CN109293494B - 1, 4-naphthoquinone compound derived from mangrove endophytic fungi, preparation method thereof and application thereof in preparation of anti-inflammatory drugs - Google Patents
1, 4-naphthoquinone compound derived from mangrove endophytic fungi, preparation method thereof and application thereof in preparation of anti-inflammatory drugs Download PDFInfo
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Abstract
The invention discloses a 1, 4-naphthoquinone compound derived from mangrove endophytic fungi, wherein the structural formula of the 1, 4-naphthoquinone compound is shown as a formula I and a formula II. The compound has certain inhibiting effect on NO generated by macrophage of RAW264.7 mouse induced by LPS, and IC50Each value is 3.9µM and 1.7µAnd M. Further research shows that the compound II can inhibit mRNA expression of induced synthases related to inflammation, such as iNOS, COX-2, TNF-alpha, IL-6, IL-1 beta and the like induced by LPS, and can also inhibit expression of iNOS and COX-2 proteins induced by LPS. Shows that the compounds I and II have the function of inhibiting macrophage inflammatory reaction, have good in-vitro anti-inflammatory activity and can be used for preparing anti-inflammatory drugs. Therefore, the 1, 4-naphthoquinone compound provided by the invention has anti-inflammatory clinical application potential.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical compounds, and particularly relates to a mangrove endophytic fungi-derived 1, 4-naphthoquinone compound, a preparation method thereof and application thereof in preparing anti-inflammatory drugs.
Background
Inflammation is a defensive response of body tissues to damaging stimuli, such as noxious stimuli, pathogens, or physical damage. The pathological changes of inflammation mainly consist of three parts of local tissue deterioration, exudation and hyperplasia, and the clinical symptoms are red, swelling, heat, pain and local dysfunction. Inflammation is also an important factor in the aging process of the human body and is closely related to many chronic diseases such as arthritis, osteoporosis, asthma, alzheimer disease, cardiovascular diseases, dementia, cancer, obesity, type ii diabetes and the like [1-3 ]. Clinically, anti-inflammatory drugs are the second largest class of drugs to anti-infective drugs. Inflammation is a common pathological process of many diseases, and if the body cannot remove inflammatory substances in time or acute inflammation is converted into chronic inflammation, the delayed inflammation seriously affects the function of the body. The anti-inflammatory drugs commonly used in clinic at present mainly comprise non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs. Although both anti-inflammatory drugs have certain clinical anti-inflammatory effects, a series of adverse reactions and tolerance, such as gastric mucosal injury, liver injury, kidney injury and the like, can be generated after long-term use of the anti-inflammatory drugs in large quantities. In order to solve the tolerance and adverse reaction of the drugs, the search for new anti-inflammatory drugs and related drugs with novel skeleton types becomes a hotspot in the research field of anti-inflammatory drugs.
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. Lipopolysaccharide (LPS) is one of the components of the cell wall of gram-negative bacteria such as Escherichia coli, and can activate various related receptors on the cell membrane and stimulate the body to initiate severe inflammatory reaction. The use of LPS to induce macrophage inflammatory responses is a cell model currently in common use for studying inflammation.
Natural products are an important source of pharmaceutical lead compounds. The natural product from marine fungi 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 antibacterial, antitumor, immunoregulation, anti-inflammatory, enzyme inhibition, etc. 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 provide two 1, 4-naphthoquinone compounds derived from mangrove endophytic fungi.
The invention also aims to provide a preparation method of the 1, 4-naphthoquinone compound derived from mangrove endophytic fungi.
The invention also aims to provide the application of the 1, 4-naphthoquinone compound derived from mangrove endophytic fungi in preparing anti-inflammatory drugs.
The technical purpose of the invention is realized by the following technical scheme:
1, 4-naphthoquinone compounds derived from mangrove endophytic fungi, wherein the structural formula of the 1, 4-naphthoquinone compounds is shown as a formula I (new) and a formula II:
the invention also provides a preparation method of the 1, 4-naphthoquinone compound from mangrove endophytic fungi, wherein the 1, 4-naphthoquinone compound is obtained by separating from fermentation liquor of the mangrove endophytic fungi Talaromyces sp.SK-S009; the Talaromyces sp.SK-S009 strain is deposited in Guangdong province microorganism culture collection center in 2018, 5 and 9 days, and the deposit number is GDMCC No: 60369.
further, the method specifically comprises the following steps:
s1, inoculating mangrove endophytic fungi Talaromyces sp.SK-S009 into a seed culture medium to obtain a seed culture solution;
s2, inoculating the seed culture solution into a fermentation culture medium for culture to obtain a fermentation product;
and S3, filtering the fermentation product to obtain thalli, purifying, concentrating and extracting the thalli, and performing chromatographic separation and elution to obtain the 1,4 naphthoquinone compound from the mangrove endophytic fungi.
Further, the seed culture solution in the S1 comprises the following components in percentage by weight: 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 93 to 98 percent of water.
Further, the culture conditions in S2 are 150-200 rpm at 28-35 ℃ for 4-8 days.
Further, the fermentation medium is a solid rice fermentation medium, and the solid rice fermentation medium is prepared by mixing rice and water according to the ratio of 1: 1, in a mass ratio of 1.
Further, standing the culture medium after the culture in the S2, wherein the standing condition is that the culture medium is kept for 1 month at 25-35 ℃.
Further concentrating to obtain extract, extracting the extract with ethyl acetate to obtain ethyl acetate crude extract, and separating the ethyl acetate crude extract by silica gel normal phase chromatography; eluting with petroleum ether/ethyl acetate, collecting 10-60% ethyl acetate/petroleum ether fraction, and separating by column chromatography to obtain 1, 4-naphthoquinone compounds shown in formulas I and II.
The invention also protects the application of the 1, 4-naphthoquinone compound from mangrove endophytic fungi in preparing anti-inflammatory drugs.
Further, the application in the preparation of the anti-inflammatory drug is provided.
Compared with the prior art, the invention has the following advantages and effects:
the invention provides two mangrove endophytic fungi-derived 1, 4-naphthoquinone compounds, which have certain inhibition effect on NO generated by macrophages of RAW264.7 mice induced by LPS and IC50The values were 3.9 and 1.7. mu.M, respectively. Further research shows that the compound II can inhibit mRNA expression of induced synthases related to inflammation, such as iNOS, COX-2, TNF-alpha, IL-6, IL-1 beta and the like induced by LPS, and can also inhibit expression of iNOS and COX-2 proteins induced by LPS. The compounds I and II have the effects of inhibiting macrophage inflammatory reaction, have good in-vitro anti-inflammatory activity, can be used for preparing anti-inflammatory drugs, and have anti-inflammatory clinical application potential.
Drawings
FIG. 1 shows the effect of compound II on the expression levels of iNOS, TNF-. alpha., COX-2, IL-1. beta. and IL-6 mRNAs.
FIG. 2 shows the effect of Compound II on the expression levels of iNOS and COX-2 proteins.
Detailed Description
The present invention will be further described with reference to the following specific examples and drawings, which are not intended to limit the invention in any manner. 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 present invention are commercially available.
Example 1
Two mangrove endophytic fungi derived 1, 4-naphthoquinone compounds are prepared, wherein the 1, 4-naphthoquinone compounds are separated from fermentation liquor of mangrove endophytic Talaromyces sp.sk-S009. The mangrove endophytic fungus Talaromyces sp.SK-S009 is isolated from the fruit of Kadelia obovata (Kadelia obovata) of Kandelia glauca plant in Guangxi.
The mangrove fungus Talaromyces sp.SK-S009 is preserved in Guangdong province microorganism culture Collection (GDMCC) in 2018, 5 and 9, and the preservation number is GDMCC No: 60369, class name Talaromyces sp. The address of the storage unit is No. 59 building No. 5 building of No. 100 college of the Pieli Zhonglu, Guangzhou city.
The specific preparation method of the 1, 4-naphthoquinone compound comprises the following steps:
s1, seed liquid culture of mangrove endophytic fungi Talaromyces sp.SK-S009: inoculating mangrove endophytic fungus Talaromyces p.SK-S009 into a seed culture medium, and culturing at 30 ℃ for 6 days at the rotating speed of a shaking table of 180rpm to obtain a seed culture solution; the seed culture medium comprises the following components in percentage by weight: 0.3 percent of glucose, 0.1 percent of yeast extract, 0.5 percent of peptone, 2.5 percent of agar, 3 percent of sodium chloride and 98 percent of water.
S2, fermentation culture of mangrove endophytic fungi Talaromyces sp.SK-S009: inoculating the strain in the seed culture solution into a solid rice fermentation culture medium (rice: tap water 1: 1), and standing at room temperature of 30 deg.C for 1 month;
and S3, extracting the cultured thalli for 3 times by using methanol, concentrating an extracting solution, and extracting an obtained concentrated extract by using ethyl acetate to obtain an ethyl acetate crude extract. Separating the ethyl acetate crude extract by silica gel normal phase chromatography; eluting with petroleum ether/ethyl acetate, collecting 10-60% ethyl acetate/petroleum ether fraction, and separating with silica gel, C-18 reverse phase column chromatography to obtain compounds I and II.
Example 2 (structural characterization of the Compound)
The following experimental data were obtained by performing structural test analyses on compounds i (new) and ii:
molecular formula C15H16O5，HRESI-MS：275.09223[M-H]-(calculated 275.09195);
the NMR data for this compound are shown in Table 1.
TABLE 1 NMR data (500/125MHz, CDCl) for compounds I and II3)
Based on the above data, the structural formulas of compounds i and ii were confirmed as follows:
example 3
Anti-inflammatory cell screening model for compounds
1. Culture and treatment of cells
RAW264.7 cells were cultured in vitro and cultured and passaged routinely at 37 ℃ and 5% carbon dioxide concentration in a DMEM high-glucose medium containing 10% FBS.
2. Compound intervention
Adjusting RAW264.7 cell density to 1 × 105cells/well in logarithmic growth phase, adding LPS (final concentration 1 μ g/mL) to induce macrophage in inflammatory state, using DMSO to prepare test compound or indomethacin into different drug concentrations, setting 3 parallel multiple wells for each concentration, setting positive control well (adding LPS only), negative control well (adding cell and culture medium)Medium), blank control wells (medium). After 24 hours of culture, 50. mu.L of cell supernatant was taken and added to a new 96-well plate, 50. mu.L of each of reagents I and II of the NO detection kit was added, and the NO content was measured by the Griess method.
Inhibition rate ([ NO ]2-]LPS-[NO2-]LPS+sample)/([NO2-]LPS-[NO2-]untreated)×100％
3. Effect of Compounds on cell viability
MTT can be reduced to water-insoluble blue crystals by succinate dehydrogenase in mitochondria of living cells and deposited in living cells, while dead cells do not have this function.
Taking RAW264.7 cells in logarithmic growth phase according to the proportion of 1 × 105cells/well were seeded in 96-well plates at 100. mu.L per well. LPS (final concentration of 1. mu.g/mL) is added to induce macrophages to be in an inflammatory state, and a test compound or indomethacin is prepared into different drug concentrations by using DMSO, wherein 3 parallel wells are arranged at each concentration, and a positive control well (only LPS is added), a negative control well (cells and culture medium) and a blank control well (culture medium) are arranged. After 24 hours of incubation, 50. mu.L of 1mg/mL MTT solution was added to each well, and after 4 hours of incubation, the medium was aspirated, and 150. mu.L DMSO was added to each well. Shaking and shaking evenly. The absorbance value (A) at 490nm was measured with a microplate reader. The inhibition of cell growth by drugs is expressed in terms of survival, with higher survival indicating lower drug toxicity.
Survival (%) - (a)1–A0)/(A2-A0)]X 100% where A0Absorbance value for blank control, A1Is the absorbance value of the sample, A2Absorbance values for positive control wells. 5 samples are measured, and a dose-inhibition rate curve is drawn to obtain CC of the sample50The value is obtained. Each sample was assayed in triplicate. The screening results are shown in Table 2.
TABLE 2 determination of NO inhibitory Activity and cytotoxicity of Compounds I and II
aPositive control
4. Expression of iNOS, COX-2, IL-1 beta, IL-6 and TNF-alpha by compound II at mRNA level
RAW264.7 cells in logarithmic growth phase are inoculated in a six-well cell plate and are randomly divided into a normal control group, a model group and an administration group, and each group is provided with 3 multiple wells. Culturing a normal control group by using a complete culture solution, adding LPS (with the final concentration of 1 mu g/mL) into a model group for stimulation, adding LPS (with the final concentration of 1 mu g/mL) and a medicament into an administration group respectively, culturing for 12h in an incubator, discarding the culture solution, adding 1mL of trizol for cracking, extracting total RNA, carrying out reverse transcription reaction, further carrying out PCR amplification by using TNF-alpha and NO primers, separating and identifying a PCR product by using 2% agar gel, wherein GAPDH is used as an internal reference, and carrying out real-time fluorescence quantitative PCR to determine the inhibition effect of a compound II on iNOS, COX-2, IL-1 beta, IL-6 and TNF-alpha mRNA gene expression.
TABLE 3 fluorescent quantitative primer Gene sequence Listing
The expression level of mRNA of normal cells not induced by LPS is set as 1, the expression level of IL-1 beta induced by LPS is obviously improved, the mRNA levels of iNOS, TNF-alpha, COX-2, IL-1 beta and IL-6 induced by LPS can be inhibited by different concentrations of compound II (P is less than 0.05), and the inhibition effect of high concentration is better than that of low concentration, and the result is shown in figure 1.
5. Western immunoblotting method for detecting expression of iNOS and COX-2 in protein level by compound II
RAW264.7 cells in logarithmic growth phase are inoculated in a six-well cell plate and are randomly divided into a normal control group, a model group and an administration group, and each group is provided with 3 multiple wells. The normal control group is cultured by complete culture solution, the model group is added with LPS (the final concentration is 1 mug/mL) for stimulation, the administration group is respectively added with LPS (the final concentration is 1 mug/mL) and drugs, the incubator is cultured for 12h, PBS is used for washing cells, the cells are collected, cell lysate is added, the cells are incubated for half an hour under the condition of 4 ℃, centrifugation is carried out for 15 minutes at 12,000rpm, supernatant is taken, 10 microliter is taken for protein quantification, the rest is added with equal 2 Xloadingbuffer, boiling water is carried out for 5 minutes, 10% SDS-PAGE (100v) is separated, the cells are transferred to a nitrocellulose membrane, 5% BSA (TBS-T buffer) is sealed for 1 hour at room temperature, i NOS and COX-2 antibodies are incubated overnight under the condition of 4 ℃, TBS-T is washed for three times, corresponding HRP-secondary antibody is used for incubation at room temperature for 1.5h, TBS-T is washed for three times, luminescent reagent is added, and color imaging is developed.
Western immunoblotting detection results show that the production of iNOS and COX-2 proteins is extremely low under the condition of not adding LPS, and the production of the iNOS and the COX-2 proteins is obviously increased after adding the LPS. After treatment with compound II at different concentrations, both iNOS and COX-2 protein expression were significantly reduced, with higher doses being better than lower doses (see FIG. 2).
Claims (4)
1. 1, 4-naphthoquinone compounds derived from mangrove endophytic fungi, which is characterized in that the structural formula of the 1, 4-naphthoquinone compounds is shown as the formula I:
2. the method for preparing 1, 4-naphthoquinone compounds derived from mangrove endophytic fungi according to claim 1, characterized in that the 1, 4-naphthoquinone compounds are obtained by separating from fermentation liquor of the mangrove endophytic fungi Talaromyces p.SK-S009; the Talaromycess p.SK-S009 strain is deposited in Guangdong province microorganism strain collection center in 2018, 5 and 9 days, and the deposit number is GDMCCNo: 60369; the preparation method specifically comprises the following steps:
s1, inoculating mangrove endophytic fungi Talaromyces p.SK-S009 into a seed culture medium to obtain a seed culture solution;
s2, inoculating the seed culture solution into a fermentation culture medium for culture to obtain a fermentation product;
s3, filtering the fermentation product to obtain thalli, purifying, concentrating and extracting the thalli, and performing chromatographic separation and elution to obtain the 1, 4-naphthoquinone compound from the mangrove endophytic fungi;
the seed culture solution in the S1 comprises the following components in percentage by weight: 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 93 to 98 percent of water; the fermentation medium is a solid rice fermentation medium, and the solid rice fermentation medium is prepared by mixing rice and water according to the ratio of 1: 1 in a mass ratio;
the culture condition in the S2 is that the culture is carried out for 4-8 days at the rotating speed of 150-200 rpm and the temperature of 28-35 ℃; standing the culture medium after the culture, wherein the standing condition is that the culture medium is kept standing for 1 month at the temperature of 25-35 ℃;
concentrating the S3 to obtain an extract, extracting the extract with ethyl acetate to obtain an ethyl acetate crude extract, and separating the ethyl acetate crude extract by silica gel normal phase chromatography; eluting with petroleum ether/ethyl acetate, collecting 10-60% ethyl acetate/petroleum ether fraction, and separating by column chromatography to obtain 1, 4-naphthoquinone compound shown in formula I.
The application of the 1, 4-naphthoquinone compound in preparing anti-inflammatory drugs is characterized in that the 1, 4-naphthoquinone compound is a compound shown as a structural formula I in claim 1 and/or a compound shown as a structural formula II
4. The use according to claim 3, in the manufacture of a medicament for inhibiting an inflammatory response in macrophages.
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Non-Patent Citations (5)
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| Antimycobacterial substances from Phaeosphaeria sp. BCC8292;Pittayakhajonwut, Pattama等;《Planta Medica (2008)》;20081231;第74卷(第13期);第281-286页 * |
| Naphthoquinone derivatives from the fungus Hendersonula toruloidea;Van Eijk,G.W.等;《Experientia (1978)》;19780402;第34卷(第10期);第1257-1258页 * |
| New bioactive metabolites from a freshwater isolate of the fungus Kirschsteiniothelia sp;Poch, Gregory K.等;《Journal of Natural Products(1992)》;19920831;第55卷(第8期);第1093-1099页 * |
| New Polyketides Isolated from Botryosphaeria australis Strain ZJ12-1A;Xu,Yu-Hang等;《Helvetica Chimica Acta(2011)》;20111231;第94卷(第5期);第897-902页 * |
| Regiospecific α-substitution of crotonic esters. Synthesis of naturally occurring derivatives of 6-ethyljuglone;Caron,Brigitte等;《Tetrahedron(1991)》;19911231;第47卷(第25期);第4287-4298页 * |
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