CN109456196B - Quinone compound from marine fungi as well as preparation method and application thereof - Google Patents
Quinone compound from marine fungi as well as preparation method and application thereof Download PDFInfo
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- CN109456196B CN109456196B CN201811238538.0A CN201811238538A CN109456196B CN 109456196 B CN109456196 B CN 109456196B CN 201811238538 A CN201811238538 A CN 201811238538A CN 109456196 B CN109456196 B CN 109456196B
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- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
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Abstract
The invention relates to the technical field of pharmaceutical compounds, in particular to a quinone compound derived from marine fungi and a preparation method and application thereof. The quinone compound has a structural formula shown in formula (I), has an anti-inflammatory effect, and can be used for preparing anti-inflammatory drugs. The quinone compound is separated and extracted from a fermentation product of Eurotium Cristatum 33YH-WZ-18, the extraction method is simple, the cost is low,
Description
Technical Field
The invention relates to the technical field of pharmaceutical compounds, in particular to a quinone compound from marine fungi and a preparation method and application thereof.
Background
Inflammation is a defense response of living tissues with vascular systems to the stimulation of various injury factors, and the typical response is the appearance of clinical symptoms such as red, swelling, heat, pain, and the like, and is a complex physiological and pathological response generated by harmful stimulation in internal and external environments of organisms. The inflammatory reaction is a protective defense reaction, is a common pathway for causing various major diseases of human, and participates in the occurrence and development processes of a plurality of major diseases such as human infection, tumor, cardiovascular and cerebrovascular diseases, senile dementia, neurodegenerative diseases, allergic diseases, psychosis and the like. Clinically, anti-inflammatory drugs are the second largest class of drugs to anti-infective drugs. Therefore, the search for new and highly effective anti-inflammatory drugs is always a research focus of researchers.
Marine organisms have developed unique metabolic modes in special environments, and many literatures prove that fungi derived from marine organisms can produce various secondary metabolites with novel structures and remarkable physiological activities. The metabolite has multiple medicinal values of antibiosis, anti-tumor, immunoregulation, enzyme inhibition and the like. At present, the search for new drug sources from marine microorganisms including marine fungi has become a hot spot of international and domestic research.
Disclosure of Invention
The invention aims to provide a novel compound capable of effectively resisting inflammation, the novel compound is separated from a fermentation product of Eurotium Cristatum 33YH-WZ-18, and the inventor discovers that the novel compound has anti-inflammatory activity through research and can be applied to preparing anti-inflammatory drugs.
It is still another object of the present invention to provide a process for preparing the novel compounds.
The above object of the present invention is achieved by the following technical solutions:
a quinone compound derived from marine fungi has a structural formula shown in formula (I):
the preparation method of the quinone compound comprises the following steps:
s1, inoculating fungus Eurotium Cristatum 33YH-WZ-18 into a seed culture medium, and performing shake culture to obtain a seed culture solution;
s2, inoculating the seed culture solution into a fermentation culture medium, and performing static culture to obtain a fermented product;
s3, separating the thallus and the bacterial liquid from the fermentation product, soaking the thallus in methanol, concentrating under reduced pressure to obtain a thallus crude product, extracting the bacterial liquid with ethyl acetate, concentrating under reduced pressure to obtain a bacterial liquid crude product, and combining the thallus and the bacterial liquid crude product to obtain a crude extract; respectively taking n-hexane, ethyl acetate and methanol as eluents, roughly separating the crude extract by adopting a reduced pressure column to respectively obtain an n-hexane phase, an ethyl acetate phase and a methanol phase, and then separating and purifying the n-hexane phase to obtain a compound shown in the formula (I);
wherein the fungus is Eurotium Cristatum 33 YH-WZ-18. The fungus Eurotium Cristatum 33YH-WZ-18 is preserved in Guangdong province microorganism strain preservation center, the preservation address is No. 59 building 5 of Mirabilitum Tokyo No. 100, Guangzhou city, the preservation date is 2018, 7 and 18 days, and the preservation number is GDMCC No. 60420.
The marine fungus Eurotium Cristatum 33YH-WZ-18 strain is derived from a brilliant red sea lily which is collected from Xuwen Wenjiang in Zhanjiang in Guangdong and is separated from wrists and feet of the brilliant red sea lily, and is classified and named as Eurotium Cristatum 33 YH-WZ-18.
Preferably, in step S1, the seed culture medium is PDB liquid culture medium. The PDB broth may be prepared with reference to existing PDB broth conditions, including but not limited to the following method, formulated as 30g sea salt and 24g PDB broth powder per liter of water.
Preferably, in step S1, the conditions of shake culture are: at 25 ℃, the rotating speed of the shaking table is 100-150 rpm, and the culture time is 3-5 days.
Preferably, in step S2, the fermentation medium is the same as the seed medium.
Preferably, in step S2, the conditions of the stationary culture are: the time of the static culture is 30 days, and the temperature of the static culture is room temperature.
Preferably, in step S3, the n-hexane phase is chromatographically separated by using a silica gel column, and the silica gel column is chromatographically separated by using petroleum ether-ethyl acetate of 10:0, 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9 and 0:10 respectively for gradient elution; and (3) combining the petroleum ether-ethyl acetate elution parts with the ratio of 8:2 and the ratio of 7:3, and purifying by using gel column chromatography and high performance liquid chromatography to obtain the compound shown in the formula (I).
The silica gel column is a conventional silica gel column used in the field, and the mesh number of the silica gel column is 200-300 meshes.
Preferably, the gel column chromatography conditions are that the gel column is Sephadex LH-20, and methanol is used as an eluent; the conditions of the high performance liquid chromatography are as follows: mobile phase: 80% MeOH-H2O; flow rate: 1mL/min, column: a semi-preparative column Ultimate XB-C18, 10X 250mm,5 μm; the instrument Essentia LC-16.
The existing anti-inflammatory activity tests show that the quinone compound has anti-inflammatory activity and can be used for preparing anti-inflammatory drugs, so that the application of the quinone compound in preparing the anti-inflammatory drugs is within the protection scope of the invention.
Compared with the prior art, the invention has the beneficial effects that:
the novel compound is separated from the fermentation product of Eurotium Cristatum 33YH-WZ-18, has anti-inflammatory activity, can be used for preparing anti-inflammatory drugs, and has wide application prospect. In addition, the preparation method is simple and the cost is low.
Drawings
FIG. 1 shows the NMR spectrum of a compound obtained in example 1 of the present invention.
FIG. 2 shows the NMR carbon spectrum of the compound obtained in example 1 of the present invention.
FIG. 3 is a HRESIMS mass spectrum of the compound obtained in example 1 of the present invention.
Detailed Description
The invention is further illustrated by the following figures and examples in conjunction with the detailed description, which are not intended to limit the invention in any way. Unless otherwise indicated, the reagents and methods referred to in the examples are those commonly used in the art.
Example 1 extraction and characterization of the Compounds
1. The specific preparation steps of the compound are as follows:
s1, obtaining seed culture solution
S11, preparing a seed culture medium:
the seed culture medium is a PDB liquid culture medium which is prepared according to 3 percent of crude sea salt and 24g of PDB per liter. Evenly distributing into 4 1L conical flasks, sterilizing at 121 deg.C (0.1MPa) for 25min, cooling to room temperature, and standing for 24 hr.
S12, seed culture: inoculating Eurotium Cristatum 33YH-WZ-18 into a seed culture medium, and placing the inoculated conical flask on a shaking table for constant temperature culture at 25 ℃ for 72 hours to obtain a seed culture solution.
S2, fermentation culture: uniformly mixing PDB liquid culture medium in a 1L conical flask, sealing, sterilizing at 121 deg.C (0.1MPa) for 25min, cooling to room temperature, standing for 2 days, selecting culture medium in the flask without contamination, inoculating 10mL strain (seed culture solution) in each flask, inoculating 104 flasks, and standing for 30 days to obtain fermented product.
S3, extraction and separation:
after fermentation culture, separating the thallus and a bacterial liquid from a fermentation product, soaking the thallus in methanol, carrying out reduced pressure concentration to obtain a thallus crude product, extracting the bacterial liquid with ethyl acetate, carrying out reduced pressure concentration to obtain a bacteria crude product, combining the thallus and the bacteria crude product to obtain a crude extract, and respectively carrying out coarse separation on the crude extract by using a reduced pressure column with n-hexane, ethyl acetate and methanol as eluents to obtain an n-hexane phase, an ethyl acetate phase and a methanol phase respectively.
Subjecting the obtained n-hexane phase to silica gel column chromatography, subjecting the silica gel column chromatography to gradient elution with petroleum ether-ethyl acetate of 10:0, 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9 and 0:10 respectively, combining the obtained petroleum ether-ethyl acetate eluates of 8:2 and 7:3, and purifying with gel column chromatography and high performance liquid chromatography under the conditions of: the gel column is Sephadex LH-20, and methanol is used as eluent. High performance liquid chromatographyThe conditions of (a) are: mobile phase: 80% MeOH-H2O; flow rate: 1mL/min, column: a semi-preparative column Ultimate XB-C18, 10X 250mm,5 μm; instrument Essentia LC-16 gave a yellow solid.
2. Characterization of
Performing nuclear magnetic resonance detection on the yellow solid, wherein the obtained spectrogram is shown in figures 1-3, and the physical and chemical property data of the structure of the compound is as follows through analysis and detection:
UV(MeOH)λmax(logε)205(3.32),264(2.90)nm；
IR(neat)νmax 2959,2920,2851,1650,1602,1444,1260,1238,1094,1029, 799cm-1；
1H and 13C NMR data(CDCl3400and 100MHz), see table 1;
TABLE 1
HR-ESIMS m/s 349.0486[M-H]-(calcd for C17H14O6Cl,349.0484), detailed information as shown in the table below:
from the results of mass spectrometry and nuclear magnetic resonance analysis, the molecular formula of the compound is determined to be C17H15O6Cl, having the formula:
example 2 anti-inflammatory Activity assay of Compounds
1. Experimental Material
Indomethacin (purchased from a source leafy organism); lipopolysaccharide (from solibao); NO kit (purchased from petunia).
2. Experimental methods
The sample obtained above was used as an experimental subject, indomethacin was used as a positive control, and the sample and indomethacin were each prepared with DMSO at an initial concentration of 50mM as a sample solution to be tested (the sample solution to be tested, indomethacin sample solution to be tested).
The method comprises the following operation steps:
s1.RAW264.7 (mouse mononuclear macrophages) were inoculated in 96-well plates (concentration 1X 10)5One/well), hatching for 12 h.
S2, discarding the old culture solution, mixing LPS (lipopolysaccharide) (1 mu g/mL) with the sample solution to be tested, diluting the mixture to corresponding concentration by using the fresh culture solution, respectively adding the diluted mixture into a 96-well plate, and acting for 24 hours.
S3, sucking 50 mu L of supernatant into a new 96-well plate, adding 50 mu L of NO reagent I and NO reagent II (Biyuntian) into each well, and measuring the OD value of the mixture in a microplate reader at 540 nm.
Anti-inflammatory activity results:
the test result of the quinone compound is IC through test calculation501.48 +/-0.84 mu M, and the inhibition rate is calculated by the formula [ OD-(model group)-OD(drug-adding group)]/[OD(model group)-OD(Normal group)]×100％。
Wherein, OD(model group)The model group in (1) refers to an LPS-induced RAW264.7 cell experimental group.
OD(drug-adding group)The medicated group in (1) refers to an experimental group of LPS-induced RAW264.7 cells added to a sample of the compound of interest.
OD(Normal group)The normal group in (1) refers to the experimental group having only RAW264.7 cells.
Relative to positive control (indomethacin, IC)5041.0 +/-1.0 mu M), and the quinone compound has good anti-inflammatory activity.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (9)
1. A quinone compound derived from marine fungi is characterized in that the structural formula is shown as the formula (I):
2. a process for producing the quinone compound as claimed in claim 1, which comprises the steps of:
s1, inoculating fungus Eurotium Cristatum 33YH-WZ-18 into a seed culture medium, and performing shake culture to obtain a seed culture solution;
s2, inoculating the seed culture solution into a fermentation culture medium, and performing static culture to obtain a fermented product;
s3, separating the thallus and the bacterial liquid from the fermentation product, soaking the thallus in methanol, concentrating under reduced pressure to obtain a crude thallus extract, extracting the bacterial liquid with ethyl acetate, concentrating under reduced pressure to obtain a crude bacterial liquid extract, and combining the thallus and the crude bacterial liquid extract to obtain a crude extract; respectively taking n-hexane, ethyl acetate and methanol as eluents, carrying out coarse separation on the crude extract by adopting a reduced pressure column to respectively obtain an n-hexane phase, an ethyl acetate phase and a methanol phase, and then carrying out separation and purification on the n-hexane phase to obtain the compound shown in the formula (I).
3. The method according to claim 2, wherein the seed culture medium is a PDB liquid culture medium in step S1.
4. The method of claim 2, wherein in step S1, the conditions of shaking culture are: at 25 ℃, the rotating speed of the shaking table is 100-150 rpm, and the culture time is 3-5 days.
5. The method according to claim 2, wherein the fermentation medium is the same as the seed medium in step S2.
6. The production method according to claim 2, wherein in step S2, the conditions of the static culture are: the time of the static culture is 30 days, and the temperature of the static culture is room temperature.
7. The method according to claim 2, wherein in step S3, the n-hexane phase is chromatographically separated by a silica gel column, and the silica gel column is chromatographically separated by a gradient elution with petroleum ether-ethyl acetate of 10:0, 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9, 0:10, respectively; and (3) combining the petroleum ether-ethyl acetate elution parts with the ratio of 8:2 and the ratio of 7:3, and purifying by using gel column chromatography and high performance liquid chromatography to obtain the compound shown in the formula (I).
8. The method according to claim 7, wherein the conditions of the gel column chromatography are methanol as an eluent, and the conditions of the high performance liquid phase are: mobile phase: 80% MeOH-H2O; flow rate: 1mL/min, column: a semi-preparative column Ultimate XB-C18, 10X 250mm,5 μm; the instrument Essentia LC-16.
9. Use of the quinone compound according to claim 1 in the manufacture of an anti-inflammatory agent.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007120423A2 (en) * | 2006-03-20 | 2007-10-25 | Microbia Precision Engineering | Production of quinone derived compounds in oleaginous yeast and fungi |
| CN101669927A (en) * | 2009-09-22 | 2010-03-17 | 中山大学 | Application of anthraquinone ZSU-H85 for preparing mycobacterium smegmatis resistant drugs |
| 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 |
| CN102603524A (en) * | 2012-01-05 | 2012-07-25 | 中国海洋大学 | Quinones derivative as well as preparation method of quinones derivative and application of quinones derivative as antibacterial agent |
| CN107473952A (en) * | 2017-08-07 | 2017-12-15 | 中国农业科学院烟草研究所 | Anthraquinone analog compound, preparation method and application |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007120423A2 (en) * | 2006-03-20 | 2007-10-25 | Microbia Precision Engineering | Production of quinone derived compounds in oleaginous yeast and fungi |
| CN101669927A (en) * | 2009-09-22 | 2010-03-17 | 中山大学 | Application of anthraquinone ZSU-H85 for preparing mycobacterium smegmatis resistant drugs |
| 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 |
| CN102603524A (en) * | 2012-01-05 | 2012-07-25 | 中国海洋大学 | Quinones derivative as well as preparation method of quinones derivative and application of quinones derivative as antibacterial agent |
| CN107473952A (en) * | 2017-08-07 | 2017-12-15 | 中国农业科学院烟草研究所 | Anthraquinone analog compound, preparation method and application |
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