CN112592350A - Polyketide lithocarpin E-G and preparation method and application thereof - Google Patents
Polyketide lithocarpin E-G and preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/18—Bridged systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin
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Abstract
The invention discloses a polyketide Lithocarpin E-G and a preparation method and application thereof. The compound Lithocarpin E-G is separated and prepared from a fermentation culture of a marine fungus Phomopsis lithocarpus FS 508. Proved by tests, the compound Lithocarpin E-G has IC on liver cancer cell HepG-2, breast cancer cell MCF-7, glioma cell SF-268 and non-small cell lung cancer cell A54950The value range is 6.3-91.6 mu M, the anti-tumor activity is relatively obvious, and the anti-tumor composition can be used for preparing anti-tumor drugs.
Description
Technical Field
The invention belongs to the technical field of medical biology, and particularly relates to a polyketide lithocarpin E-G, and a preparation method and application thereof.
Background
Cancer is a serious threat to human health. At present, the number of people dying from cancer every year in the world is about 1000 thousands, the number of people dying from cancer every year in China is about 250 thousands, and the number is increased year by year. Currently, the market share of antitumor drugs is also expanding continuously, and anticancer drugs account for up to 30% of the pharmaceutical market. However, most of the existing anticancer drugs have the defects of poor specificity, strong toxic and side effects, high price and the like, so that cancer patients often abandon treatment due to the high cost of the drugs or have great side effects and are accidentally killed. Therefore, the improvement of the specificity of the anti-cancer drug and the reduction of the toxic and side effects can benefit cancer patients, and have very important practical significance for human health and social development.
Fungi from deep sea have the advantages of abundant metabolites, large yield, various structural types, remarkable activity and the like compared with other marine microorganisms, and become a hotspot for researching and developing marine drugs. Over the past decades, a large number of new natural products have been discovered from marine microorganisms, some of which have attracted the attention of a large number of organic synthetic and pharmaceutical chemists as lead compounds, and some of which have entered clinical drug trials via semisynthetic derivatization. Therefore, the discovery of new natural products with unique structures from marine microorganisms is of great significance and economic value.
Disclosure of Invention
The first object of the present invention is to provide the polyketide lithocarpin E-G with antitumor activity.
The structure of the compound lithocarpin E-G is shown as the formula (I):
wherein 1 is a compound lithocarpin E, 2 is a compound lithocarpin F, and 3 is a compound lithocarpin G.
The second purpose of the invention is to provide a preparation method of a polyketide lithocarpin E-G, wherein the compound lithocarpin E-G is separated and prepared from a fermentation culture of a marine fungus Phomopsis lithocarpin FS508, and the preparation method specifically comprises the following steps:
(1) preparing a solid fermentation culture of a marine fungus Phomopsis lithocarpus FS508, extracting the solid fermentation culture by using ethyl acetate, concentrating an ethyl acetate extract to obtain an extract, dispersing the extract by using a methanol water solution, extracting by using petroleum ether, and distilling and concentrating the residual methanol water solution part after extraction to obtain a crude extract;
(2) subjecting the crude extract to silica gel column chromatography, performing gradient elution with petroleum ether-ethyl acetate at volume ratios of 10:1,7:1,9:2,2:1,1:1,0:1 and dichloromethane-methanol at volume ratios of 5:1 and 0:1 respectively as eluents, collecting the eluate obtained by eluting petroleum ether-ethyl acetate at volume ratios of 1:1 and 0:1 and performing TLC thin layer chromatography with n-hexane: developing ethyl acetate at a ratio of 1:1v/v to obtain a component Fr.9 with Rf of 0.3-0.7;
performing C18 reverse phase column chromatography on the component Fr.9 at the volume ratio of methanol to water of 30: 70; 40: 60; 50: 50; 60: 40; 70: 30; 80: 20; 90: 10; performing gradient elution at a ratio of 100:0, collecting eluted components with a methanol-water volume ratio of 80:20 to obtain a component Fr.9.6, performing silica gel column chromatography on the component Fr.9.6, performing gradient elution with petroleum ether-ethyl acetate volume ratio of 3:1,2:1,1:1,1:2,0:1, and collecting the component Fr.9.6.6 eluted with petroleum ether-ethyl acetate volume ratio of 0: 1; subjecting the component Fr.9.6.6 to gel column chromatography Sephadex LH-20, eluting with dichloromethane-methanol at a volume ratio of 1:1 as eluent, collecting TLC, and performing thin layer chromatography with n-hexane: ethyl acetate 1:1v/v gave a composition fr.9.6.6.1 with Rf 0.3-0.4 and n-hexane: developing ethyl acetate at a ratio of 1:1v/v to obtain a component Fr.9.6.6.2 with Rf of 0.5-0.6; fractions Fr.9.6.6.1 and Fr.9.6.6.2 were separately purified by HPLC to give the compound lithocarpin E-G.
Further, the separation and purification of the components Fr.9.6.6.1 and Fr.9.6.6.2 by HPLC specifically comprises the following steps: semi-preparative HPLC is carried out on the component Fr.9.6.6.1, A YMCpack ODS-A/AQ column is used, A mobile phase is methanol/water with A volume ratio of 86:14, the flow rate is 3mL/min, elution components with the retention time of 9min are collected to obtain A compound litocarpin F, and elution components with the retention time of 12.4min are collected to obtain A compound litocarpin G;
subjecting the component Fr.9.6.6.2 to full preparative HPLC, using A YMC ODS-A column, using A mobile phase of methanol/water with A volume ratio of 90:10 and A flow rate of 8mL/min for preliminary purification, further performing semi-preparative HPLC, using A YMCpack ODS-A/AQ column, using A mobile phase of methanol/water with A volume ratio of 80:20 and A flow rate of 3mL/min, and collecting an eluted component with A retention time of 11.4min to obtain A compound lithocarpin E.
The solid fermentation culture for preparing the marine fungus Phomopsis lithocarpus FS508 comprises the following specific steps: inoculating FS508 mycelium into potato glucose liquid culture medium, culturing at 28 deg.C and 120r/min for 5 days to obtain seed solution, inoculating the seed solution into rice culture medium at 0.1mL/g, and culturing at 28 deg.C for 30 days to obtain FS508 solid fermentation culture; the potato glucose liquid culture medium is prepared by the following method per liter: boiling 200g of potato in 500mL of pure water for 20min, filtering to obtain potato juice, and adding glucose 20g and KH2PO4 3g、MgSO41.5g, vitamin B110mg, supplementing water to 1000mL, and sterilizing; the rice culture medium is prepared by the following method: is prepared by mixing 480g rice with 600mL of crude sea salt water solution with mass volume ratio of 0.5% g/mL and sterilizing.
The third purpose of the invention is to provide the application of the polyketide lithocarpin E-G or the medicinal salt thereof in preparing antitumor drugs. The anti-tumor drug is preferably a drug for resisting liver cancer, breast cancer, glioma or non-small cell lung cancer.
Experiments show that the compound lithocarpin E-G can be used for treating liver cancer cells HepG-2, breast cancer cells MCF-7, glioma cells SF-268 and non-human cancer cellsIC of small cell lung carcinoma cell A54950The value range is 6.3-91.6. mu.M, see Table 1. IC of positive control cisplatin on four tumor cell lines50The values were 2.4, 3.2, 3.3 and 1.6. mu.M, respectively. This result shows that: the compounds of the invention, lithocarpin E-G, all have relatively significant antitumor activity.
TABLE 1 inhibitory Effect of the Compound lithocarpin E-G on cancer cells
The fourth purpose of the invention is to provide an anti-tumor drug, which comprises at least one of the polyketide lithocarpin E-G or the pharmaceutical salt thereof as an active ingredient, preferably, the anti-tumor drug is a drug for resisting liver cancer, breast cancer, glioma or non-small cell lung cancer.
The fifth purpose of the invention is to provide the application of the marine fungus Phomopsis lithocarpus FS508 in the preparation of the polyketide Lithocarpin E-G.
Compared with the prior art, the invention has the advantages that:
the compound lithocarpin E-G is separated and prepared from marine fungus lithocarpus FS508, has relatively obvious antitumor activity, can be used for preparing antitumor drugs, provides candidate compounds for researching and developing new antitumor drugs, and provides scientific basis for developing and utilizing natural active substances from marine microorganisms.
The marine fungus Phomopsis lithocarpus FS508 of the present invention was deposited at the Guangdong province culture Collection (GDMCC) at 8.8.15.2018, with the address: guangzhou city, Xielizhou No. 100 large yard No. 59, floor 5, with the collection number GDMCC No. 60433.
Drawings
FIG. 1 is a scheme of Compound 1(lithocarpin E)1H NMR spectrum;
FIG. 2 is a scheme of Compound 1(lithocarpin E)13C NMR spectrum;
FIG. 3 is a COSY spectrum of Compound 1(lithocarpin E);
FIG. 4 is the HSQC spectrum of Compound 1(lithocarpin E);
FIG. 5 is an HMBC spectrum of Compound 1(lithocarpin E);
FIG. 6 is a NOESY spectrum of Compound 1(lithocarpin E);
FIG. 7 is an HR-ESIMS spectrum of Compound 1(lithocarpin E);
FIG. 8 is a scheme of Compound 2(lithocarpin F)1H NMR spectrum;
FIG. 9 shows the preparation of Compound 2(lithocarpin F)13C NMR spectrum;
FIG. 10 is a COSY spectrum of Compound 2(lithocarpin F);
FIG. 11 is the HSQC spectrum of Compound 2(lithocarpin F);
FIG. 12 is an HMBC spectrum of Compound 2(lithocarpin F);
FIG. 13 is a NOESY spectrum of Compound 2(lithocarpin F);
FIG. 14 is a HR-ESIMS spectrum of Compound 2(lithocarpin F);
FIG. 15 shows the preparation of Compound 3(lithocarpin G)1H NMR spectrum;
FIG. 16 shows the preparation of Compound 3(lithocarpin G)13C NMR spectrum;
FIG. 17 is a COSY spectrum of Compound 3(lithocarpin G);
FIG. 18 is the HSQC spectrum of Compound 3(lithocarpin G);
FIG. 19 is an HMBC spectrum of compound 3(lithocarpin G);
FIG. 20 is a NOESY spectrum of Compound 3(lithocarpin G);
FIG. 21 is an HR-ESIMS spectrum of Compound 3(lithocarpin G).
Detailed Description
The following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1
1. Isolation, purification and characterization of the marine fungus Phomopsis lithocarpus FS508
The marine fungus Phomopsis lithocarpus FS508 of the invention is separated from deep sea sediments of Indian ocean (16 degrees 50.508'N,111 degrees 53.335' E, water depth 3606 meters) in 2016 (5 months) in 2016, and is identified by ITS sequence analysis, and GenBank gene accession numbers are: MG686131, identified by blast alignment and homology analysis as belonging to the genus Phomopsis, named Phomopsis lithocarpus FS508, deposited at the guangddong collection of microbial cultures (GDMCC) at 8, 15 months in 2018, address: guangzhou city, Xielizhou No. 100 large yard No. 59, floor 5, with the collection number GDMCC No. 60433.
2. Solid fermentation of Phomopsis lithocarpus FS508
Inoculating activated deep-sea fungus FS508 mycelium into potato glucose liquid culture medium (per liter culture medium is prepared by decocting 200g potato in 500mL pure water, boiling for 20min, filtering to obtain potato juice, adding glucose 20g and KH2PO4 3g、MgSO41.5g, vitamin B110mg, made by supplementing to 1000mL with water and sterilizing), cultured at 28 ℃ for 5 days at 120r/min to prepare a seed solution, and then inoculated into a rice medium in an inoculum size of 0.1mL/g (prepared by the following method: mixing 480g rice with 600mL of crude sea salt water solution with mass volume ratio of 0.5% mg/mL, autoclaving at 121 deg.C for 20min, and cooling) and culturing at 28 deg.C for 30 days to obtain FS508 solid fermentation culture.
3. Preparation of the Compound Lithocarpin E
(1) Adding ethyl acetate into the solid fermentation culture of FS508, soaking and extracting for 24 hours, repeatedly extracting for 3 times, and concentrating the extracting solution to obtain an extract (99.8 g); dispersing the extract with 80% methanol water solution, extracting with petroleum ether for four times, removing liposoluble components, and distilling and concentrating the residual methanol water solution to obtain crude extract.
(2) Subjecting the crude extract obtained in the step (1) to silica gel column chromatography, performing gradient elution by using petroleum ether-ethyl acetate as eluent in a volume ratio of 10:1,7:1,9:2,2:1,1:1,0:1 and dichloromethane-methanol in a volume ratio of 5:1 and 0:1 respectively, collecting the crude extract obtained by eluting petroleum ether-ethyl acetate in a volume ratio of 1:1 and 0:1, and performing TLC thin layer chromatography by using n-hexane: developing ethyl acetate at a ratio of 1:1v/v to obtain a component Fr.9 with Rf of 0.3-0.7;
performing C18 reverse phase column chromatography on the component Fr.9 at the volume ratio of methanol to water of 30: 70; 40: 60; 50: 50; 60: 40; 70: 30; 80: 20; 90: 10; performing gradient elution at a ratio of 100:0, collecting eluted components with a methanol-water volume ratio of 80:20 to obtain a component Fr.9.6, performing silica gel column chromatography on the component Fr.9.6, performing gradient elution with petroleum ether-ethyl acetate volume ratio of 3:1,2:1,1:1,1:2,0:1, and collecting the component Fr.9.6.6 eluted with petroleum ether-ethyl acetate volume ratio of 0: 1; subjecting the component Fr.9.6.6 to gel column chromatography Sephadex LH-20, eluting with dichloromethane-methanol at a volume ratio of 1:1 as eluent, collecting TLC, and performing thin layer chromatography with n-hexane: ethyl acetate 1:1v/v gave a composition fr.9.6.6.1 with Rf 0.3-0.4 and n-hexane: developing ethyl acetate at a ratio of 1:1v/v to obtain a component Fr.9.6.6.2 with Rf of 0.5-0.6;
subjecting fraction Fr.9.6.6.1 to preparative HPLC using YMCpack ODS-A/AQ column with A mobile phase of methanol/water at A volume ratio of 86:14 and A flow rate of 3mL/min, collecting the eluate fraction with A retention time of 9min to give Compound 2 (i.e., Compound litocarpin F) (1.0mg), and collecting the eluate fraction with A retention time of 12.4min to give Compound 3 (i.e., Compound litocarpin G) (1.0 mg);
fraction Fr.9.6.6.2 was subjected to full preparative HPLC using A YMC ODS-A column with A methanol/water volume ratio of 90:10 and A flow rate of 8mL/min for preliminary purification, and further subjected to semi-preparative HPLC using A YMCpack ODS-A/AQ column with A methanol/water volume ratio of 80:20 and A flow rate of 3mL/min, and the eluate fraction with A retention time of 11.4min was collected to give Compound 1 (i.e., Compound lithocarpin E) (5.0 mg).
4. Structural identification of compound lithocarpin E-G
1H-NMR、13C-NMR and HMBC nuclear magnetic resonance spectrograms are measured by a Bruker advanced-600 nuclear magnetic resonance spectrometer, and Tetramethylsilane (TMS) is taken as an internal standard; ESI-MS data were measured with VG Autospec-3000 type mass spectrometer; the ultraviolet spectrum is measured by an Shimadzu UV-2600 spectrophotometer, and the structure identification is as follows:
as shown in FIGS. 1-21, FIG. 1 is 1 of compound1H NMR spectrum; FIG. 2 is a drawing of Compound 113C NMR spectrum; FIG. 3 isCOSY spectrum of compound 1; FIG. 4 is the HSQC spectrum of Compound 1; FIG. 5 is an HMBC spectrum of compound 1; FIG. 6 is a NOESY spectrum of Compound 1; FIG. 7 is an HR-ESIMS spectrum of Compound 1. FIG. 8 is 2 of Compound No. 21H NMR spectrum; FIG. 9 is a drawing of Compound 213C NMR spectrum; FIG. 10 is a COSY spectrum of Compound 2; FIG. 11 is the HSQC spectrum of Compound 2; FIG. 12 is an HMBC spectrum of compound 1; FIG. 13 is a NOESY spectrum of Compound 2; FIG. 14 is an HR-ESIMS spectrum of Compound 2. FIG. 15 is 3 of compound1H NMR spectrum; FIG. 16 is of Compound 313C NMR spectrum; FIG. 17 is a COSY spectrum of Compound 3; FIG. 18 is the HSQC spectrum of Compound 3; FIG. 19 is an HMBC spectrum of compound 3; FIG. 20 is a NOESY spectrum of Compound 3; FIG. 21 is an HR-ESIMS spectrum of Compound 3.
Compound 2 was a white powder (its nuclear magnetic data are shown in table 3); according to high resolution mass spectrometry (HRESIMS) [ M-H ]]-m/z 645.2700，C37H41O10Calculated value of 645.2705, the molecular formula of the compound was determined to be C37H42O10The unsaturation degree is 17; the 1D and 2D spectra of the compound 2 are analyzed to find that the spectrum of the compound 2 has great similarity with the spectrum of the compound 1, and the main difference is that the compound 2 has one more acetyl signal (delta)C 172.6,20.7,δH2.19), the structure of compound 2 was thus determined. Likewise, the absolute configuration of compound 2 was determined by ECD calculations.
Compound (I)3 is white powder (the nuclear magnetic data is shown in table 4); according to high resolution mass spectrometry (HRESIMS) [ M-H ]]-m/z C37H43O10647.2868 calculated 647.2868, determination of the formula C37H42O10The unsaturation degree is 17; the 1D and 2D spectra of compound 3 are very similar and analysis shows that compound 3 has essentially the same parent nucleus as compound 2, with the difference being the lack of a double bond signal at the 3 "position in compound 3. Thus, the planar structure of compound 3 was determined. Finally we determined the absolute configuration of compound 3 by ECD calculations.
TABLE 2 Nuclear magnetic data [ CD ] of Compound 13COOD3,1H-NMR (600MHz) and13C-NMR(150MHz)]
TABLE 3 Nuclear magnetic data [ CD ] of Compound 23OD,1H-NMR (600MHz) and13C-NMR(150MHz)]
TABLE 4 Nuclear magnetic data [ CD ] of Compound 33OD,1H-NMR (600MHz) and13C-NMR(150MHz)]
the target compound 1 separated by the method is named as a compound lithocarpin E, the target compound 2 is named as a compound lithocarpin F, the target compound 3 is named as a compound lithocarpin G, and the structural formula is shown as the formula (I):
example 2
The antitumor activity of compound lithocarpin E-G was tested by the SRB method (Skehan P, stopping R, Dominic S.New colorimetric cytoxicity assay for anti-cancer-drug screening [ J ]. J Natl Cance Inst,1990,82: 1107-1112.).
1. Test reagents: the compound, lithocarpin E-G, prepared according to the present invention was dissolved in dimethyl sulfoxide (DMSO) to obtain a mother solution with a concentration of 10mg/mL, which was then diluted to the desired concentration in RPMI-1640 medium. The positive control is cisplatin aqueous solution.
The tumor cell strains used in the experiment are liver cancer cell HepG-2, breast cancer cell MCF-7, glioma cell SF-268 and non-small cell lung cancer cell A549.
2. The experimental method comprises the following steps: taking HepG-2, MCF-7, SF-268 and A549 cells in logarithmic growth phase, digesting with pancreatin, staining and counting with trypan blue, adjusting the cell concentration to 3 x 10 by using fresh RPMI-1640 culture medium after detecting that the cell activity is more than 95% by using trypan blue exclusion experiment4one/mL, cells were seeded in 96-well plates, 180. mu.L of cell suspension was added to each well, and 3 blank wells were set to zero, at 37 ℃ with 5% CO2The incubator is used for 24 h. After the cells are attached to the wall, 20. mu.L of a solution of the compound lithocarpin E-G with a certain concentration is added into each well, 20. mu.L of RPMI-1640 medium is added into the negative control, and cisplatin is used as the positive control. Placing at 37 ℃ and 5% CO2Culturing in incubator for 72h, adding 50 μ L cold trichloroacetic acid aqueous solution with volume fraction of 50% to fix cells, standing at 4 deg.C for 1h, washing with distilled water for 5 times, and air drying. Then adding Sulforhodamine B (SRB) solution with volume fraction of 1% glacial acetic acid aqueous solution and concentration of 4mg/mL solution 100 μ L/well, dyeing at room temperature for 30min, removing supernatant, washing with 1% v/v glacial acetic acid aqueous solution for 5 timesAnd air drying. Finally adding 200 mu L/hole of Tris solution with the concentration of 10mmol/mL, measuring the absorbance (A) at 570nm by using a microplate reader, and calculating the inhibition rate of the drug on the cell growth by using the following formula: cell growth inhibition (%) - (1-A)Sample set/AControl group)×100％。
3. The experimental results are as follows: the cytotoxicity of the compound of lithocarpin E-G prepared by the invention on four tumor cells is shown in Table 1. This result shows that: the compound lithocarpin E-G has relatively obvious antitumor activity, so that the invention provides a candidate compound for researching and developing a new antitumor drug and provides a scientific basis for developing and utilizing natural active substances derived from deep-sea microorganisms.
TABLE 1 inhibitory Effect of the Compound lithocarpin E-G on cancer cells
The above is only a preferred embodiment of the present invention, and it should be noted that the above preferred embodiment should not be considered as limiting the present invention, and the protection scope of the present invention should be subject to the scope defined by the claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and these modifications and adaptations should be considered within the scope of the invention.
Claims (9)
1. A compound, lithocarpin E-G, of formula (I):
wherein 1 is a compound lithocarpin E, 2 is a compound lithocarpin F, and 3 is a compound lithocarpin G.
2. A process for the preparation of the compound lithocarpin E-G according to claim 1, characterized in that said compound lithocarpin E-G is isolated from the fermentation culture of the marine fungus Phomopsis lithocarpus FS 508.
3. The preparation method according to claim 2, characterized by comprising the following steps:
(1) preparing a solid fermentation culture of a marine fungus Phomopsis lithocarpus FS508, extracting the solid fermentation culture by using ethyl acetate, concentrating an ethyl acetate extract to obtain an extract, dispersing the extract by using a methanol water solution, extracting by using petroleum ether, and distilling and concentrating the residual methanol water solution part after extraction to obtain a crude extract;
(2) subjecting the crude extract to silica gel column chromatography, performing gradient elution with petroleum ether-ethyl acetate at volume ratios of 10:1,7:1,9:2,2:1,1:1,0:1 and dichloromethane-methanol at volume ratios of 5:1 and 0:1 respectively as eluents, collecting the eluate obtained by eluting petroleum ether-ethyl acetate at volume ratios of 1:1 and 0:1 and performing TLC thin layer chromatography with n-hexane: developing ethyl acetate at a ratio of 1:1v/v to obtain a component Fr.9 with Rf of 0.3-0.7;
performing C18 reverse phase column chromatography on the component Fr.9 at the volume ratio of methanol to water of 30: 70; 40: 60; 50: 50; 60: 40; 70: 30; 80: 20; 90: 10; performing gradient elution at a ratio of 100:0, collecting eluted components with a methanol-water volume ratio of 80:20 to obtain a component Fr.9.6, performing silica gel column chromatography on the component Fr.9.6, performing gradient elution with petroleum ether-ethyl acetate volume ratio of 3:1,2:1,1:1,1:2,0:1, and collecting the component Fr.9.6.6 eluted with petroleum ether-ethyl acetate volume ratio of 0: 1; subjecting the component Fr.9.6.6 to gel column chromatography Sephadex LH-20, eluting with dichloromethane-methanol at a volume ratio of 1:1 as eluent, collecting TLC, and performing thin layer chromatography with n-hexane: ethyl acetate 1:1v/v gave a composition fr.9.6.6.1 with Rf 0.3-0.4 and n-hexane: developing ethyl acetate at a ratio of 1:1v/v to obtain a component Fr.9.6.6.2 with Rf of 0.5-0.6; fractions Fr.9.6.6.1 and Fr.9.6.6.2 were separately purified by HPLC to give the compound lithocarpin E-G.
4. The preparation method according to claim 3, wherein the separation and purification of the components Fr.9.6.6.1 and Fr.9.6.6.2 by HPLC specifically comprises: semi-preparative HPLC is carried out on the component Fr.9.6.6.1, A YMCpackODS-A/AQ column is used, A mobile phase is methanol/water with A volume ratio of 86:14, the flow rate is 3mL/min, elution components with the retention time of 9min are collected to obtain A compound litocarpin F, and elution components with the retention time of 12.4min are collected to obtain A compound litocarpin G;
subjecting the component Fr.9.6.6.2 to full preparative HPLC, using A YMC ODS-A column, using A mobile phase of methanol/water with A volume ratio of 90:10 and A flow rate of 8mL/min for preliminary purification, further performing semi-preparative HPLC, using A YMCpack ODS-A/AQ column, using A mobile phase of methanol/water with A volume ratio of 80:20 and A flow rate of 3mL/min, and collecting an eluted component with A retention time of 11.4min to obtain A compound lithocarpin E.
5. The preparation method according to claim 3, wherein the step (1) of preparing the solid fermentation culture of the marine fungus Phomopsis lithocarpus FS508 comprises the following specific steps: inoculating FS508 hyphae into a potato glucose liquid culture medium, culturing for 5 days at 28 ℃ and 120r/min to prepare a seed solution, then inoculating the seed solution into a rice culture medium according to the inoculation amount of 0.1mL/g, and culturing for 30 days at 28 ℃ to prepare a solid fermentation culture of FS508, wherein each liter of the potato glucose liquid culture medium is prepared by the following method: boiling 200g of potato in 500mL of pure water for 20min, filtering to obtain potato juice, and adding glucose 20g and KH2PO4 3g、MgSO41.5g, vitamin B110mg, supplementing water to 1000mL, and sterilizing; the rice culture medium is prepared by the following method: is prepared by mixing 480g rice with 600mL of crude sea salt water solution with mass volume ratio of 0.5% g/mL and sterilizing.
6. Use of the compound lithocarpin E-G according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of an anti-tumor medicament.
7. The use of claim 7, wherein the anti-tumor drug is a drug against liver cancer, breast cancer, glioma or non-small cell lung cancer.
8. An antitumor agent comprising at least one compound of lithocarpin E-G according to claim 1, or a pharmaceutically acceptable salt thereof as an active ingredient.
9. Use of the marine fungus Phomopsis lithocarpus FS508 for the preparation of the compound lithocarpin E-G according to claim 1.
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| CN114920721B (en) * | 2022-04-19 | 2024-05-07 | 新疆农业科学院微生物应用研究所(中国新疆—亚美尼亚生物工程研究开发中心) | Polyketide with anti-tumor activity and preparation method and application thereof |
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