CN114716312B - Labdane diterpene compound and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a labdane diterpenoid compound and a preparation method and application thereof; the labdane diterpenoid compound is separated and prepared from a fermentation culture of Aspergillus fungus Talaromyces amestolkiae30# GDMCC 3.619; the compound has stronger inhibitory activity on human lung cancer cells and human prostate cancer cells and better migration inhibition effect on human prostate cancer cells, so that the compound provides a lead compound for researching and developing novel anti-lung cancer and anti-prostate cancer medicines and has potential application as an anti-tumor medicine; belongs to the field of medical biotechnology.
Description
Technical Field
The invention belongs to the technical field of medical biology, and particularly relates to a labdane diterpenoid compound, a preparation method of the labdane diterpenoid compound, and application of the labdane diterpenoid compound in preparation of antitumor drugs.
Background
Malignant tumor is one of the main diseases seriously harming human life and life quality, seriously threatens the health of people, and the prevention and treatment of the tumor are always the key points and difficulties of research in the field of medicine. The natural product and the derivative drug thereof play an important role in the anti-tumor treatment and prevention, wherein the marine fungus has a specific metabolic mode due to the unique environment of the sea,can be metabolized to generate natural compounds with novel structures and various biological activities, and is one of important sources of novel antitumor drug leads. Marine fungiTalaromyces amestolkiae30# is a aspergillus basket fungus from mangrove rhizosphere soil, the crude extract of the aspergillus basket fungus has strong anti-tumor activity, and the secondary metabolite of the strain is worthy of deep research.
Disclosure of Invention
In view of the above problems, it is a first object of the present invention to provide labdane-type diterpenoids having tumor-inhibiting activity.
The structure of the compound of the invention is shown as formula (1030):
formula (1030.
The second purpose of the invention is to provide a preparation method of the above labdane diterpenoid compound, which is separated and prepared from the fermentation culture of Talaromyces amestolkiae No. 30 of the Aspergillus talaroides.
The invention provides a fungusTalaromyces amestolkiae30# was deposited at 31.12.2021 in the culture collection of microorganisms of Guangdong province (GDMCC), with accession numbers: GDMCC NO. 62147. Address: the institute of microbiology, national institute of sciences of Guangdong province, no. 59, zhou, mieli, guangzhou, guangdong province.
Preferably, the specific steps are as follows:
A. preparing a fermentation culture of a marine fungus Talaromyces amestolkiae30 #.
B. Extracting and concentrating the fermented product by using chloroform-methanol (volume ratio is 1);
the crude extract obtained is subjected to silica gel column chromatography, and is subjected to gradient elution with petroleum ether-ethyl acetate at a volume ratio of 9.
Collect petroleum ether/ethyl acetate volume ratio 7 elution fraction fr.3, continue to use silica gel column chromatography, with chloroform-methanol system, in a gradient elution sequence of 1, 50, 1, 30, 1, 10 to obtain 5 fractions fr.3.1-fr.3.5.
And continuously performing sephadex LH-20 column chromatography separation on the component Fr.3.4, eluting by using pure methanol as an eluent, and separating and purifying to obtain the labdane diterpenoid compound.
The fermentation product for preparing the marine fungus Talaromyces aestivalis 30# is obtained by culturing the marine fungus Talaromyces aestivalis 30# serving as a fermentation strain in an amplified fermentation culture medium; the amplification culture medium is a rice solid culture medium: according to the proportion of a single culture medium, the culture medium comprises 100g of rice and 100mL of self-made seawater (sea salt is 2g, and water is 100 mL), and through the evaluation of the anti-tumor activity of the labdane diterpenoid compounds, the labdane diterpenoid compounds are found to have obvious inhibition effects on human lung cancer cell strains (A549), human prostate cancer cell strains (PC-3) and (VCap), and have obvious inhibition effects on cell migration of the human prostate cancer cell strains (PC-3).
Therefore, the third purpose of the invention is to provide the application of the labdane diterpenoid compound in preparing the anti-tumor medicine.
Preferably, the anti-tumor drug is an anti-human lung cancer drug.
The fourth purpose of the invention is to provide an anti-tumor drug, which comprises an effective amount of labdane diterpenoid compounds or medicinal salts thereof as active ingredients and a pharmaceutically acceptable carrier.
Preferably, the anti-tumor drug is an anti-human lung cancer drug.
The labdane diterpenoid compounds have obvious inhibition effect on tumor cells, also have inhibition effect on tumor migration, can be used for preparing antitumor drugs and preventing and treating tumors, and therefore, the invention provides candidate compounds for developing new antitumor drugs and has important significance for developing marine drug resources in China.
Drawings
FIG. 1 is a drawing showing the preparation of labdane-type diterpene compounds 1 H NMR spectrum;
FIG. 2 is a drawing showing the preparation of labdane-type diterpene compounds 13 C NMR spectrum;
FIG. 3 is an HR-ESIMS spectrum of a labdane diterpene compound;
FIG. 4 is a drawing of a labdane-type diterpene compound 1 H- 1 H COSY and partial HMBC related information;
FIG. 5 is an ECD spectrum of a labdane-type diterpene compound;
FIG. 6 is a graph showing a cell scratch test of a labdane-type diterpene compound (10. Mu.M).
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
1. Talaromyces amestolkiae30# GDMCC No. 62147 by the following steps:
according to the inventionTalaromyces amestolkiae30#, GDMCC NO. 62147, deposited in the Guangdong province culture Collection of microorganisms (GDMCC).
(1) Seed culture:
fungus of genus Aspergillus glaucoidesTalaromyces amestolkiae30#, GDMCC NO. 62147 into Potato Dextrose Agar (PDA) plate, static culturing at 28 deg.C for 12 days to activate the strain, and then taking about 1.5X 1.5cm 2 The agar block with mycelium was inoculated into Potato Dextrose Broth (PDB) medium and cultured at 28 ℃ and 160rpm for 7 days to obtain a seed culture.
(2) Amplification culture:
the amplification culture medium is a rice solid culture medium: according to the proportion of a single culture medium, a 1000mL triangular flask comprises 100g of rice, 100mL of self-made seawater (2 g of sea salt and 100mL of water), and the pH value is 7.2-7.4.
Culturing the cultured seeds under aseptic conditionsThe culture solution is respectively inoculated in an amplification fermentation solid culture medium, 5mL of seed culture solution is added into each 1000mL conical flask (containing 100g of rice and 100mL of self-made seawater), and 70 bottles are counted. Standing and culturing at 28 deg.C for 28 days to obtain marine fungusTalaromyces amestolkiae30# fermentation product.
2. Preparation of the Compounds
And (2) leaching the fermentation product with chloroform-methanol (volume ratio is 1: 1) for 3 times, concentrating to obtain a chloroform-methanol extract, distributing and extracting the extract with water-ethyl acetate (volume ratio is 1: 1) for 3 times, combining organic phases, and concentrating an ethyl acetate layer to obtain 26.8 g of an ethyl acetate crude extract.
Subjecting the ethyl acetate crude extract to silica gel column chromatography, and performing gradient elution by using petroleum ether-ethyl acetate as an eluent in a volume ratio of 9.
Fraction fr.3 (2.8 g) was collected from petroleum ether/ethyl acetate in a volume ratio of 7, and was subjected to silica gel column chromatography using a chloroform-methanol system in a gradient elution sequence of 1, 0, 50.
Fraction fr.3.4 (0.4 g) was further separated by sephadex LH-20 column chromatography, eluting with pure methanol as eluent, and TLC chromatography was carried out with dichloromethane: methanol = 20 (v/v) developed a labdane-type diterpene compound (13.1 mg) with Rf = 0.5.
3. Structure identification of labdane diterpene compound
1 H-NMR、 13 C-NMR nuclear magnetic resonance spectrograms are measured by a Bruker-Advance 400M nuclear magnetic resonance spectrometer, and Tetramethylsilane (TMS) is taken as an internal standard; HRMS data were measured on a ThermoFisher LTQ Qrbitrap mass spectrometer; the optical rotation data were measured using a JASCO P-1020 digital polarimeter (JASCO, japan) polarimeter; ECD was measured by JASCO-810 ECD spectrometer.
As shown in FIGS. 1 to 4, FIG. 1 is a view of a labdane-type diterpene compound 1 H NMR Spectrum (DMSO-d) 6 ) (ii) a FIG. 2 is a drawing showing the preparation of labdane-type diterpene compounds 13 C NMR Spectrum (DMSO-d) 6 ) (ii) a FIG. 3 is an HR-ESIMS spectrum of a labdane-type diterpene compound; FIG. 4 is a graph of the absolute configuration of a compound determined by comparing experimental and calculated values of an ECD profile; fig. 5 is an ECD spectrum of a labdane-type diterpene compound.
The structure analysis and test of the labdane diterpenoid compound are carried out, the following physicochemical property data are obtained, and the nuclear magnetic data are shown in table 1:
labdane diterpene compound, white powder, HR-ESI-MSm/z 317.1763 [M-H] + ( calcd for C 19 H 26 O 4 , 318.1831)。
Table 1: labdane diterpene compound in DMSO-d 6 In (1) 1 H (400 MHz) and 13 c NMR (100 HMz) data.
The structural formula of the target labdane diterpenoid compound separated by the method is shown as the formula (II):
the formula (II).
Example 2
The in vitro antitumor activity of labdane diterpene compounds was tested.
The human cells tested in this experiment were as follows: human lung cancer cell strain (A549), human prostate cancer cell strain (PC-3) and (VCap).
1. MTT method: the succinate dehydrogenase existing in the mitochondria of the living cells can reduce exogenous yellow thiazole blue MTT (3- (4, 5-dimethylthionazo-2-yl) -2, 5-diphenyltetrazolium bromide) into insoluble blue-purple Formazan (Formazan), the enzyme disappears in dead cells, and the MTT is not reduced. After the formazan is dissolved in dimethyl sulfoxide (DMSO), the Optical Density (OD) can be detected at 570 nm by an enzyme labeling instrument, and the optical density value is in direct proportion to the number of living cells.
2. The test method comprises the following steps: MTT method: taking cells in logarithmic growth phase, digesting, fully blowing to obtain single cell suspension, counting, diluting to 5X 10 4 cells/mL, seeded in 96-well plates at 100. Mu.L/well. The samples to be tested are designed into 4 concentration levels, the positive control is designed into 4 concentration levels, and then 100 mu L of culture medium containing samples with different concentrations are added into the experimental wells and are paralleled to 3 wells. Equal volume of medium was added to the blank. Placing 96 well culture plates at 37 ℃ C. 5% CO 2 After culturing for 72 hours in a saturated humidity incubator, the culture medium was discarded, 100. Mu.L of a freshly prepared serum-free medium containing 0.20 mg/mL MTT was added to each well, and after further culturing for 4 hours at 37 ℃, the supernatant was removed. Add 150. Mu.L DMSO per well to dissolve the Formazan precipitate, and shake on a micro-shaker for 5 minutes to dissolve it sufficiently. The production rate at 570 nm was plotted on a Multiskan FC-type calibrator to obtain a measurement curve from which the half Inhibitory Concentration (IC) of the drug was read 50 ) The value is obtained. The positive control compound was Docetaxel (Docetaxel).
The calculation method comprises the following steps: tumor cell growth inhibition (%) = (blank measurement-sample set measurement/blank measurement) × 100%.
The concentration is used as the abscissa and the cell survival rate is used as the ordinate to draw a cell growth curve, and a two-point method (Reed and Muench method) is applied to calculate the IC of the compound 50 The value is obtained. Three replicates were run per cell line.
TABLE 2 inhibition of tumor cell lines and Normal cells by labdane diterpene Compounds (IC) 50 , μM)
As can be seen from the results in Table 2, the labdane diterpenoid compounds have strong inhibitory activity on human lung cancer cell strains (A549), human prostate cancer cell strains (PC-3) and (VCap), and have low cytotoxicity on RAW 264.7.
3. Cell scratch test (wound healing test)
The cell scratch test is a main test method for testing the cell migration ability in vitro, and the principle is that when the cells are paved on the bottom of a culture dish, a blank area, namely a scratch, is artificially manufactured, and the cells at the edge of the scratch gradually move to the blank area, namely the scratch is healed. The migration ability of the cells can be judged by observing the healing degree of the scratches in different periods, and the specific experimental steps are as follows:
(1) Firstly, drawing three equidistant parallel straight lines on the bottom of a 6-well plate by using a mark pen, then digesting the prostate cancer cells PC-3 and VCaP, centrifuging to prepare single cell suspension, calculating and adjusting the cell density to be 5 multiplied by 10 5 cells/mL; the single cell suspension was seeded in 6-well plates at 2mL per well and then cultured for 24h.
(2) After 24h, the scratch test can be carried out when the cell density is 95% -100% of the bottom of the full-spread pore plate. The tip of 10. Mu.L was aligned with the ruler and perpendicular to the line drawn behind the well plate, where the tip was perpendicular during scoring to draw a uniform line across the cell surface.
(3) After scratching, the old medium was removed, washed three times with PBS and the floating cells removed. Serum-free fresh medium was then added, and drugs were added to the single-dose group and the combination-dose group. 4 sites were randomly selected at 0h of dosing and photographed under a microscope and the photographed sites were recorded. After 24h, pictures were taken at the selected locations at 0h and the distance of cell migration was recorded.
(4) Calculating the moving distance of the cell by using Image J software of the shot photo, and judging the influence of the medicine on the cell migration capacity according to the moving distance of the cell in a specific time, wherein the specific calculation formula is as follows:
as is clear from the experimental results shown in FIG. 6, the cell migration rate was 76%, and the labdane-type diterpene compound (10. Mu.M) of the present invention had the effect of inhibiting the migration of PC-3 cells of human prostate cancer.
The experimental results show that the labdane diterpenoid compound has obviously stronger inhibitory activity on tumor cells, has obviously weaker inhibitory activity on normal cells and has smaller toxicity on the normal cells compared with the tumor cells.
In conclusion, the invention provides lead compound candidates for creating new antitumor drugs, and has important significance for developing Chinese marine biological resources.
Claims (8)
1. A labdane-type diterpenoid compound is characterized by having a labdane-type diterpenoid compound shown as a formula (I):
2. a process for the preparation of a labdane-type diterpene compound of claim 1 characterized in that the labdane-type diterpene compound is prepared and isolated from a secondary metabolite of the marine fungus talaromycesastolkiae # 30; the method comprises the following steps in sequence:
(1) Preparing a fermentation product of a marine fungus Talaromycesamestolkiae No. 30;
(2) Extracting and concentrating the fermentation product prepared in the step (1) by using chloroform and methanol with the volume ratio of 1;
(3) Subjecting the crude extract obtained in the step (2) to silica gel column chromatography, and performing gradient elution by using petroleum ether-ethyl acetate as an eluent in a volume ratio of 9;
(4) Collecting petroleum ether and ethyl acetate in a volume ratio of 7:3, eluting a component Fr.3, continuously performing silica gel column chromatography, and performing gradient elution by using a chloroform-methanol system, wherein the volume ratio is 1; continuously carrying out sephadexLH-20 column chromatography separation on the component Fr.3.4, eluting by using pure methanol as an eluent, and separating and purifying to obtain a labdane diterpenoid compound;
the fermentation culture comprises the following steps:
1) Seed culture
Inoculating mycelium of Talaromycesamestolkiae30# belonging to Aspergillus into potato glucose agar culture medium plate, standing at 28 deg.C for 12 days to activate strain, and collecting about 1.5 × 1.5cm 2 Inoculating agar block with mycelium into potato glucose broth culture medium, and culturing at 28 deg.C and 160rpm for 7 days to obtain seed culture solution;
2) Amplification culture
The amplification culture medium is a rice solid culture medium: according to the proportion of a single culture medium, a 1000mL triangular flask comprises 100g of rice, 100mL of self-made seawater and pH7.2-7.4; under the aseptic operation, respectively inoculating the cultured seed culture solution into an amplification fermentation solid culture medium, adding 5mL of the seed culture solution, and standing and culturing at 28 ℃ for 28 days to obtain a marine fungus Talaromyces amestolkiae30# fermentation product.
3. The method of claim 2, wherein the amplified fermentation solid medium is an amplified fermentation solid medium containing 100g of rice per 1000mL and 100mL of self-made seawater.
4. The method for preparing a labdane diterpenoid compound according to claim 2, wherein the ratio of water to sea salt in the homemade seawater is 100mL:2g of the total weight.
5. Use of the labdane-type diterpene compound or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of an antitumor agent.
6. The use of claim 5, wherein the anti-neoplastic agent is an anti-human lung cancer or human prostate cancer agent.
7. An antitumor agent comprising the labdane-type diterpene compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.
8. The antitumor drug as claimed in claim 7, wherein the antitumor drug is a human lung cancer or human prostate cancer drug.
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