CN113527238B - Polyketide derived from sponge endophytic fungi and application thereof in preparation of anti-inflammatory drugs - Google Patents
Polyketide derived from sponge endophytic fungi and application thereof in preparation of anti-inflammatory drugs Download PDFInfo
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Abstract
The invention discloses a polyketide compound separated from endophytic fungus pestalotiopsis cavernosum and application thereof in preparing anti-inflammatory drugs, belonging to the technical field of medical compounds. The invention provides a polyketide derivative derived from sponge endophytic fungi and application thereof in preparation of anti-inflammatory drugs. The invention separates and obtains a strain of endophytic fungus Pestalotiopsis hirsutella (Pestalotiopsis heperoconis) from Phakelliacea Islands in China, and separates and identifies polyketide derivatives from fermentation culture products of the fungus, the derivatives have stronger NO production resistance activity, the anti-inflammatory activity of the derivatives is equivalent to that of a positive drug, and the derivatives have NO cytotoxic activity and have great safety factors. Therefore, the polyketone derivatives provided by the invention have good clinical application prospects in preparation of anti-inflammatory drugs, especially drugs for inhibiting generation of NO induced by LPS.
Description
Technical Field
The invention belongs to the technical field of medical compounds, and relates to a polyketide compound separated from endophytic fungus Pestalotiopsis spongiella and application thereof in preparing anti-inflammatory drugs.
Background
For the past decades, endophytic fungi of the sponge have been considered as an important source of new drugs. The fungi has the characteristics of various metabolic pathways, rich metabolites, sustainability, environmental friendliness and the like, and is an important source for drug screening. Secondly, the metabolite of the fungus has wide physiological activities, such as multiple activities of antibiosis, tumor resistance, immunoregulation, anti-inflammation, enzyme inhibition and the like. At present, the search for new drug source molecules from sponge endophytic fungi has become a hot point of international and domestic research. However, most biosynthetic gene clusters are silent under laboratory conditions, and only a small fraction of the gene clusters are transcribed. To expand the diversity of metabolites, different strategies like OSMAC strategy, epigenetic modification and genome mining have been used to activate silent gene clusters.
Inflammation is an immune response that eliminates damaged cells and foreign antigens when the body is exogenously infected, and the body adopts self-tissue repair. However, this immune response must be rapid and controllable to prevent further inflammatory disorders from occurring, which can result in severe tissue damage. Inflammation has been reported to be directly associated with obesity, diabetes, thrombosis, and even cancer. There are two main classes of anti-inflammatory drugs currently used clinically: non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs. Although they have anti-inflammatory effect to a certain extent, a series of adverse reactions and tolerance, such as gastric mucosa injury, liver injury, kidney injury and the like, can be generated after long-term use in large quantities. In order to solve the tolerance and adverse reaction of the drugs, the search for new anti-inflammatory drugs becomes a hotspot in the research field of anti-inflammatory drugs.
In earlier research work, the inventor separates and screens a sponge endophytic fungus from brown flat sponge (Phakellia fusca) collected from Hsisha Islands in China, identifies the sponge endophytic fungus as Pestalotiopsis hepetoceronis, and ferments the fungus to obtain a secondary metabolite. And the polyketide is found to have good anti-inflammatory activity, can remarkably inhibit NO generation induced by LPS, and shows that sponge endophytic fungi are fermented to produce more compounds with anti-inflammatory activity, so that the polyketide has important significance for treating inflammatory diseases.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a novel sponge endophytic fungi-derived polyketide which can inhibit LPS-induced mouse mononuclear macrophage leukemia cells (RAW 264.7 cells) from releasing NO, has a remarkable anti-inflammatory effect and has a great market prospect in preparing anti-inflammatory drugs.
The invention aims to provide polyketides I and II derived from endophytic fungus Pestalotiopsis herbaconis spongiensis.
Another object of the present invention is to provide a process for the preparation of polyketides I and II.
(1) Inoculating a seed culture medium with a fungus (Pestalotiopsis heterocernis) separated from Phakellia fusca to obtain a seed culture solution;
(2) And (3) fungus fermentation culture: inoculating the seed culture solution into a solid fermentation culture medium, and standing for culture;
(3) Crude extraction: soaking the total fermentation product in ethyl acetate, extracting for 3-5 times, collecting the extract, and concentrating to obtain an extract;
(4) Separation and purification: and (3) performing silica gel column chromatography on the extract to obtain a compound I and a compound II.
Further, the components of the seed culture medium in the step (1) are as follows (by weight ratio): 5-20 g of malt extract, 10-20g of crude sea salt, 1000-2000ml of distilled water and 7.4-8.2 of pHvalue.
Further, the solid rice fermentation culture composition in the step (2) comprises: 100-200 g of rice, 2-10 g of crude sea salt, 200-1000 m of tap water, and culture time: 28-60 days, static culture temperature: 25 to 30 ℃.
Further, the separation and purification steps in the step (4) are specifically: subjecting the extract to silica gel column chromatography, wherein the elution conditions are as follows: dichloromethane-methanol (30; and (3) eluting Fr.5 by using a silica gel chromatographic column under the following conditions: dichloromethane-acetone (3; and then eluting the Fr.5.3 component by using a normal-pressure reverse phase column (ODS), wherein the elution conditions are as follows: methanol-water (80-40%) to obtain 1-5 components, expressed as Fr.5.3.1-Fr.5.3.5, and subjecting Fr.5.3.5 to semi-preparative liquid phase to obtain compound I and compound II; the semi-preparative liquid phase is methanol-water, and the volume ratio of the semi-preparative liquid phase is 40.
Description of the physical and chemical properties of the compounds:
compound i, white amorphous solid, optical rotation value: 10.0 (c 0.2, meOH); ultraviolet absorption (MeOH) lambda max (log ε) 273.8 (3.62), 213 (4.40) nm; infrared absorption (film) v max 3414,2940,2870,1732,1717, 1640,1456,1373,1149,1024cm -1 (ii) a High resolution mass spectrum m/z 415.1755[ m ] +Na ]] + (calcd for C 21 H 28 NaO 7 ,415.1733).
Compound IIWhite amorphous solid, optical rotation-14.6 (c 0.1, meOH); ultraviolet absorption (MeOH) lambda max (log ε) 272 (3.78), 208 (4.60) nm; infrared absorption (film) v max 3414,2941,2870,1732,1716,1650, 1490,1485,1373,1240,1026cm -1 (ii) a High resolution Mass Spectrometry M/z415.1745[ M + Na [)] + (calcd for C 21 H 28 NaO 7 ,415.1733)。
The invention also aims to provide the application of the polyketide derived from the sponge endophytic fungi in preparing anti-inflammatory drugs.
The invention further aims to provide application of the sponge endophytic fungi derived polyketide in preparation of medicines capable of inhibiting LPS (lipopolysaccharide) induced NO production.
The invention provides a polyketide derivative derived from sponge endophytic fungi and application thereof in preparation of anti-inflammatory drugs. The invention separates and obtains a strain of endophytic fungus Pestalotiopsis hepialis from Phakellia fusca of Islands of Western Sasa, china, and separates and identifies polyketide derivatives from fermentation culture products of the fungus, the derivatives have stronger NO production resistance activity, the anti-inflammatory activity of the derivatives is equivalent to that of a positive medicament Saemide, and the derivatives have NO cytotoxic activity and have great safety factors. Therefore, the polyketone derivatives provided by the invention have good clinical application prospects in preparation of anti-inflammatory drugs, especially drugs for inhibiting generation of NO induced by LPS.
Drawings
FIG. 1 is a graph comparing the inhibition of LPS-induced NO release from RAW264.7 cells by compounds I and II;
FIG. 2 is a graph showing the comparison of LPS-induced expression of RAW264.7 iNOS proteins by the compounds I and II.
Detailed Description
Example 1 obtaining of sponge endophytic fungi
1. Experimental method
The inventor group isolated a sponge endophytic fungus from Phakellia fusca (Phakellia fusca) collected from Islands Satsuga, china, and identified the fungus as Pestalotiopsis heterosporidium (Pestalotiopsis) by rDNA area analysis.
2. Results of the experiment
The ITS-rRNA gene sequence of the sponge endophytic fungi is shown in SEQ ID NO. 1:
EXAMPLE 2 identification of polyketide preparation
In the embodiment, the polyketone derivatives are produced by fermenting sponge endophytic fungi, and the specific experimental method and experimental results are as follows:
2.1 preparation of derivatives
The preparation method of the derivative comprises the following steps:
(1) Inoculating a seed culture medium with a fungus (Pestalotiopsis heterocernis) separated from Phakellia fusca to obtain a seed culture solution; the components of the seed culture medium (by weight ratio): 5-20 g of malt extract, 10-20g of crude sea salt, 1000-2000ml of distilled water and 7.4-8.2 of pH value;
(2) And (3) fungus fermentation culture: inoculating the seed culture solution into a solid fermentation culture medium, and performing static culture; the solid rice fermentation culture comprises the following components: 100-200 g of rice, 2-10 g of crude sea salt, 200-1000 m of tap water, and culture time: 28-60 days, static culture temperature: 25 to 30 ℃;
(3) Crude extraction: soaking the total fermentation product in ethyl acetate, extracting for 3-5 times, collecting the extract, and concentrating to obtain an extract;
(4) Separation and purification: and (3) performing silica gel column chromatography on the extract to obtain a compound I and a compound II, wherein the compound I and the compound II are as follows: the elution conditions were: dichloromethane-methanol (30; and (3) eluting Fr.5 by using a silica gel chromatographic column under the following conditions: dichloromethane-acetone (3; and then eluting the Fr.5.3 component by using a normal-pressure reverse phase column (ODS), wherein the elution conditions are as follows: methanol-water (80-40%) to obtain 1-5 components, expressed as Fr.5.3.1-Fr.5.3.5, and subjecting Fr.5.3.5 to semi-preparative liquid phase to obtain compound I and compound II; the semi-preparative liquid phase is methanol-water, and the volume ratio of the methanol-water to the water is 40.
2.2 identification of derivatives
The structure of the derivatives I and II is analyzed, and the physicochemical data of the compound 1 and the compound 2 are as follows:
the formula of derivative I: c 21 H 28 O 7 High resolution mass spectrum (HRESIMS) 415.1755[ 2 ], [ M + [ Na ]] + (calcd for C 21 H 28 NaO 7 ,415.1733).
Derivative II has the formula: c 21 H 28 O 7 High resolution mass spectrum HRESIMSm/z415.1745[ M + Na ]] + (calcd for C 21 H 28 NaO 7 ,415.1733)
Nuclear magnetic data for derivatives I and II are shown in Table 1
The structural formula of the derivative is respectively shown as the formula (I):
I R 1 ＝H,R 2 ＝COCH 3
II R 1 ＝cocH 3 ,R 2 ＝H
description of the physical and chemical properties of the compounds:
compound i, white amorphous solid, optical rotation value: -10.0 (c 0.2, meOH); ultraviolet absorption (MeOH) λ max (log ε) 273.8 (3.62), 213 (4.40) nm; infrared absorption (film) v max 3414,2940,2870,1732,1717, 1640,1456,1373,1149,1024cm -1 (ii) a High resolution mass spectrum m/z 415.1755[ m ] +Na ]] + (calcd for C 21 H 28 NaO 7 ,415.1733).
Compound ii, a white amorphous solid with an optical rotation value of-14.6 (c 0.1, meOH); ultraviolet absorption (MeOH) lambda max (log ε) 272 (3.78), 208 (4.60) nm; infrared absorption (film) v max 3414,2941,2870,1732,1716,1650, 1490,1485,1373,1240,1026cm -1 (ii) a High resolution mass spectrum m/z415.1745[ m ] +Na ]] + (calcd for C 21 H 28 NaO 7 ,415.1733).
EXAMPLE 3 anti-inflammatory Activity of polyketides
1. Cell culture and anti-inflammatory Activity detection
(1) RAW264.7 cells were seeded in 10% FBS DMEM high-glucose medium, and cultured and passaged routinely at 37 ℃ under 5% carbon dioxide.
(2) Anti-inflammatory Activity detection
Taking RAW264.7 cells grown in logarithmic phase at 1 × 10 6 Cells/well were seeded in 6-well plates. After 24h, the cells were pretreated with compounds I (0, 3, 11, 33. Mu.M), II (0, 3, 11, 33. Mu.M) and the positive drug dexamethasone DXM (33. Mu.M) for 2h, respectively, and stimulated with LPS (1. Mu.g/mL) for 24h. Collecting supernatant, and detecting the NO content by a Griess method. The results are shown in figure 1, and the compounds I and II can obviously inhibit the release of macrophage NO induced by LPS, and simultaneously have NO cytotoxicity, so that the compounds I and II can be preliminarily concluded to have good anti-inflammatory activity.
Immunoblot analysis: RAW264.7 cells were stimulated with LPS (1. Mu.g/mL) for 2h using compounds 7 (33. Mu.M on days 0, 3, 11), 8 (33. Mu.M on days 0, 3, 11) and DXM (33. Mu.M). Total protein extraction the BCA protein assembly tool (Beyotime, beijing) was measured by Ripa (Beyotime, beijing) and concentration. Proteins were separated by 10% SDS-PAGE (40. Mu.g), transferred to PVDF membrane (Millipore, billerca, MA, USA) and blocked with 5% skimmed milk in TBS for 1h at room temperature. Primary antibody was incubated overnight, washed 3 times with TBST, horseradish peroxidase-conjugated secondary antibody was incubated at room temperature for 1h, washed 3 times with TBST, and revealed by CEL (Millipore). GAPDH was used as an internal control. The band diagrams were analyzed using the Fluor Chem FC3 system (protein simple, USA). Data are expressed as mean ± s.e. of at least three independent experiments. Where appropriate, the statistical significance of the differences between the means is determined using t-test or one-way analysis of variance. If significant differences in the mean values were found, multiple pairwise comparisons were performed by Tukey's post-hoc test. The difference acceptance threshold is 5% (p.ltoreq.0.05).
As can be seen from FIG. 2, the expression of iNOS in LPS model group was high compared with that in blank group, which indicates that the inflammatory reaction was successfully induced, while the expression of the protein was significantly inhibited in positive drug (dexamethasone) group, and the expression of iNOS protein was significantly inhibited in both compounds I and II. This further demonstrates that compounds i and ii have strong anti-inflammatory activity.
SEQUENCE LISTING
<110> Kunming academy of academic
<120> polyketide from sponge endophytic fungi and application thereof in preparation of anti-inflammatory drugs
<130> 4
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 588
<212> DNA
<213> Pestalotiopsis heterocornis
<400> 1
ggtgaacctg cggagggatc attatagagt tttctaaact cccaacccat gtgaacttac 60
cattgttgcc tcggcagaag ctgctcggta taccctacct tggaacggcc taccctgtag 120
cgccttaccc tggaacggct taccctgcaa cggctgccgg tggactacca aactcttgtt 180
attttattgt aatctgagcg tcttatttta ataagtcaaa actttcaaca acggatctct 240
tggttctggc atcgatgaag aacgcagcga aatgcgataa gtaatgtgaa ttgcagaatt 300
cagtgaatca tcgaatcttt gaacgcacat tgcgcccatt agtattctag tgggcatgcc 360
tgttcgagcg tcatttcaac ccttaagcct agcttagtgt tgggagccta ctgcttttgc 420
tagttgtagc tcctgaaata caacggcgga tctgcgatat cctctgagcg tagtaatttt 480
tatctcgctt ttgactggag ttgcagcgtc tttagccgct aaacccccca atttttaatg 540
gttgacctcg gatcaggtag gaatacccgc tgaacttaag catatcaa 588
Claims (6)
1. Application of polyketide from sponge endophytic fungi in preparation of anti-inflammatory drugs, and is characterized in that the molecular formula of the polyketide is C 21 H 28 O 7， The structural formula is shown as the following formula:
2. use of a sponge endophytic fungus-derived polyketide in the preparation of an anti-inflammatory drug according to claim 1, wherein said sponge endophytic fungus-derived polyketide is capable of inhibiting LPS-induced NO production.
3. The use of polyketides of endophytic fungi origin in the preparation of anti-inflammatory drugs according to claim 1, wherein said preparation of polyketides of endophytic fungi origin in the sponge comprises the steps of:
(1) Inoculating Pestalotiopsis heterocernis fungi separated from Phakellia fusca into a seed culture medium to obtain a seed culture solution;
(2) And (3) fungus fermentation culture: inoculating the seed culture solution into a solid fermentation culture medium, and performing static culture;
(3) Crude extraction: soaking the total fermentation product in ethyl acetate, extracting for 3-5 times, collecting the extract, and concentrating to obtain an extract;
(4) Separation and purification: and (3) performing silica gel column chromatography on the extract to obtain a compound I and a compound II.
4. Use of a polyketide of endophytic fungi origin according to claim 3, wherein the components of the seed culture medium in step (1) are, in terms of specific gravity ratio: 5-20 g of malt extract, 10-20g of crude sea salt, 1000-2000ml of distilled water and 7.4-8.2 of pH value.
5. Use of a polyketide of endophytic fungal origin according to claim 3 in the preparation of an anti-inflammatory drug, wherein the composition of the solid fermentation medium in step (2): 100-200 g of rice, 2-10 g of crude sea salt, 200-1000 ml of tap water, and culture time: 28-60 days, static culture temperature: 25 to 30 ℃.
6. The use of polyketides of endophytic fungi origin in the preparation of anti-inflammatory drugs according to claim 3, wherein the separation and purification steps in step (4) are specifically: subjecting the extract to silica gel column chromatography, wherein the elution conditions are as follows: dichloromethane-methanol is eluted according to a ratio of 30; and (4) eluting the Fr.5 through a silica gel chromatographic column under the following elution conditions: dichloromethane-acetone 3, to give 1 to 5 fractions, expressed as fr.5.1 to 5.5; and then the Fr.5.3 component is eluted by a normal pressure reverse phase column ODS under the following elution conditions: eluting with 80-40% methanol-water to obtain 1-5 components, and performing semi-preparative liquid phase on Fr.5.3.5-Fr.5.3.5 to obtain compound I and compound II; the semi-preparative liquid phase is methanol-water, and the volume ratio of the methanol-water to the water is 40.
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