CN110117546B - Naphthoquinone compound derived from marine fungi and anti-inflammatory application thereof - Google Patents
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Abstract
The invention discloses a naphthoquinone compound derived from marine fungi and an anti-inflammatory application thereof. The marine fungus Diaporthe sp.GZU-1021 is obtained by separation and purification, and is preserved in Guangdong province microbial culture collection center (GDMCC) in 2019, 3 and 4 days, and the preservation number is GDMCC No: 60601. the strain can secrete and generate a brand-new naphthoquinone compound, and the compound has the effect of remarkably inhibiting the generation of NO induced by LPS and has the clinical application potential of anti-inflammatory treatment. Therefore, the naphthoquinone compound provided by the invention has a good application prospect and a wide development space in preparing anti-inflammatory drugs.
Description
Technical Field
The invention belongs to the technical field of medical compounds, and particularly relates to a naphthoquinone compound derived from marine fungi and an anti-inflammatory application thereof.
Background
Inflammation is a defensive response of body tissues to damaging stimuli (e.g., noxious stimuli, germs, or physical damage) and is also an important factor in the aging process of the human body.
There are two main classes of anti-inflammatory drugs currently used clinically: non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs. But a series of adverse reactions, side effects and tolerance can be generated after long-term use in large quantities, such as gastric mucosa injury, liver injury, kidney injury and the like. Therefore, in order to solve the tolerance and adverse reaction of the drugs, the search for new anti-inflammatory drugs becomes a hot point of research.
Natural products are an important source of drug development. The secondary metabolite of the marine fungus is an important component of a natural product, has the characteristics of sustainability, environmental friendliness, abundant and various metabolites and the like, and is always an important source for drug screening. The metabolite of fungus has wide physiological activity, such as multiple activities of antibiosis, anti-tumor, immunoregulation, anti-inflammation, enzyme inhibition and the like. At present, the search for new drug source molecules from marine fungi has become a hot spot of international and domestic research.
Disclosure of Invention
The invention aims to solve the technical problems that the existing anti-inflammatory drug has the defects of side effect, adverse reaction, tolerance and the like on patients, provides a marine fungus capable of producing anti-inflammatory substances, and separates a new anti-inflammatory drug from the fungus, in particular to a brand-new naphthoquinone compound which can inhibit LPS (low-temperature lipoprotein) to stimulate macrophages to produce NO (nitric oxide), has a remarkable anti-inflammatory effect and has a great market prospect in preparing the anti-inflammatory drug.
The first purpose of the invention is to provide a marine fungus Diaporthe sp.GZU-1021.
The second purpose of the invention is to provide a naphthoquinone compound.
The third purpose of the invention is to provide a preparation method of the naphthoquinone compound.
The fourth purpose of the invention is to provide the application of the naphthoquinone compound.
The above purpose of the invention is realized by the following technical scheme:
the invention provides a marine fungus Diaporthe sp.GZU-1021, which is preserved in Guangdong province microorganism strain collection center in 2019, 3 and 4 days, and the preservation number is GDMCC No: 60601.
the nucleotide sequence of ITS-rRNA gene of the marine fungus Diaporthe sp.GZU-1021 is shown in SEQ ID NO. 1.
The invention also provides a naphthoquinone compound, and the structural formula of the naphthoquinone compound is shown as the formula (I):
in addition, the invention also provides a preparation method of the naphthoquinone compound, which is obtained by fermenting and producing the marine fungus Diaporthe sp.
Specifically, preferably, the naphthoquinone compound can be obtained by performing fungal seed culture, fermentation, crude extraction, separation and purification on the marine fungus Diaporthe sp.
Preferably, the temperature of the fermentation is 30-35 ℃.
More preferably, the temperature of the fermentation is 35 ℃.
Preferably, the fermentation time is 30-60 days.
More preferably, the fermentation time is 60 d.
Preferably, the temperature for the cultivation in step S1 is 28-35 ℃.
More preferably, the temperature for the cultivation in step S1 is 28 to 30 ℃.
Still more preferably, the temperature of the cultivation in the step S1 is 30 ℃.
Preferably, the culturing time in the step S1 is 4-10 d.
More preferably, the culturing time in the step S1 is 4-8 days.
Still more preferably, the incubation time of step S1 is 6 d.
Preferably, the separation and purification is performed by using silica gel column chromatography, gel column chromatography and/or C-18 reverse phase column chromatography separation technology.
Preferably, the culture medium for the fungal seed culture is a slant culture medium.
More preferably, the formula of the slant culture medium is as follows: calculated by mass ratio, 0.3 percent of glucose, 0.1 percent of yeast extract, 0.1 to 0.5 percent of peptone, 1.5 to 2.5 percent of agar, 1.5 to 4 percent of sodium chloride and the balance of water to 100 percent.
Still more preferably, the formula of the slant culture medium in step S1 is: by mass ratio, glucose 0.3%, yeast extract 0.1%, peptone 0.5%, agar 2.5%, sodium chloride 3%, and water make up to 100%.
Preferably, the fermentation medium is a solid rice medium.
More preferably, the formula of the solid rice culture medium is as follows: rice, by mass ratio: 1, sea water: 1 to 2.
Still more preferably, the formulation of the solid rice medium is: rice, by mass ratio: 1, sea water: 1.
as a preferred embodiment, the preparation method of the naphthoquinone compound comprises the following steps:
s1, fungal seed culture: inoculating the marine fungus Diaporthe sp.GZU-1021 to a slant culture medium, and culturing to obtain a seed solution;
s2, fungus fermentation culture: inoculating the seed liquid obtained in the step S1 into a solid rice culture medium, and standing for 30-60 days at 25-35 ℃;
s3, crude extraction: extracting the product fermented and cultured in the step S2 with methanol for 2-5 times, concentrating the extracting solution, and extracting the obtained concentrated extract with ethyl acetate to obtain an ethyl acetate crude extract;
s4, separation and purification: separating the ethyl acetate crude extract obtained in the step S3 by using normal phase silica gel chromatography, eluting by using petroleum ether/ethyl acetate, collecting 10-50% ethyl acetate/petroleum ether part, and then separating and purifying by using silica gel column chromatography, gel column chromatography and/or C-18 reverse phase column chromatography separation technology to obtain the compound.
Preferably, the petroleum ether/ethyl acetate in the step S4 is a mixture of 50-80% ethyl acetate and 20-50% petroleum ether.
More preferably, the petroleum ether/ethyl acetate of step S4 is a mixture of 70% ethyl acetate and 30% petroleum ether.
Preferably, the number of times of methanol extraction in step S3 is 3.
In addition, experiments prove that the naphthoquinone compound derived from the marine fungi can inhibit NO generation induced by LPS, has the clinical application potential of anti-inflammatory treatment, and can be used for preparing anti-inflammatory drugs.
Therefore, the application of the compound in preparing anti-inflammatory drugs and drugs capable of inhibiting NO production induced by LPS also falls within the protection scope of the present invention.
Compared with the prior art, the invention has the following beneficial effects:
through a large amount of creative researches, firstly, a marine fungus Diaporthe sp.GZU-1021 capable of producing anti-inflammatory substances is obtained through separation and screening, and a new anti-inflammatory drug, in particular to a brand new naphthoquinone compound is obtained through separation from the fungus, the compound can obviously inhibit NO production induced by LPS, the IC50 value of the compound is 11.5 mu M, and the compound has the clinical application potential of anti-inflammatory treatment. Therefore, the naphthoquinone compound provided by the invention has good application prospect and wide development space in the preparation of anti-inflammatory drugs and drugs capable of inhibiting NO generation induced by LPS.
Detailed Description
The present invention is further illustrated by the following specific examples, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1 obtaining of the marine fungus Diaporthe sp.GZU-1021
The inventor group separated and screened a fungus (number: GZU-1021) from the trunk of a sea crab which is a small animal in Longjingdao island of southern Shajima, Guangdong province, and identified the fungus by DNA amplification and sequencing of ITS region of the fungus.
Specific step references (Nature protocols,2010,5, 480-: extracting DNA of the fungus by adopting a DNeasy Plant Mini Kit according to the steps of the specification, carrying out PCR amplification by using a fungal ITS region design primer, and sequencing an amplified product to obtain the nucleotide sequence of the ITS-rRNA gene of the fungus as shown in SEQ ID NO. 1; carrying out similarity retrieval comparison analysis on the sequence through a BLAST database, and obtaining that the similarity of the sequence and a Diaporthe sp fungus sequence is more than 99 percent through comparison; thus, the fungus was determined to be the marine fungus Diaporthe sp.
The marine fungus Diaporthe sp.GZU-1021 is preserved in Guangdong province microorganism culture Collection (GDMCC) in 2019, 3 and 4, and the preservation number is GDMCC No: 60601.
EXAMPLE 2 isolation and identification of naphthoquinones
1. Isolation of Compound 1
The compounds were isolated from the fermentation broth of the marine fungus Diaporthe sp.GZU-1021 obtained in example 1 by the following specific method:
s1, seed liquid culture of a fungus Diaporthe sp.GZU-1021: the culture medium comprises the following components in percentage by weight: glucose 0.3%, yeast extract 0.1%, peptone 0.5%, agar 2.5%, sodium chloride 3%, and water to make up 100%; preparing a test tube inclined plane, selecting a strain, inoculating the strain to the inclined plane, and culturing for 6d at 30 ℃;
s2, fermentation culture of the fungus Diaporthe sp.GZU-1021: inoculating the strain obtained by seed liquid culture in step S1 into solid rice culture medium (rice: seawater 1: 1), and standing at room temperature of 35 deg.C for 60 d;
s3, extracting the product fermented and cultured in the step S2 for 3 times by using methanol, concentrating an extracting solution, and extracting the obtained concentrated extract by using ethyl acetate to obtain an ethyl acetate crude extract;
s4, separating the ethyl acetate crude extract obtained in the step S3 by using normal phase silica gel chromatography, eluting by using petroleum ether/ethyl acetate, collecting 10-50% ethyl acetate/petroleum ether part, and sequentially separating and purifying by using silica gel column chromatography, gel column chromatography and C-18 reverse phase column chromatography separation technology to obtain the compound 1.
2. Structural analysis of Compound 1
The following experimental data were obtained by performing structural testing and analysis on compound 1:
the compound 1 is a naphthoquinone compound, and the molecular formula of the compound is as follows: c14H10O6High resolution mass spectrometry (HRESI-MS): 275.0523[ M + H]+(calculated 275.0521).
Nuclear Magnetic Resonance (NMR) data of the naphthoquinone compounds are shown in table 1.
TABLE 1 NMR data for naphthoquinones (CDCl3, 400MHz/100MHz, ppm)
The structural formula of the naphthoquinone compound is shown as the formula (I):
example 3 anti-inflammatory cell screening model and cytotoxicity screening study of naphthoquinone Compounds
Macrophages are an important immune cell in the body, are the main cells for starting the production of inflammatory mediators in the body, and have the functions of resisting infection, resisting tumor and regulating immunity. At present, the macrophage and inflammatory mediators released by the macrophage are considered to be involved in the occurrence and development of various inflammatory diseases, such as atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, septicemia, gouty arthritis and the like. In the development process of anti-inflammatory drugs, macrophage RAW264.7 is an important screening model. When exogenous antigen Lipopolysaccharide (LPS) stimulates macrophages, a series of immune reactions are generated, and inflammatory factors NO are released2 -，NO2 -The level may indirectly reflect the degree of inflammation. The Griess reagent is a reagent which can react with NO2 -Azo dye compound with pigment generated by interaction can judge NO by detecting the absorbance of the dye by a microplate reader2 -And thereby using this model to screen for small molecule inhibitors with anti-inflammatory activity. Thus, the following protocol was employed in this example 3 to study and demonstrate the anti-inflammatory effects of naphthoquinones.
1. Anti-inflammatory cell screening model
(1) Culture and treatment of cells
RAW264.7 cells were cultured in DMEM medium (penicillin 60U/mL, streptomycin 100. mu.g/mL) containing 10% serum and placed in 5% CO2The temperature in the incubator is set to 37 ℃, and conventional maintenance culture and passage are carried out;
(2) compound intervention
After the cells had stabilized after one generation of culture, they were plated in 96-well plates at a concentration of 2X 104cells/well, adherent for 24 hours; naphthoquinone compoundsDissolving the mother solution in DMSO, and diluting with DMEM culture medium to ensure that the concentration of DMSO is not higher than 0.1%; compound samples (2-50 μ M, final concentration) of different concentration gradients were applied to a 96-well plate (200 μ L, LPS: 1g/mL) while a positive control (indomethacin) was set;
the NO inhibitory effect was determined using a Griess kit, i.e., 100. mu.L of cell supernatant was mixed with an equal volume of Griess reagent (0.2% naphtylenediamine dihydrate and 2% sulfonilamide in 5% H3PO 4); testing the absorbance of the naphthoquinone compound by using an enzyme-labeling instrument at the wavelength of 540nm, and judging the inhibition effect of the naphthoquinone compound according to the absorbance of the added naphthoquinone compound and the positive control; sodium nitrite was used to make a standard curve and the experiment was run in triplicate.
Inhibition rate ([ NO ]2 -]LPS-[NO2 -]LPS+sample)/([NO2 -]LPS-[NO2 -]untreated)×100
(3) Anti-inflammatory cell screening model experimental results
The results of the anti-inflammatory activity test of the naphthoquinone compound and the positive control are shown in table 2, and the results show that the naphthoquinone compound has stronger activity for resisting NO generation induced by LPS, the IC50 of the naphthoquinone compound is 11.5 mu M, and the activity of the naphthoquinone compound is nearly 3 times stronger than that of indometacin (IC 5029.7 mu M) which is a positive control.
TABLE 2 anti-inflammatory Activity and cytotoxicity test results of naphthoquinone Compounds
2. Cytotoxicity screening
(1) Principle of
The chemical name of MTT is 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazole bromide salt determined by an MTT method, and the commercial name is as follows: thiazole blue. The detection principle is as follows: the live and dead cells differ in that the presence of succinate dehydrogenase in mitochondria in live cells reduces exogenous MTT to the water-insoluble blue crystalline formazan. Dimethyl sulfoxide (DMSO) can solubilize the formazan deposited within the cells, whose absorbance, measured at 490 or 540nm wavelength, can indirectly reflect the number of cell survivors, depending on the intervening and positive control groups to which the compound is added.
(2) Cytotoxicity screening assay
RAW264.7 cells were cultured in DMEM medium (penicillin 60U/mL, streptomycin 100. mu.g/mL) containing 10% serum and placed in 5% CO2The temperature in the incubator is set to 37 ℃;
after the cells had stabilized after one generation of culture, they were plated in 96-well plates at a concentration of 2X 104cells/well, adherent for 24 hours; dissolving a compound mother solution in DMSO, and diluting with a DMEM culture medium to ensure that the concentration of the DMSO is not higher than 0.1%; compound samples (2-50 μ M, final concentration) of different concentration gradients were applied to a 96-well plate (200 μ L, LPS: 1 g/mL);
after 24 hours of culture, adding 20 mu L of MTT solution (5mg/mL, prepared by PBS) into each hole, continuing to incubate for 4 hours, terminating the culture, carefully sucking the supernatant, adding 150 mu L of DMSO into each hole, and shaking for 10min to fully dissolve crystals; the 490nm wavelength absorption was detected by a microplate reader and the results recorded.
The inhibition rate was calculated by the following formula: the inhibition ratio (%) [ (a 0-a)/a 0] × 100%, where a0 is the absorbance OD value of the blank and a is the absorbance OD value of the sample.
5 concentrations of samples are measured, and a dose-inhibition rate curve is drawn to obtain the IC50 value; each sample was assayed in triplicate and the results expressed as mean ± standard deviation.
(3) Results of cytotoxicity screening experiments
The results of the cytotoxicity test of naphthoquinone compounds are shown in table 2, and the results show that: the naphthoquinone compound does not show cytotoxic activity at a concentration of 50 mu M, and has a large safety factor compared with the IC50 of the naphthoquinone compound.
The above detailed description is of the preferred embodiment for the convenience of understanding the present invention, but the present invention is not limited to the above embodiment, that is, it is not intended that the present invention necessarily depends on the above embodiment for implementation. It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention.
Sequence listing
<110> Guangzhou college of traditional Chinese medicine (Guangzhou institute of traditional Chinese medicine)
<120> naphthoquinone compound derived from marine fungi and anti-inflammatory application thereof
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tacctgcgga gggatcattg ctggaacgcg cttcggcgca cccagaaacc ctttgtgaac 60
ttatacctat ttgttgcctc ggcgtaggcc ggcctcttca ctgaggcccc ctggaaacag 120
ggagcagccc gccggcggcc aactaaactc ttgtttctat agtgaatctc tgagtaaaaa 180
cataaatgaa tcaaaacttt caacaacgga tctcttggtt ctggcatcga tgaagaacgc 240
agcgaaatgc gataagtaat gtgaattgca gaattcagtg aatcatcgaa tctttgaacg 300
cacattgcgc cctctggtat tccggagggc atgcctgttc gagcgtcatt tcaaccctca 360
agcctggctt ggtgatgggg cactgccttc tagcgagggc aggccctgaa atctagtggc 420
gagctcgcta ggaccccgag cgtagtagtt atatctcgtt ctggaaggcc ctggcggtgc 480
cctgccgtta aacccccaac ttctgaaaat ttgacctcgg atcaggtagg aatacccgct 540
gaacttaagc atatcaaaa 559
Claims (10)
1. A marine fungus Diaporthe sp.GZU-1021 is characterized by being preserved in Guangdong province microorganism culture collection center in 2019, 3 and 4 days, and the preservation number is GDMCC No: 60601.
2. a naphthoquinone compound is characterized in that the structural formula of the compound is shown as the formula (I):
3. the method for producing naphthoquinone compounds according to claim 2, wherein said naphthoquinone compounds are produced by fermentation of the marine fungus Diaporthe sp.
4. The method according to claim 3, wherein the naphthoquinone compound is obtained by culturing the marine fungus Diaporthe sp.GZU-1021 of claim 1, fermenting, crudely extracting, separating and purifying.
5. The preparation method according to claim 4, wherein the fermentation temperature is 30-35 ℃ and the fermentation time is 30-60 days.
6. The method according to claim 4, wherein the temperature of the culture is 28 to 35 ℃ and the time is 4 to 10 days.
7. The preparation method according to claim 4, wherein the separation and purification is performed by silica gel column chromatography, gel column chromatography and/or C-18 reverse phase column chromatography.
8. The method according to claim 4, wherein the culture medium for fungal seed culture is a slant culture medium; the formula of the slant culture medium is as follows: calculated by mass ratio, 0.3 percent of glucose, 0.1 percent of yeast extract, 0.1 to 0.5 percent of peptone, 1.5 to 2.5 percent of agar, 1.5 to 4 percent of sodium chloride and the balance of water to 100 percent.
9. Use of a compound according to claim 2 or a compound prepared by a method according to any one of claims 3 to 8 in the preparation of an anti-inflammatory medicament.
10. Use of a compound according to claim 2 or a compound prepared by a method according to any one of claims 3 to 8 in the manufacture of a medicament for inhibiting LPS-induced NO production.
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| CN103910701A (en) * | 2014-02-28 | 2014-07-09 | 中山大学 | Marine fungus-derived naphthoquinone compound, and preparation method and application thereof |
| CN109456196A (en) * | 2018-10-23 | 2019-03-12 | 中山大学 | A kind of quinones and the preparation method and application thereof in marine fungi source |
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| CN103910701A (en) * | 2014-02-28 | 2014-07-09 | 中山大学 | Marine fungus-derived naphthoquinone compound, and preparation method and application thereof |
| CN109456196A (en) * | 2018-10-23 | 2019-03-12 | 中山大学 | A kind of quinones and the preparation method and application thereof in marine fungi source |
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