CN113185580A - Cyclic peptide compound derived from artemisia annua endophytic fungi and application of cyclic peptide compound as antitumor drug - Google Patents
Cyclic peptide compound derived from artemisia annua endophytic fungi and application of cyclic peptide compound as antitumor drug Download PDFInfo
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- 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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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- General Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention relates to a cyclic peptide compound derived from artemisia annua endophytic fungi and application thereof as an anti-tumor medicament. 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 cyclic peptide compound derived from artemisia annua endophytic fungi and application thereof as an anti-tumor medicament.
Background
Cancer is a major public health problem, has become the second leading cause of death worldwide, second only to cardiovascular and cerebrovascular diseases. Since the 40 th century 20, the research on chemical antitumor drugs has been greatly developed since the first antitumor drug, nitrogen mustard, was clinically used to successfully treat malignant lymphoma, but there is still no effective therapeutic drug for solid tumors that are the most serious health-threatening to human life and account for more than 90% of malignant tumors. Drug resistance and malignant tumor invasion/metastasis are major challenges faced by current chemotherapeutic drugs, and more research is devoted to the development of novel chemotherapeutic drugs. Although the development of new antitumor drugs is accelerated by the cross-combination of modern combinatorial chemistry and high-throughput drug screening technology, the search for lead compounds with antitumor activity from natural products is still the main way to find new drugs.
Compared with the traditional small-molecule chemotherapy medicament which can inhibit the growth of normal and tumor tissue cells at the same time in a non-selective way, the natural peptide compound has incomparable properties: the amino acid sequence usually contains 5-50 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 common multi-target action mechanism and can resist drug resistance in certain modes. The natural peptide compounds become an emerging source of chemotherapeutic drugs, and show the advantages of drug resistance and broad-spectrum antitumor activity in clinic. Some active peptide compounds and derivatives thereof enter clinical trials due to their remarkable antitumor effects, and the successful marketing of Polatuzumab, Plutidiepsin and the like indicates that more active peptide compounds become effective chemotherapeutic drugs or drug leads.
Disclosure of Invention
The invention provides a cyclopeptide compound with a structure shown in formula I or a pharmaceutically acceptable salt thereof, which is characterized in that the structure shown in 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 the steps of:
(1) inoculating fungus Myrothecium roridum IFB-E091 into PD culture medium, and shake culturing at 28 deg.C and 140rpm for 5-7 days to obtain seed solution;
(2) fermenting and culturing the fungus 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 performing static culture at the temperature of 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, combining leaching liquor, and concentrating under reduced pressure to obtain a fermentation product extract;
(4) and (4) carrying out chromatographic separation on the fermentation product extract obtained in the step (3) 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 potato 200g, cutting into pieces, adding water, boiling for 30min, filtering with gauze, adding water to the filtrate to 1000mL, adding glucose 20g to dissolve, subpackaging, and sterilizing at 121 deg.C for 20 min; the culture conditions were: the culture was carried out on a rotary shaker at 28 ℃ and 140rpm for 5 to 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 which is conventional in the field, and preferably 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. One or more combinations described herein include the reuse of the same separation means. The chromatographic separation is further preferably to perform normal phase silica gel column chromatography on the fermentation product extract, and perform gradient elution with chloroform/methanol (v/v 100:0 → 0:100) to obtain 8 polar components Fr.1-Fr.8; wherein the Fr.5 component is subjected to normal phase silica gel column chromatography, and is eluted by chloroform/methanol gradient (v/v 100:0 → 100:30) to obtain 6 components Fr.5-1-Fr.5-6; 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 Primaide high performance liquid chromatograph, Sinochrom ODS-AP liquid chromatography column (4.6 × 250mm, 5 μm), wavelength 254nm, mobile phase methanol-water (v/v) ═ 85:15, flow rate 1 mL/min.
Another embodiment of the present invention provides the use of a compound of formula I as described above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer. In particular to the application in preparing anti-gastric cancer drugs.
Another embodiment of the invention provides an application of the compound of the formula I or the pharmaceutically acceptable salt thereof in preparing medicines for inhibiting human gastric cancer cell strains SGC-7901, AGS or MGC-803.
In another embodiment, the present invention provides the use of a compound of formula I as described above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting SGC-7901 cell migration.
Another embodiment of the present invention provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof as described above for the preparation of an anticancer drug lead compound. In particular to the application in preparing anti-gastric cancer drug lead compounds.
Another embodiment of the present invention provides the use of a compound of formula I as described above, or a pharmaceutically acceptable salt thereof, for the manufacture of a candidate anti-cancer drug. In particular to the application in preparing the anti-gastric cancer drug candidate.
Another embodiment of the present invention provides a pharmaceutical composition characterized in that the pharmaceutical composition comprises the above 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 solid preparation, liquid preparation or 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 separated from Artemisia annua artemisinia roridum IFB-E091 which is an endophytic fungus of Artemisia annua (Asteraceae) for the first time by an applicant, shows extremely strong antitumor activity (SGC-7901, AGS or MGC-803), and is expected to be developed and used for preparing an anti-gastric cancer medicament.
Drawings
FIG. 1 is a graph of the effect of compounds of formula I on the cell cycle of SGC-7901 cells;
FIG. 2 is a graph of the effect of compounds of formula I on the apoptosis rate of SGC-7901 cells;
FIG. 3 is a graph of the effect of compounds of formula I on the migratory capacity of SGC-7901 cells observed in an in vitro cell scratch assay (100X);
FIG. 4 is a graph of the effect of the compound of formula I on the migratory capacity of SGC-7901 cells observed in a Transwell in vitro migration assay (100X);
FIG. 5 is a drawing of a compound of formula I1H-NMR Spectrum (CDCl)3，600MHz)；
FIG. 6 is a drawing of a compound of formula I13C-NMR Spectrum (CDCl)3，150MHz)；
FIG. 7 is an HSQC spectrum of the compound of formula I;
FIG. 8 is an HMBC spectrum of a compound of formula I;
FIG. 9 is a drawing of a compound of formula I1H-1H COSY spectrum.
Detailed Description
In order to facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. However, these examples are only for better understanding of the present invention and are not intended to limit the scope or the principle of the present invention, and the embodiments of the present invention are not limited to the following.
Example 1 isolation and characterization of the Artemisia annua endophytic fungus Myrothecium roridum IFB-E091
The strain IFB-E091 is an endophytic fungus which is obtained by separating roots of healthy Artemisia annua (Asteraceae) collected from suburbs of south Jing of Jiangsu in 2006 and 7 months, and the separation and purification are carried out according to a conventional method, for example, the following steps can be carried out:
washing fresh plant sample with tap water for a long time, cleaning dust on the surface, air drying slightly, cutting into 1cm2Small blocks; the root and stem are cut into small sections of about 1cm, and both ends are cut. Sequentially soaking the above leaves and rhizome segments in 75% ethanol for 1min, and 1% sodium hypochlorite solution (containing free chlorine)>2.5%) for 10-15 min, sterilizing the surface of the culture dish by using 75% alcohol for 1min, washing the culture dish by using sterile water for 3 times, then sucking water on sterile filter paper, placing the culture dish on the surface of a separation flat plate by using a pair of tweezers under the sterile condition, slightly pressing, placing 4 pieces (or sections) on each dish, numbering the pieces in sequence according to sources, placing the culture dish in an incubator at 28 ℃ upside down for culture, and observing the culture dish day by day. After hyphae grow out of the cut of the plant material onto the culture medium, carefully picking tip hyphae (together with small pieces of culture medium) at the edges of the bacterial colonies by using an inoculating needle in time, transferring the hyphae to a fresh plate, sequentially numbering and recording,the separation was continued. According to the colony morphology, color difference and growth time, an inoculating needle is used for picking the agar block with the size of rice grains at the edge of the colony on each plate, the agar block is transferred to a fresh culture medium for culture, and the operation is repeated until pure colonies are obtained.
It was identified as Myrothecium roridum (Planta Medica,2010,76(10): 1004-. The "Artemisia annua endophytic fungus Myrothecium roridum IFB-E091" according to the present invention can be obtained according to the isolation and identification method described in the present example or according to the method described in the related research article.
EXAMPLE 2 isolation and identification of Compounds of formula I
(1) Culture of artemisia annua endophytic fungus Myrothecium roridum IFB-E091
Firstly, 20 fungi Myrothecium roridum IFB-E091 are inoculated into 1000mL conical flasks which are respectively filled with 400mL PD culture medium (200 g of peeled potatoes are cut into small pieces, water is added for boiling for 30min, residues are filtered by gauze, the filtrate is added with water for supplementing to 1000mL, 20g glucose is added for dissolving, subpackaging is carried out, and the filtrate is sterilized for 20min at 121 ℃ for standby), and the shaking culture is carried out for 7 days on a rotary shaking table (28 ℃ and 140rpm) 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 (15mL 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) in 15mL each. Then standing in a greenhouse at 28 ℃ for 30 days to obtain a solid fermentation product.
(3) Extraction, separation and identification of compound
And (3) crushing the solid fermentation product obtained in the step (2), drying in the shade, leaching for three times by using a chloroform/methanol (1:1, v/v) mixed solvent, and removing the solvent under reduced pressure to obtain 38g of a crude extract. Separating the crude extract by a silica gel column, and performing gradient elution by chloroform/methanol (v/v 100:0 → 0:100) to obtain 8 components Fr.1-Fr.8. Fr.5 is separated by a silica gel column, and 6 components Fr.5-1 to Fr.5-6 are obtained by chloroform/methanol gradient elution (v/v 100:0 → 100: 30); wherein Fr.5-3 is prepared by HPLC, HITACHI Primaide high performance liquid chromatography, Sinochrom ODS-AP liquid chromatography column (4.6X 250mm, 5 μm), wavelength 254nm, mobile phase methanol-water (v/v) ═ 85:15, flow rate 1mL/min to obtain the compound of formula I of the present invention (20 mg). Through structure confirmation (Marfey, LC-MS, HR-ESI-MS, one-dimensional, two-dimensional NMR and other data), the compound of the formula I has the following structure:
a compound of formula I: c54H82N10O12White powder. High resolution electrospray mass spectrometry (HR-ESI-MS) showed [ M + Na [ ]]+1085.5995 and [ M-H]-1061.6024, determining its molecular weight of 1062 and molecular formula of C54H82N10O12. It is composed of1H-and13the C-NMR spectrum data are shown in Table 1.
TABLE 1 preparation of compounds of formula I1H-and13C-NMR spectroscopic data (AVANCE 600, CDCl)3,δ：ppm，J：Hz)
*overlapped signal
The invention adopts a Marfey method to determine the spatial configuration of a compound shown in a formula I, and the specific method comprises the following steps:
marfey method and LC-MS analysis: the compound (1mg) 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-dinophenyl-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 with 1N hydrochloric acid (100. mu.L) to neutrality, and the resulting mixture was added 1000. mu.L acetonitrile to obtain the sample to be analyzed. The FDAA derivative of the compound hydrolysate and the FDAA derivative of the amino acid reference product are respectively subjected to LC-MS analysis by Agilent TQ-MS, Betasil C18 liquid chromatographic column (150 multiplied by 4.6mm,5 mu m), the wavelength is 340nm, 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 is 75min), and the flow rate is 0.5 mL/min.
Experiments show that LC-MS cannot distinguish between the FDAA derivatives of NMe-L-Ala and NMe-D-Ala, therefore, the derivatization of the two amino acids adopts a modified marfey method, namely FDLA (1-fluoro-2, 4-dinitrophenyl-5-leucoamide) is used as a derivatization reagent instead of FDAA. The retention times of the D, L-amino acid control FDAA (or FDLA) derivatives and the hydrolysis products FDAA (or FDLA) derivatives of the compounds of formula I are shown in tables 2 and 3, respectively, and the analysis of tables 2 and 3 reveals that all the amino acids in the hydrolysis products of the compounds of formula I are L-form, i.e., all the amino acids in the structure of the compounds of formula I are L-form amino acids (glycine is not chiral).
TABLE 2 Retention time of amino acid control derivatives
Improved mark method
TABLE 3 Retention time of hydrolysate derivatives of the Compounds of formula I
Improved mark method
EXAMPLE 3 proliferation inhibitory Effect of the Compound of formula I of the present invention on human gastric cancer cell lines
Human gastric cancer cell strains SGC-7901, AGS and MGC-803 used in the experiment are provided by Shanghai institute of Life sciences 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 the cells in logarithmic growth phase into single cell suspension, and adjusting the cell concentration to 1 × 105The amount of the active carbon is one/mL,inoculating into 96-well plate at 100 μ L/well, 5% CO at 37 deg.C2Culturing for 24h in an incubator; adding a compound and a positive control drug with certain concentration into each well, and adding 100 mu L of culture medium into each of the negative control group and the blank control group; after 48h incubation, 20. mu.L MTT was added to each well at 37 ℃ with 5% CO2Culturing for 4h in a cell culture box; the liquid was aspirated, 100. mu.L of DMSO was added to each well to dissolve, the solution was shaken for 10min, and the absorbance (OD) was read at 490nm using a microplate reader. The proliferation inhibition rate of the compound on tumor cells is calculated according to the following formula:
half maximal Inhibitory Concentration (IC) of the compound was calculated using the modified Korotkoff method50)。
TABLE 4 proliferation inhibitory Activity of the Compounds of formula I of the present invention on human gastric cancer cell lines
As can be seen from Table 4, the compound of formula I has significant proliferation inhibition effect on human gastric cancer cell strains SGC-7901, AGS and MGC-803, and is equivalent to the positive control drug cisplatin.
EXAMPLE 4 Effect of Compounds of formula I of the invention on the cell cycle of SGC-7901 cells
The effect of the compound of formula I on the SGC-7901 cell cycle was analyzed by flow cytometry. Adjusting the cell concentration in logarithmic growth phase to 1.0 × 106one/mL of the cells were inoculated in a 6-well plate at 37 ℃ with 5% CO2Culturing for 24h in an incubator; the compound with a certain concentration is added into each hole for 48 hours. Collecting cells, fixing the cells with precooled 70% ethanol at 4 ℃ for more than 18h, centrifuging the cells at 2400rpm for 10min to remove supernatant, washing the cells twice with PBS, suspending the cells in 0.4mL of PI staining solution containing RNaseA, incubating the cells at 37 ℃ for 30min, filtering the cells with a 400-mesh screen, analyzing the cells in each stage of the cell cycle by using a flow cytometer, and analyzing the percentage of the cells in each stage of the cell cycle in the total cells by using ModFit LT3.0 software.
As shown in fig. 1, after the compound of formula I is dried, the G1 phase cell ratio of SGC-7901 cell is significantly increased and is concentration-dependent compared with the control group; at 50. mu.g/mL, the proportion of cells in G1 phase in the treated group was (59.06. + -. 8.62)% (P <0.05), indicating that: the compound of the formula I can induce cell cycle arrest of G1 phase of SGC-7901 cells; its proliferation inhibitory effect on SGC-7901 cells may be related to its induction of cell G1 phase cycle arrest.
EXAMPLE 5 apoptosis-inducing Effect of Compounds of formula I of the invention on SGC-7901 cells
The effect of the compound of formula I on SGC-7901 apoptosis was observed by Annexin V-FITC/PI double staining. Adjusting the cell concentration in logarithmic growth phase to 1.0 × 106one/mL of the cells were inoculated in a 6-well plate at 37 ℃ with 5% CO2Culturing for 24h in an incubator, adding a compound with a certain concentration for intervention for 48h, collecting cells into a 1.5mL centrifuge tube, centrifuging for 5min at 1000rpm, washing twice with PBS, discarding supernatant, and adding 500 μ L of 1 × binding buffer to each tube to resuspend the cells; adding 5 μ L FITC Annexin V and 5 μ L PI into each tube, mixing, and incubating at room temperature for 15min in dark place; and (5) detecting by using a flow cytometer, and analyzing the apoptosis rate by using FlowJo VX software.
As shown in fig. 2, compared to the control group, the apoptosis rate of the compound of formula I after treatment was significantly increased, and at 50 μ g/mL, the early apoptosis rate and the late apoptosis rate of the treated cells increased to (18.07 ± 2.18)% (P <0.001) and (4.97 ± 2.84)%, respectively, suggesting that: the compound of the formula I can promote SGC-7901 cell apoptosis in a dose-dependent manner; the proliferation inhibition effect on SGC-7901 cells is probably related to the apoptosis induction effect.
EXAMPLE 6 anti-SGC-7901 cell migration of Compounds of formula I of the invention
The influence of the compound on the migration capacity of the tumor cells is observed by adopting an in vitro cell scratch experiment. Drawing a cross line at the bottom of a 6-hole plate by using a marker pen in advance, and adjusting the cell concentration in the logarithmic growth phase to be 1.0 multiplied by 106one/mL of the cells were inoculated in a 6-well plate, and the plate was incubated at 37 ℃ with 5% CO2Culturing in an incubator, after observing the formation of a single cell layer under a microscope, scratching the cell by adopting a white gun head of 10 mu L to be vertical to a transverse line marked by a marker pen as much as possible, washing for 2-3 times by PBS, and then, every timeThe wells were filled with a certain concentration of compound for intervention, and the cells were photographed at 24h and 48h, respectively, to record the condition of the compound treated cells. As shown in fig. 3, after 24h, the cell density at the scratch of the control group is increased, the width of the scratch is obviously reduced, and the scratch is healed to a certain extent; after 48h, the cell density at the scratch of the control group is further increased, the width of the scratch is obviously reduced, and the scratch is about to heal; compared with the control group, after the compound shown in the formula I is treated for 24h and 48h, the scratch width of each concentration group is not obviously changed basically, and the healing degree of the scratch is obviously lower than that of the control group. The phenomenon shows that the compound shown in the formula I can obviously inhibit the healing of the scratch and reduce the migration capacity of SGC-7901 cells.
The effect of the compound of formula I on the migratory capacity of SGC-7901 cells was further observed using a Transwell in vitro migration assay. Adjusting the cell concentration in logarithmic growth phase to 1.0 × 105Inoculating to upper chamber of transwell, adding compound with certain concentration into each hole of the upper chamber for intervention after cell adherence, adding 600 μ L culture medium containing 20% FBS into lower chamber, further adding medium at 37 deg.C and 5% CO2Culturing for 48 hours in an incubator, taking out the small chamber, cleaning cells on a bottom membrane of the upper chamber by using a cotton swab, washing for 2 times by using PBS (phosphate buffer solution), after 1-2 min, fixing for 10min by using 100% methanol, absorbing fixing liquid, washing for 2-3 times by using PBS, dyeing for 10min by using crystal violet dyeing liquid, discarding the crystal violet dyeing liquid, washing for 2-3 times by using PBS, after the upper chamber is naturally dried in the air, observing under a 100-fold inverted microscope, and taking a picture. As shown in FIG. 4, the number of the transmembrane cells of the groups with the concentration of 20 μ g/mL and 50 μ g/mL was significantly reduced after 48h of treatment with the compound of formula I compared with the control group, indicating that the compound of formula I can significantly reduce the migration capacity of SGC-7901 cells.
Claims (10)
1. A cyclic peptide compound of the structure of formula I, or a pharmaceutically acceptable salt thereof, wherein the structure of formula I is as follows:
2. a process for the preparation of a compound of formula I according to claim 1, characterized in that it comprises the following steps:
(1) inoculating fungus Myrothecium roridum IFB-E091 into PD culture medium, and shake culturing at 28 deg.C and 140rpm for 5-7 days to obtain seed solution;
(2) fermenting and culturing the fungus 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 performing static culture at the temperature of 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, combining leaching liquor, and concentrating under reduced pressure to obtain a fermentation product extract;
(4) and (4) carrying out chromatographic separation on the fermentation product extract obtained in the step (3) to obtain the compound shown in the formula I.
3. The method according to claim 2, wherein the PD medium of step (1) is prepared by: peeling potato 200g, cutting into pieces, adding water, boiling for 30min, filtering with gauze, adding water to the filtrate to 1000mL, adding glucose 20g to dissolve, subpackaging, and sterilizing at 121 deg.C for 20 min; the culture conditions were: the culture was carried out on a rotary shaker at 28 ℃ and 140rpm for 5 to 7 days.
4. The method according to any one of claims 2 to 3, wherein the solid fermentation medium of step (2) has a formulation of: 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.
5. The method as claimed in any one of claims 2 to 4, wherein the chromatographic separation in step (4) is one or more of normal phase silica gel column chromatography, reverse phase silica gel column chromatography, gel column chromatography and HPLC preparation.
6. The use of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of an anticancer agent, lead compound, candidate drug. In particular to the application in preparing anti-gastric cancer drugs.
7. The use of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting human gastric cancer cell line SGC-7901, AGS or MGC-803.
8. The use of a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting SGC-7901 cell migration.
9. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
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| CN109456191A (en) * | 2018-09-06 | 2019-03-12 | 广东省微生物研究所（广东省微生物分析检测中心） | Compound cerrenin D and preparation method thereof and application in preparation of anti-tumor drugs |
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