CN115584330A - Nocardiopsis, compound Novofuran and preparation method and application thereof - Google Patents

Nocardiopsis, compound Novofuran and preparation method and application thereof Download PDF

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CN115584330A
CN115584330A CN202210818662.4A CN202210818662A CN115584330A CN 115584330 A CN115584330 A CN 115584330A CN 202210818662 A CN202210818662 A CN 202210818662A CN 115584330 A CN115584330 A CN 115584330A
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nocardiopsis
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蒋永俊
田雨红
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Zhejiang Ocean University ZJOU
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Abstract

The invention relates to the technical field of natural medicine and medicine, and discloses a new compound norfuran prepared from nocardiopsis, a preparation method and application thereof. The Nocardiopsis ZHD is separated and obtained from sediments collected from the sea area around the Zhoushan for the first time, and the Nocardiopsis ZHD is further separated and researched to obtain the fermentation product Nocardiopsis of the Nocardiopsis ZHD001. The chemical structure of the new compound norofuran is determined by analyzing data of a high-resolution mass spectrum HRESIMS, a hydrogen spectrum, a carbon spectrum, an HMQC spectrum, an HMBC spectrum and a COSY spectrum of the norofuran. A series of researches show that the dinofuran can obviously accumulate lipid in a HepG2 cell lipid model, has the biological activity of reducing blood fat, can be used for preparing medicines for reducing blood fat or health-care food for reducing blood fat, and has good development and application prospects.

Description

Nocardiopsis, compound Novofuran and preparation method and application thereof
Technical Field
The invention belongs to the technical field of natural medicine and medicine, and particularly relates to nocardiopsis, a compound nocfuran, and preparation methods and applications thereof.
Background
The incidence and mortality of cardiovascular disease is still at an elevated stage. The cardiovascular disease burden is becoming more and more severe and has become a significant public health problem. Research has proved that hyperlipidemia is one of the major factors causing cardiovascular diseases, and reducing the blood lipid level can significantly improve the quality of life of patients with cardiovascular diseases and effectively reduce the incidence of cardiovascular diseases.
At present, statins are the first choice drugs for clinically treating hyperlipidemia, but long-term administration of statins can cause a considerable part of patients to have toxic and side effects such as blood sugar rise, muscle soreness, rhabdomyolysis, liver and kidney toxicity, and the like. Therefore, the discovery of a safe and effective novel hypolipidemic drug has important application value. Natural products are an important source of new drugs, and the diversity of marine organisms is far higher than that of land, and 80% of organisms on the earth exist in the sea, and the abundant biodiversity is equal to the abundant chemical structure diversity. The ocean will likely step up into the main battlefield for new drug discovery.
The marine organism medicament is a medicament extracted from marine animals and plants, the abundant marine animals and plants in the sea not only provide a large amount of food for human beings, but also provide a plurality of medicaments for human beings, and a plurality of marine medicaments have obvious curative effect, low price and unique effect, so the research on the marine medicaments has very important significance. And the natural products of marine microorganisms are important sources of marine medicines. Marine actinomycetes are an important component of marine microorganisms, and provide abundant lead compounds for the development of marine drugs, such as a proteasome inhibitor NPI-0052 derived from marine actinomycetes Salinippora tropica CNB-392, which has been approved by the FDA as an orphan drug for the treatment of multiple myeloma. The secondary metabolites of marine actinomycetes have rich structure types, and mainly comprise polyketides, polyethers, quinones, alkaloids, macrolides, peptides and the like.
Therefore, the invention takes Nocardiopsis as a research object to search a novel compound with the activity of reducing blood fat and a preparation method thereof.
Disclosure of Invention
In order to provide a marine natural active compound with the function of reducing blood fat, the invention provides a new compound norofuran prepared from nocardiopsis, a preparation method and application thereof. The dinofuran provided by the invention is a new compound derived from marine microorganisms, can obviously inhibit lipid accumulation in a HepG2 cell lipid model, and is used for preparing a blood fat reducing medicine or a health food for reducing blood fat.
The specific scheme of the invention is as follows:
on one hand, the invention provides a compound norofuran, and the chemical structure of the compound norofuran is determined by analyzing data of a high-resolution mass spectrum HRESIMS, a hydrogen spectrum, a carbon spectrum, an HMQC spectrum, an HMBC spectrum and a COSY spectrum of the norofuran. The chemical structural formula is as follows:
Figure BDA0003741820780000021
the compound provided by the invention is a new compound. A series of researches show that the dinofuran can obviously accumulate lipid in a HepG2 cell lipid model and has the biological activity of reducing blood fat. The invention provides a novel compound which can be applied to the preparation of a blood fat reducing medicine.
In another aspect, the invention provides a nocardiopsis, named as ZHD, which has been preserved in the chinese type culture collection at 20/06/2022, with the microorganism preservation number of CCTCC NO: m2022921, microbial classification named Nocardia pseudonocardiopsis sp.
The strain is separated from sediments collected from the sea area around the Zhoushan for the first time by the applicant, and no published documents report the strain at present. The applicant finds that the strain ZHD001 has excellent inhibitory activity on lipid accumulation of HepG2 cells after fermentation through research, and confirms that the strain ZHD001 has biological activity of reducing blood fat. Further studies confirmed that strain ZHD produces the aforementioned compound, norofuran, upon fermentation.
In addition, the invention provides a preparation method of the new compound of the paranorfuran. The preparation method of the paranorfuran comprises the following steps: (1) Fermenting in a liquid culture medium by using a strain ZHD001 to obtain a fermentation liquid containing a compound norofuran; (2) Extracting the fermentation liquor by using an organic solvent to obtain an organic extracting solution; (3) And concentrating the organic extracting solution, separating and purifying to obtain the paranorfuran.
Preferably, the fermentation conditions in step (1) are: the fermentation medium is a liquid medium; the fermentation temperature is 28-32 ℃; the fermentation time is 10-12 days. The liquid culture medium is preferably Gao's No. one liquid culture medium.
Preferably, in the step (2), the organic solvent is an ester organic solvent. More preferably, the organic solvent is ethyl acetate.
Specifically, the organic extract concentrating method described in the step (3) is preferably: drying under vacuum or reduced pressure to remove part of the solvent.
Specifically, the separation and purification step in the step (3) is as follows: (a) Separating the concentrated product by silica gel column chromatography, gradient eluting with mixed solvent of dichloromethane and methanol, collecting eluate, detecting each component, and mixing the components containing dinofuran; (b) Separating and purifying the obtained components by adopting preparative high performance liquid chromatography to obtain the paranoid furan, wherein the preparative high performance liquid chromatography separation method comprises the following steps: adopting an Agilent pursuit C18 chromatographic column of 21.2 multiplied by 250mm and 10 mu m, the detection wavelength is 210nm, adopting an acetonitrile-water system with the volume percentage of 10-20 percent, and carrying out isocratic elution at 10 mL/min; collecting the eluent for 32.2-33.5 minutes. Preferably, in step (a), the dichloromethane and methanol mixed solvent gradient is from 95 to 110.
The novel compound of the invention, namely the paranorfuran, has the following effects:
(1) In order to further test the biological activity of the separated norofuran, a HepG2 cell lipid model is adopted to evaluate the in-vitro blood lipid reducing activity. Experiments show that the dinofuran obtained by separation can obviously accumulate lipid in a HepG2 cell lipid model and has the biological activity of reducing blood fat.
(2) The reduction of the blood fat level can obviously improve the life quality of patients with cardiovascular diseases and effectively reduce the incidence rate of the cardiovascular diseases, and the dinofuran can be used for preparing medicines for reducing the blood fat or health-care food for reducing the blood fat, and is helpful for human health.
(3) The dinofuran is a natural product new compound with the activity of reducing blood fat, and has important application value for finding safe and effective novel blood fat reducing drugs.
Drawings
FIG. 1 is a high resolution mass spectrum of a dinofuran;
FIG. 2 is a hydrogen diagram of norofuran;
FIG. 3 is a carbon diagram of a dinofuran;
FIG. 4 is a HSQC plot of norofuran;
FIG. 5 is a HMBC plot of norofuran;
FIG. 6 is a COSY plot of norofuran;
fig. 7 is test data of hypolipidemic activity of paranorfuran.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
1. Acquisition of Strain ZHD001
Nocardiopsis strain ZHD001 is obtained by separating sediments collected from the perinavicular sea area. The culture is preserved in China center for type culture Collection at 20/2022, 06/20, with the preservation address: wuhan, china, the preservation number of the microorganisms is CCTCC NO: m2022921, microbial classification named Nocardia pseudonocardiopsis sp.
2. Preparation of Nocardia pseudonana Nocardiaopsis sp.ZHD001 fermentation broth
Taking a proper amount of Nocardiopsis strain ZHD, inoculating the Nocardiopsis strain on a Gao's No. one solid culture medium, then placing the Nocardiopsis strain in an incubator at 37 ℃, standing, and performing activated culture for 3 days. A single colony of activated Nocardiopsis strain ZHD001 was inoculated in a 500mL conical flask containing 250mL of the first Gao's liquid medium per flask, and cultured with shaking at 180rpm in a shaker at 28 ℃ for 10 days to obtain a fermentation broth. The formula of the solid culture medium of Gao's I is as follows: 20g of soluble starch, 1g of potassium nitrate, 0.5g of dipotassium hydrogen phosphate, 0.5g of magnesium sulfate, 0.01g of ferrous sulfate, 20g of agar, 25g of sea salt and 1L of water. The formula of the adopted Gao's No. one liquid culture medium is as follows: 20g of soluble starch, 1g of potassium nitrate, 0.5g of dipotassium hydrogen phosphate, 0.5g of magnesium sulfate, 0.01g of ferrous sulfate, 25g of sea salt and 1L of water.
3. Preparation of dinofuran
Extracting the fermentation liquor with ethyl acetate of the same volume for 3 times, and distilling the obtained ethyl acetate extract liquor by a rotary evaporator under reduced pressure to remove the ethyl acetate solvent to obtain concentrated liquor. The resulting concentrate was chromatographed on silica gel, eluting with a mixed solvent gradient of dichloromethane and methanol of mixed gradient 100, 1, 50.
And separating and purifying the obtained fraction containing the new compound by using a preparative Shimadzu LC-20AP high performance liquid chromatograph, using an Agilent pursuit C18 chromatographic column with the size of 21.2 multiplied by 250mm and the detection wavelength of 10 μm, adopting an acetonitrile-water system with the volume percentage of 15 percent, carrying out isocratic elution at the rate of 10mL/min, and collecting the eluent for 32.2-33.5 minutes to obtain the active compound pseudonorfuran.
4. Confirmation of Novofuran structure
Dinofuran, a pale yellow powder, dissolved in methanol. Molecular formula is calculated as C according to high resolution mass spectrum HRESIMS 16 H 22 O 7 ([M + Na] + 349.1264 And the high-resolution mass spectrum of the pseudonorfuran is shown in figure 1. As shown in fig. 2 to fig. 6, the hydrogen spectrum, the carbon spectrum, the HMQC spectrum, the HMBC spectrum and the COSY spectrum of the norofuran are respectively shown, and the chemical structure of the norofuran is determined by analyzing the data of the spectrums, and the norofuran is a new compound.
The nuclear magnetic resonance data of the paranorfuran are shown in table 1.
TABLE 1 method for producing norfuran 13 C (150 MHz) and 1 h (600 MHz) NMR data (solvent is deuterated methanol-d 4 )
Figure BDA0003741820780000041
The chemical structure of the dinofuran is as follows:
Figure BDA0003741820780000051
4. hypolipidemic activity of norofuran
HepG2 cells were treated with 10% Fetal Bovine Serum (FBS) -containing DMEM medium at 37 ℃ with a volume fraction of 5% CO 2 The cells were digested with 0.25% trypsin every 3 days, passaged at 1:3, and the cells in log phase were made into suspension, inoculated in a 24-well plate, incubated for 24h, and then divided into 4 groups: (1) blank control group: DMEM medium containing 10% FBS for 24h; (2) model group: culturing for 24 hours in DMEM medium containing 1mM oleic acid; (3) positive control group: 1mM oleic acid and simvastatin (10 μ M) in DMEM medium for 24h; (4) sample group: DMEM medium with 1mM oleic acid and paranorfuran (10. Mu.M) was cultured for 24h.
Removing culture solution from each group, washing with PBS for 3 times, adding 80 μ L of 4% paraformaldehyde into each well, fixing for 40min, washing with PBS for 3 times, treating with 60% isopropanol/water for 10 min, adding 50 μ L of oil red working solution (prepared from 0.3 g/100mL of mother solution of oil red/isopropanol to water at a volume ratio of 3:2) for 20min, removing the oil red working solution, washing with PBS for 3 times, and observing intracellular lipid drop staining condition with an inverted microscope. After the stained lipid droplets were dissolved in 80. Mu.L of isopropyl alcohol, OD was measured at a wavelength of 520nm using a microplate reader. The experimental results are shown in figure 7 (p < 0.001;. P <0.01, compared to the model group). The results show that the norofuran can obviously inhibit the lipid accumulation of the HepG2 lipid model.
The raw materials and equipment used in the invention are common raw materials and equipment in the field if not specified; the methods used in the present invention are conventional in the art unless otherwise specified.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, alterations and equivalents of the above embodiments according to the technical spirit of the present invention are still within the protection scope of the technical solution of the present invention.

Claims (10)

1. The Nocardiopsis is named as ZHD and is preserved in the China center for type culture Collection at 20/06/2022, and the preservation number of the microorganism is CCTCC NO: m2022921, microbial classification named Nocardia pseudonocardiopsis sp.
2. A compound norofuran secreted by the nocardiopsis of claim 1, having the chemical formula:
Figure FDA0003741820770000011
3. the use of the compound pseudonorfuran of claim 2 in the preparation of a hypolipidemic medicament.
4. A process for the preparation of the compound pseudonorfuran of claim 2, comprising the steps of:
(1) Inoculating the nocardiopsis sp strain as defined in claim 1 into a liquid culture medium for fermentation to obtain a fermentation liquid containing a compound nocfuran;
(2) Extracting the fermentation liquor by using an organic solvent to obtain an organic extracting solution;
(3) And concentrating the organic extracting solution, separating and purifying to obtain the paranoin.
5. The method according to claim 4, wherein in the step (1), the fermentation conditions are: the fermentation temperature is 28-32 ℃; the fermentation time is 10-12 days.
6. The method according to claim 4, wherein in the step (2), the organic solvent is an ester organic solvent.
7. The method according to claim 6, wherein the organic solvent is ethyl acetate.
8. The method according to claim 4, wherein the organic extract is concentrated in step (3) by removing a part of the solvent by drying under reduced pressure.
9. The method according to claim 4, wherein in the step (3), the separation and purification step comprises:
(a) Separating the concentrated product by silica gel column chromatography, gradient eluting with mixed solvent of dichloromethane and methanol, collecting eluate, detecting each component, and mixing the components containing dinofuran;
(b) Separating and purifying the obtained components by adopting preparative high performance liquid chromatography to obtain the paranoid furan, wherein the preparative high performance liquid chromatography separation method comprises the following steps: adopting an Agilent pursuit C18 chromatographic column with the size of 21.2mm multiplied by 250mm multiplied by 10 mu m, and adopting acetonitrile-water system with the volume percentage of 10-20 percent to carry out isocratic elution; collecting the eluent for 32.2-33.5 minutes; the detection wavelength was 210nm.
10. The preparation method according to claim 9, wherein in step (a), the dichloromethane and methanol mixed solvent gradient is from 95 to 110.
CN202210818662.4A 2022-07-12 2022-07-12 Nocardiopsis, compound Novofuran and preparation method and application thereof Pending CN115584330A (en)

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