9.4 × 250mm, 7
M, flow velocity 2mL/min, mobile phase MeOH: H2O=70: 30 finally obtain the chloroanthraquinone compound.
Wherein the ratio of the eluant, eluent or mobile phase is volume ratio；Contain glucose in the seed culture medium
1.5% -3.0%, yeast extract 0.1% -0.5%, peptone 0.1% -0.5%, coarse sea salt 0.11% -0.6%, suitable water；
Contain glucose 1.6% -3.5%, yeast extract 0.1% -0.5%, peptone 0.1% -0.5%, thick in the fermentation medium
Sea salt 0.11% -0.6%, suitable water；Above-mentioned percentage is weight percentage；The seed culture medium and fermentation medium
120 DEG C are both needed to go out 25-30 minutes.
The present invention provides a kind of antibacterial agent, it is characterised in that with chloroanthraquinone compound of the present invention or its pharmaceutically
Acceptable salt is as active constituent.
Above-mentioned antibacterial agent provided by the invention also includes other antibacterials；Also it may include pharmaceutically acceptable load
Body.
Chloroanthraquinone compound or its pharmaceutically acceptable salt of the present invention can be used for preparing antibacterials.It is described
Antibacterials are preferred for inhibiting staphylococcus aureus or vibrio parahemolyticus.
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 beneficial effects of the present invention are: compared with general anthraquinone compounds (compound 2 and 3), chloro that the present invention obtains
Anthraquinone compounds (compound 1) to Gram-negative bacteria (especially vibrio parahemolyticus) there is significant inhibitory activity (to be detailed in
Embodiment 4).
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) Spawn incubation of fungi Penicillium citrinum HL-5126
Prepare seed culture medium: glucose 80g, peptone 8g, yeast extract 8g, coarse sea salt 10g, water 4.0L, average packing
In 8 1000mL conical flasks, 120 DEG C go out 25-30 minutes.
Fungi Penicillium citrinum HL-5126 bacterial strain is accessed in prepared seed culture medium, in 26~
At 28 DEG C, seed culture fluid is obtained within culture 3 days；
(2) fermentation of fungi Penicillium citrinum HL-5126
Preparation fermentation medium: glucose 1.1kg, peptone 100g, yeast extract 100g, sea salt 125g, water 50L are average
It is sub-packed in 75 1000mL conical flasks, 120 DEG C go out 25-30 minutes.
The access of seed culture fluid obtained in appropriate step (1) is taken equipped in the conical flask of fermentation medium, in 26~
28 DEG C stationary culture 21 days.
(3) the extraction separation of chloroanthraquinone compound
The fermentation material filtering for taking step (2) to obtain, separation and fermentation liquid and thallus, after filtrate is concentrated, respectively with isometric
Ethyl acetate extraction concentration after filtrate and thallus each 3 times；Combining extraction liquid is adopted by depressurizing silica gel column chromatography after concentration
With petroleum ether-ethyl acetate by 100:0 to 0:100 gradient elution, wherein 20% ethyl acetate-light petrol elution fraction passes through
Sephadex LH-20 gel filtration chromatography, eluant, eluent CHCl3: MeOH=1: 1, then prepared through high-efficient liquid phase chromatogram HPLC, color
Composing column is Agilent C18,9.4 × 250mm, 7 μm, flow velocity 2mL/min, mobile phase MeOH: H2O=70: 30, final
To chloroanthraquinone compound (16.0mg), HRESIMS m/z 775.0687 [2M+Na]+(calcd for C36H26Cl2O14Na,
775.0683).Through structural identification, the structure of chloroanthraquinone compound:
NMR data (the 400MHz of chloroanthraquinone compound1H NMR, 100MHz13C NMR)
Embodiment 2
(1) Spawn incubation of fungi Penicillium citrinum HL-5126
It prepares seed culture medium (5.0L): glucose 1.5% (weight percent, similarly hereinafter), yeast extract 0.5%, peptone
0.1%, coarse sea salt 0.11%, remaining is water；Average mark is loaded on 8 1000mL conical flasks, and 120 DEG C go out 25-30 minutes.
Fungi Penicillium citrinum HL-5126 bacterial strain is accessed in prepared seed culture medium, in 26~
At 28 DEG C, seed culture fluid is obtained within culture 4 days；
(2) fermentation of fungi Penicillium citrinum HL-5126
It prepares fermentation medium (100L): glucose 1.6% (weight percent, similarly hereinafter), yeast extract 0.5%, peptone
0.1%, coarse sea salt 0.11%, remaining is water；Average mark is loaded on 150 1000mL conical flasks, and 120 DEG C go out 25-30 minutes.
The access of seed culture fluid obtained in appropriate step (1) is taken equipped in the conical flask of fermentation medium, in 26~
28 DEG C stationary culture 24 days.
(3) the extraction separation of chloroanthraquinone compound
According to separation method similar in embodiment 1, chloroanthraquinone compound, structural identification data and embodiment can be obtained
1 is consistent.
Embodiment 3
(1) Spawn incubation of fungi Penicillium citrinum HL-5126
It prepares seed culture medium (1.0L): glucose 3.0% (weight percent, similarly hereinafter), yeast extract 0.1%, peptone
0.5%, coarse sea salt 0.6%, remaining is water；Average mark is loaded on 3 500mL conical flasks, and 120 DEG C go out 25-30 minutes.
Fungi Penicillium citrinum HL-5126 bacterial strain is accessed in prepared seed culture medium, in 26~
At 28 DEG C, seed culture fluid is obtained within culture 4 days；
(2) fermentation of fungi Penicillium citrinum HL-5126
It prepares fermentation medium (20L): glucose 3.5% (weight percent, similarly hereinafter), yeast extract 0.1%, peptone
0.5%, coarse sea salt 0.6%, remaining is water；Average mark is loaded on 30 1000mL conical flasks, and 120 DEG C go out 25-30 minutes.
The access of seed culture fluid obtained in appropriate step (1) is taken equipped in the conical flask of fermentation medium, in 26~
28 DEG C stationary culture 22 days.
(3) the extraction separation of chloroanthraquinone compound
According to separation method similar in embodiment 1, chloroanthraquinone compound, structural identification data and embodiment can be obtained
1 is consistent.
The measurement of the antibacterial activity of 4 the compounds of this invention of embodiment
The compound of the present invention is according to literature method (Pierce C.G.；Uppuluri P.；Teistan A.R.；
Wormley Jr.F.L.；Mowat E.；Ramage G.；Lopez-ribot J.L.Nat.Protoc.2008,3,1494-
1500), test is to staphylococcus aureus (Staphylococcus aureus) and vibrio parahemolyticus (Vibrio
Parahaemolyticus antibacterial activity).As shown in table 1.
The antibacterial activity of 1 the compounds of this invention of table
Claims (2)
1. a kind of preparation method of chloroanthraquinone compound, it is characterised in that include the following steps:
(1) prepare seed culture medium, by fungi Penicillium citrinum HL-5126 bacterial strain access seed culture medium, 26
~28 DEG C, obtain seed culture fluid within culture 3~4 days；
(2) in the seed culture fluid access fermentation medium obtained step (1), 26~28 DEG C must send out for stationary culture 21~24 days
Ferment object；
(3) fermentation liquid in the fermentation material for obtaining step (2) and thallus separation, fermentation liquid and thallus use isometric second respectively
Acetoacetic ester extracts 3~5 times, and medicinal extract is concentrated under reduced pressure to give after combining extraction liquid；
(4) medicinal extract that step (3) obtains presses 100:0 to 0: 100 by decompression silica gel column chromatography, using petroleum ether-ethyl acetate
Gradient elution, wherein 20% ethyl acetate-light petrol elution fraction, through Sephadex LH-20 gel filtration chromatography, eluant, eluent is
CHCl3: MeOH=1: 1, then prepared through high-efficient liquid phase chromatogram HPLC, chromatographic column is Agilent C18,9.4 × 250mm, 7 μm,
Flow velocity is 2mL/min, mobile phase MeOH: H2O=70: 30 finally obtain the chloroanthraquinone compound；
The chloroanthraquinone compound has the following structure:
2. preparation method described in claim 1, it is characterised in that contain glucose 1.5%-in the seed culture medium
3.0%, yeast extract 0.1% -0.5%, peptone 0.1% -0.5%, coarse sea salt 0.11% -0.6%, suitable water；The hair
Contain glucose 1.6% -3.5%, yeast extract 0.1% -0.5%, peptone 0.1% -0.5%, coarse sea salt in ferment culture medium
0.11% -0.6%, suitable water；Above-mentioned percentage is weight percentage；
The seed culture medium and fermentation medium are both needed to 120 DEG C and go out 25-30 minutes.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603525A (en) * | 2012-01-05 | 2012-07-25 | 中国海洋大学 | Anthraquinone derivative, as well as preparation method and application of anthraquinone derivative serving as antibacterial agent |
| JP2015527322A (en) * | 2012-07-10 | 2015-09-17 | ジョージア ステイト ユニバーシティ リサーチ ファンデーション， インコーポレイテッド | Anthraquinone analogs and methods for making and using the same |
-
2016
- 2016-11-17 CN CN201611010857.7A patent/CN106631803B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603525A (en) * | 2012-01-05 | 2012-07-25 | 中国海洋大学 | Anthraquinone derivative, as well as preparation method and application of anthraquinone derivative serving as antibacterial agent |
| JP2015527322A (en) * | 2012-07-10 | 2015-09-17 | ジョージア ステイト ユニバーシティ リサーチ ファンデーション， インコーポレイテッド | Anthraquinone analogs and methods for making and using the same |
Non-Patent Citations (2)
| Title |
|---|
| Studies on the Metabolic Products of Aspergillus fumigates （J-4）.Chemical structure of Metabolic Products;Yuzuru Yamamoto 等;《Chem.Pharm.Bull.》;19681231;第16卷(第2期);第304-310页 |
| 蒽醌类化合物抗菌与抗肿瘤活性的研究进展;郑言博 等;《湖北中医杂志》;20120227;第34卷(第2期);第74-76页 |
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