CN113185580B - Cyclopeptide compound derived from endophytic fungi of artemisia annua and application of cyclopeptide compound as antitumor drug - Google Patents
Cyclopeptide compound derived from endophytic fungi of artemisia annua and application of cyclopeptide compound as antitumor drug Download PDFInfo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention relates to a cyclopeptide compound derived from endophytic fungi of artemisia annua and application of the cyclopeptide compound as an antitumor drug. The cyclic peptide compound has the structure of formula I:
Description
Technical Field
The invention belongs to the field of natural products, and particularly relates to a cyclopeptide compound derived from endophytic fungi of artemisia annua and application of the cyclopeptide compound as an anti-tumor drug.
Background
Cancer is a major public health problem and has become the second leading cause of death worldwide, second only to cardiovascular and cerebrovascular diseases. Since the 40 s of the 20 th century, the clinical application of the first antitumor drug, nitrogen mustard, for the successful treatment of malignant lymphomas, the research of chemical antitumor drugs has been greatly developed, but there is still a lack of effective therapeutic drugs for solid tumors which are the most serious in the life and health of humans and account for more than 90% of malignant tumors. Drug resistance and malignant tumor invasion/metastasis are significant challenges facing current chemotherapeutic agents, and more research is devoted to the development of novel chemotherapeutic agents. Although modern combinatorial chemistry and high-throughput drug screening technology are combined in a cross way to accelerate the development of new anti-tumor drugs, the search for lead compounds with anti-tumor activity from natural products is still a main way to find new drugs.
In contrast to traditional small molecule chemotherapeutics which do not selectively inhibit both normal and tumor tissue cell growth, natural peptide compounds have incomparable properties: it generally contains 5 to 50 amino acid residues and is easy to chemically synthesize and modify; some selectively active peptides often exhibit minimal off-target effects; the natural active peptide has a common multi-target action mechanism and can resist the drug resistance of certain modes. The natural peptide compounds become an emerging source of chemotherapeutic drugs and have the advantages of drug resistance and broad-spectrum anti-tumor activity in clinic. Some active peptide compounds and their derivatives enter clinical trials for their remarkable antitumor effects, while the successful marketing of Polatuzumab, plitidepsin, etc. predicts that more active peptide compounds will become effective chemotherapeutic drugs or drug leads.
Disclosure of Invention
The invention provides a cyclic peptide compound with a structure shown in a formula I or pharmaceutically acceptable salt thereof, which is characterized in that the structure shown in the formula I is as follows:
another embodiment of the present invention provides a process for preparing a compound of formula I as described above, characterized by comprising the steps of:
(1) Inoculating fungus Myrothecium roridum IFB-E091 into PD culture medium, shake culturing at 28deg.C and 140rpm for 5-7 days to obtain seed solution;
(2) Fermenting and culturing the fungi Myrothecium roridum IFB-E091 cultured in the step (1); inoculating the seed liquid obtained in the step (1) into a solid fermentation culture medium, and standing and culturing at 28-30 ℃ for 28-30 days to obtain a solid fermentation product;
(3) Crushing the solid fermentation product obtained in the step (2), drying in the shade, leaching for 2-3 times by using a chloroform/methanol mixed solvent with the volume ratio of 1:1, merging leaching solutions, and concentrating under reduced pressure to obtain a fermentation product extract;
(4) And (3) separating the fermented product extract obtained in the step (3) by chromatography to obtain the compound shown in the formula I.
The preparation method of the PD medium in the step (1) comprises the following steps: peeling 200g of potato, cutting into pieces, adding water, boiling for 30min, filtering with gauze, adding water to 1000mL, adding 20g of glucose for dissolving, packaging, and sterilizing at 121deg.C for 20 min; the culture conditions are as follows: the culture was carried out on a rotary shaker at 28℃and 140rpm for 5-7 days.
The formula of the solid fermentation medium in the step (2) is as follows: 15mL of water, 7.5g of millet, 7.5g of bran, 0.5g of yeast extract, 0.1g of sodium tartrate, 0.1g of sodium glutamate, 0.01g of copperas and 0.1mL of corn oil.
The chromatographic separation in the step (4) is a chromatographic separation method conventional in the art, preferably one or a combination of a plurality of normal phase silica gel column chromatography, reverse phase silica gel column chromatography, gel column chromatography and HPLC preparation. One or a combination of several of the herein described, including repeated use of the same separation means. The chromatographic separation further preferably comprises the steps of subjecting the fermentation product extract to normal phase silica gel column chromatography, and performing gradient elution by chloroform/methanol (v/v 100:0- & gt 0:100) to obtain 8 polar components Fr.1-Fr.8; wherein Fr.5 components are subjected to normal phase silica gel column chromatography, and 6 components Fr.5-1 to Fr.5-6 are obtained by gradient elution of chloroform/methanol (v/v 100:0-100:30); wherein the Fr.5-3 component is prepared by HPLC to obtain the compound of formula I. Wherein the HPLC preparation conditions are as follows: HITACHI prism high performance liquid chromatograph, sinochrom ODS-AP liquid chromatograph column (4.6X250 mm,5 μm), wavelength 254nm, mobile phase methanol/water (v/v) =85:15, flow rate 1mL/min.
Another embodiment of the present invention provides the use of a compound of formula I above or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer. In particular to the application in preparing anti-gastric cancer drugs.
Another embodiment of the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof as described above for the preparation of a medicament for inhibiting human gastric cancer cell lines SGC-7901, AGS or MGC-803.
Another embodiment of the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, as described above, in the manufacture of a medicament for inhibiting SGC-7901 cell migration.
Another embodiment of the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, as described above in the preparation of an anticancer drug lead compound. In particular to application in preparing gastric cancer resistant drug lead compounds.
Another embodiment of the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, as described above in the manufacture of a candidate anti-cancer drug. In particular to application in preparing candidate medicines of anti-gastric cancer medicines.
Another embodiment of the present invention provides a pharmaceutical composition, which is characterized in that the pharmaceutical composition comprises the compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition also comprises pharmaceutically acceptable auxiliary materials, and the dosage form of the pharmaceutical composition is preferably a solid preparation, a liquid preparation or a semisolid preparation.
Compared with the prior art, the invention has the advantages that: the compound shown in the formula I is a novel cyclic decapeptide compound, is obtained by separating the compound from a Artemisia annua (Asteraceae) endophytic fungus Myrothecium roridum IFB-E091 for the first time by the applicant, shows extremely strong antitumor activity (SGC-7901, AGS or MGC-803), and is hopeful to be developed for preparing an anti-gastric cancer medicament.
Drawings
FIG. 1 is a graph showing the effect of a compound of formula I on SGC-7901 cell cycle;
FIG. 2 is a graph showing the effect of compounds of formula I on SGC-7901 apoptosis rate;
FIG. 3 is a graph (100X) of the effect of in vitro cell scratch experiments observing the compound of formula I on SGC-7901 cell migration capacity;
FIG. 4 is a graph (100X) of the effect of a compound of formula I on SGC-7901 cell migration capacity observed in a Transwell in vitro migration assay;
FIG. 5 is a compound of formula I 1 H-NMR spectrum (CDCl) 3 ,600MHz);
FIG. 6 is a compound of formula I 13 C-NMR spectrum (CDCl) 3 ,150MHz);
FIG. 7 is a HSQC spectrum of a compound of formula I;
FIG. 8 is a HMBC pattern of a compound of formula I;
FIG. 9 is a compound of formula I 1 H- 1 H COSY profile.
Detailed Description
The examples provided below are presented in more detail to facilitate a further understanding of the present invention. These examples are provided only for better understanding of the present invention and are not intended to limit the scope or practice of the present invention, and the embodiments of the present invention are not limited to the following.
Example 1 isolation and identification of Artemisia annua endophytic fungus Myrothecium roridum IFB-E091
Strain IFB-E091 is an endophytic fungus isolated from the root of healthy Artemisia annua (Asteraceae) harvested from suburban areas of south of the jury, jiangsu, at 2006, and isolated and purified according to conventional methods, for example, the following steps:
washing fresh plant sample with tap water for a long time, cleaning dust and dirt on the surface, air drying slightly, and cutting into 1cm pieces 2 A small block; the root and stem are cut into small sections of about 1cm, and both ends are required to be cut. Soaking the above leaves and rhizome sections in 75% alcohol 1min,1% sodium hypochlorite solution (containing free chlorine) in an ultra-clean bench>2.5%) for 10-15 min, immersing in 75% alcohol for 1min, sucking water on aseptic filter paper, putting on the surface of separating plate under aseptic condition, slightly pressing, putting 4 sheets (or segments) on each dish, numbering according to source, inverting the dish, culturing in 28 deg.C incubator, and observing day by day. After hyphae grow out of the plant material incision onto the culture medium, tip hyphae (together with small pieces of culture medium) at the edge of the colony are carefully picked up by an inoculating needle in time, transferred to a fresh plate, sequentially numbered and recorded, and separation is continued. According to the differences of colony morphology, color and growing time, agar blocks with the grain size of the edge rice of the colony on each plate are picked by an inoculating needle, transferred to a fresh culture medium for culture, and the operation is repeated until pure colonies are obtained.
Based on morphological characteristics of strain IFB-E091 and comparison of the 18S rDNA sequence (Genbank accession No. GU074399), it was identified as Myrothecium roridum (Planta medical, 2010,76 (10): 1004-1006). The public can obtain the 'Artemisia annua endophytic fungus Myrothecium roridum IFB-E091' according to the invention according to the isolation and identification method described in the example or the method described in the related research paper.
EXAMPLE 2 isolation and identification of Compounds of formula I
(1) Cultivation of Artemisia annua endophytic fungus Myrothecium roridum IFB-E091
Firstly, putting fungi Myrothecium roridum IFB-E091 into 20 1000mL conical flasks each filled with 400mL PD culture medium (peeled potato 200g, chopped into pieces, boiled for 30min with water, filtered with gauze to remove residues, adding water to the filtrate to make up to 1000mL, adding 20g glucose to dissolve, split charging, sterilizing at 121 ℃ for 20min for later use), and shaking and culturing in a rotary shaking table (28 ℃ at 140 rpm) for 7 days to obtain seed liquid.
(2) Fermentation of Artemisia annua endophytic fungus Myrothecium roridum IFB-E091
The seed solution obtained in step (1) was inoculated into 400 sterilized 250mL jars containing solid medium (15 mL water, 7.5g millet, 7.5g bran, 0.5g yeast extract, 0.1g sodium tartrate, 0.1g sodium glutamate, 0.01g copperas and 0.1mL corn oil), 15mL per jar. And then standing in a greenhouse at 28 ℃ for 30 days to obtain a solid fermentation product.
(3) Extraction, separation and identification of compounds
Crushing the solid fermentation product obtained in the step (2), drying in the shade, leaching with chloroform/methanol (1:1, v/v) mixed solvent for three times, and removing the solvent under reduced pressure to obtain 38g of crude extract. Separating the crude extract by a silica gel column, and performing chloroform/methanol gradient elution (v/v 100:0-0:100) to obtain 8 components Fr.1-Fr.8. Separating Fr.5 by a silica gel column, and performing gradient elution (v/v 100:0-100:30) by chloroform/methanol to obtain 6 components Fr.5-1-Fr.5-6; wherein Fr.5-3 is prepared by HPLC, HITACHI prism high performance liquid chromatograph, sinochrom ODS-AP liquid chromatograph column (4.6X250 mm,5 μm), wavelength 254nm, mobile phase methanol: water (v/v) =85:15, flow rate 1mL/min, get the compound of formula I (20 mg) of the invention. The structure of the compound of the formula I is confirmed by structure (Marfey, LC-MS, HR-ESI-MS, one-dimensional, two-dimensional NMR and the like data) as follows:
a compound of formula I: c (C) 54 H 82 N 10 O 12 White powder. High resolution electrospray mass spectrometry (HR-ESI-MS) showed [ M+Na] + 1085.5995 and [ M-H ]] - 1061.6024 it has a molecular weight of 1062 and a molecular formula of C 54 H 82 N 10 O 12 . Which is a kind of 1 H-sum 13 The C-NMR spectrum data are shown in Table 1.
TABLE 1 Compounds of formula I 1 H-sum 13 C-NMR Spectroscopy data (AVANCE 600, CDCl) 3 ,δ:ppm,J:Hz)
* overlapped signal
The invention adopts a Marfey method to determine the three-dimensional configuration of the compound of the formula I, and the specific method is as follows:
marfey method and LC-MS analysis: the compound (1 mg) was dissolved in 2mL of 6N hydrochloric acid, heated at 110℃for 20 hours, then cooled to room temperature, and the solvent was removed under reduced pressure. The hydrolysate was dissolved in 500. Mu.L of water and treated with 200. Mu.L of 2%1-fluoro-2, 4-dinitratophenyl-5-L-alaninamide (FDAA) in acetone (w/v) and 100. Mu.L of 1N sodium bicarbonate. The mixture was heated at 40℃for 6h, cooled to room temperature, treated to neutrality with 1N hydrochloric acid (100. Mu.L), and 1000. Mu.L acetonitrile was added to the resulting mixture to obtain a sample to be analyzed. LC-MS analysis was performed on the compound hydrolysate FDAA derivative and the amino acid control FDAA derivative by Agilent TQ-MS, respectively, using Betasil C18 liquid chromatography column (150×4.6mm,5 μm), gradient elution (mobile phase A:0.1% formic acid aqueous solution, mobile phase B:0.1% formic acid acetonitrile solution, elution gradient: 10% -50% mobile phase B, elution time 75 min), flow rate 0.5mL/min.
It was found experimentally that LC-MS is unable to distinguish FDAA derivatives of NMe-L-Ala from NMe-D-Ala, and therefore, the two amino acids were derivatized using a modified marfey method, namely FDLA (1-fluoro-2, 4-dinitolenyl-5-leucomide) as the derivatizing agent instead of FDAA. The retention times of the D, L-amino acid reference FDAA (or FDLA) derivative and the retention times of the hydrolysis product of the compound of formula I FDAA (or FDLA) derivative are shown in tables 2 and 3, respectively, and analysis of tables 2 and 3 shows that all the amino acids in the hydrolysis product of the compound of formula I are L-type, i.e. the amino acids in the structure of the compound of formula I are all L-type amino acids (glycine is not chiral).
TABLE 2 retention time of amino acid control derivatives
* Improved marfey process
TABLE 3 retention time of hydrolysis product derivatives of compounds of formula I
* Improved marfey process
EXAMPLE 3 proliferation inhibition of human gastric cancer cell lines by Compounds of formula I of the present invention
Human gastric cancer cell lines SGC-7901, AGS and MGC-803 used in the experiments are provided by Shanghai life sciences institute cell banks. The proliferation inhibition activity of the compound shown in the formula I on the three human gastric cancer cell lines is determined by adopting an MTT method, and the positive control drug is cisplatin. Digesting logarithmic growth phase cells into single cell suspension, and adjusting cell concentration to 1×10 5 mu.L of each well was inoculated into a 96-well plate at 37℃in 5% CO 2 Culturing in an incubator for 24 hours; each hole is respectively added with a compound with a certain concentration and a positive control drug, and each of a negative control group and a blank control group is respectively added with 100 mu L of culture medium; after 48h of incubation, 20. Mu.L MTT,37℃and 5% CO were added to each well 2 Culturing in a cell incubator for 4 hours; the liquid was aspirated, dissolved by adding 100. Mu.L of DMSO to each well, and subjected to a microseismic for 10min, and absorbance (OD) values were read at 490nm using a microplate reader. The proliferation inhibition rate of the compound on tumor cells is calculated as follows:
the median Inhibitory Concentration (IC) of the compounds was calculated using the modified koehne method 50 )。
TABLE 4 proliferation inhibitory Activity of the Compounds of formula I of the invention against human gastric cancer cell lines
As shown in Table 4, the compound of formula I has remarkable proliferation inhibition effect on human gastric cancer cell lines SGC-7901, AGS and MGC-803, and is equivalent to that of positive control drug cisplatin.
EXAMPLE 4 Effect of the Compounds of formula I of the invention on SGC-7901 cell cycle
Flow cytometry was used to analyze the effect of compounds of formula I on SGC-7901 cell cycle. The cell concentration in the logarithmic phase was adjusted to 1.0X10 6 The cells are inoculated in 6-well plates at 37 ℃ and 5% CO 2 Culturing in an incubator for 24 hours; each well was separately added with a concentration of compound for 48h of intervention. After cells were collected, they were fixed with pre-chilled 70% ethanol at 4℃for 18h or more, centrifuged at 2400rpm for 10min to remove supernatant, washed twice with PBS, resuspended in 0.4mL of RNaseA-containing PI dye solution, incubated at 37℃for 30min, filtered through a 400 mesh screen and analyzed by flow cytometry, and the percentage of cells in each phase of the cell cycle was analyzed using ModFit LT3.0 software.
As shown in fig. 1, the G1 phase cell proportion of SGC-7901 cells was significantly increased after the compound of formula I was dried, and was concentration-dependent, compared to the control group; the G1 phase cell fraction of treated group cells was (59.06.+ -. 8.62)% (P < 0.05) at 50. Mu.g/mL, indicating: the compound of the formula I can induce G1 phase cell cycle arrest of SGC-7901 cells; its proliferation-inhibiting effect on SGC-7901 cells may be related to its induction of cell G1 phase cycle arrest.
EXAMPLE 5 apoptosis inducing effects of the Compounds of formula I of the invention on SGC-7901 cells
The effect of the compounds of formula I on SGC-7901 apoptosis was observed using an Annexin V-FITC/PI double staining method. The cell concentration in the logarithmic phase was adjusted to 1.0X10 6 The cells are inoculated in 6-well plates at 37 ℃ and 5% CO 2 Culturing in incubator for 24h, adding compound with certain concentration respectively for intervention for 48h, collecting cells into 1.5mL centrifuge tube, centrifuging at 1000rpm for 5min, washing with PBS for two times, discarding supernatant, and adding 500 μl of 1×binding buffer for cell resuspension; 5 mu L of FITC Annexin V and 5 mu L of PI are added into each tube and mixed uniformly, and incubated for 15min at room temperature in a dark place; flow cytometer inletAnd (3) performing row detection, and analyzing the apoptosis rate by using FlowJo VX software.
As shown in fig. 2, the apoptosis rate of the cells of the treatment group increased significantly after the treatment with the compound of formula I to (18.07±2.18)% (P < 0.001) and (4.97±2.84)%, respectively, at 50 μg/mL, suggesting that: the compound of formula I can promote SGC-7901 apoptosis in a dose-dependent manner; its proliferation-inhibiting effect on SGC-7901 cells may be related to its apoptosis-inducing effect.
EXAMPLE 6 anti-SGC-7901 cell migration effect of Compounds of formula I of the invention
In vitro cell scratch experiments were used to observe the effect of compounds on tumor cell migration capacity. Marking cross line on the bottom of 6-well plate with marker pen, and adjusting cell concentration in logarithmic phase to 1.0X10% 6 Inoculating the mixture into 6-well plate, placing into 37 deg.C and 5% CO 2 Culturing in an incubator, observing the formation of a single cell layer under a microscope, adopting a 10 mu L white gun head to be perpendicular to a transverse line scratch cell marked by a marker pen as much as possible, washing for 2-3 times by PBS, then adding a compound with a certain concentration into each hole for intervention, and photographing at 24h and 48h respectively to record the condition of the cell after the compound is treated. As shown in fig. 3, after 24 hours, the cell density at the scratch of the control group is increased, the scratch width is obviously reduced, and the scratch heals to a certain extent; after 48 hours, the cell density at the scratch of the control group is further increased, the scratch width is obviously reduced, and the scratch is about to heal; the scratch widths of the groups at each concentration were substantially unchanged from the control groups after 24h and 48h treatment with the compound of formula I, and the degree of scratch healing was significantly lower than in the control group. The above phenomenon shows that the compound of the formula I can obviously inhibit scratch healing and reduce the migration capacity of SGC-7901 cells.
The effect of the compounds of formula I on SGC-7901 cell migration capacity was further observed using a Transwell in vitro migration assay. The cell concentration in the logarithmic phase was adjusted to 1.0X10 5 Inoculating into transwell upper chamber, adding compound with certain concentration into each hole of upper chamber for intervention after cell adhesion, adding 600 μl of 20% FBS-containing culture medium into lower chamber, and continuously adding 37 deg.C and 5% CO 2 Culturing in incubator 48Taking out the cell, scrubbing cells on the basement membrane of the upper chamber by using a cotton swab, washing for 2 times by using PBS, fixing by using 100% methanol for 10min after 1-2 min, sucking the fixing liquid, washing for 2-3 times by using PBS, dyeing by using crystal violet dyeing liquid for 10min, discarding the crystal violet dyeing liquid, washing for 2-3 times by using PBS, and observing and photographing under a 100-time inverted microscope after the upper chamber is naturally air-dried. As shown in FIG. 4, the number of cells passing through the membrane was significantly reduced in the 20 and 50. Mu.g/mL concentration groups after 48h treatment with the compound of formula I, compared with the control group, indicating that the compound of formula I significantly reduced the ability of SGC-7901 cells to migrate.
Claims (6)
1. A process for the preparation of a compound of formula I, characterized by the steps of:
(1) Inoculating fungus Myrothecium roridum IFB-E091 into PD culture medium, shake culturing at 28deg.C and 140rpm for 5-7 days to obtain seed solution;
(2) Fermenting and culturing the fungi Myrothecium roridum IFB-E091 cultured in the step (1); inoculating the seed liquid obtained in the step (1) into a solid fermentation culture medium, and standing and culturing at 28-30 ℃ for 28-30 days to obtain a solid fermentation product;
(3) Crushing the solid fermentation product obtained in the step (2), drying in the shade, leaching for 2-3 times by using a chloroform/methanol mixed solvent with the volume ratio of 1:1, merging leaching solutions, and concentrating under reduced pressure to obtain a fermentation product extract;
(4) The fermented product extract obtained in the step (3) is subjected to chromatographic separation to obtain the compound of the formula I;
the preparation method of the PD medium in the step (1) comprises the following steps: peeling 200g of potato, cutting into pieces, adding water, boiling for 30min, filtering with gauze, adding water to 1000mL, adding 20g of glucose for dissolving, packaging, and sterilizing at 121deg.C for 20 min; the culture conditions are as follows: rotating shaking table, culturing at 28deg.C and 140rpm for 5-7 days;
the formula of the solid fermentation medium in the step (2) is as follows: 15mL of water, 7.5g of millet, 7.5g of bran, 0.5g of yeast extract, 0.1g of sodium tartrate, 0.1g of sodium glutamate, 0.01g of copperas and 0.1mL of corn oil;
the chromatographic separation in the step (4) is one or a combination of more of normal phase silica gel column chromatography, reverse phase silica gel column chromatography, gel column chromatography and HPLC preparation;
the structure of the compound of the formula I is as follows:
2. the use of a compound of formula I prepared by the method of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-gastric cancer medicament.
3. The use of a compound of formula I prepared by the method of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting human gastric cancer cell lines SGC-7901, AGS or MGC-803.
4. The use of a compound of formula I prepared by the method of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting SGC-7901 cell migration.
5. A pharmaceutical composition comprising as active ingredient a compound of formula I prepared according to the process of claim 1 or a pharmaceutically acceptable salt thereof.
6. The pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable adjuvant.
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