CN115385878B - Natural active compound moenofuran and preparation method and application thereof - Google Patents

Natural active compound moenofuran and preparation method and application thereof Download PDF

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CN115385878B
CN115385878B CN202210820329.7A CN202210820329A CN115385878B CN 115385878 B CN115385878 B CN 115385878B CN 202210820329 A CN202210820329 A CN 202210820329A CN 115385878 B CN115385878 B CN 115385878B
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CN115385878A (en
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蒋永俊
田雨红
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Zhejiang Ocean University ZJOU
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    • A—HUMAN NECESSITIES
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Abstract

The invention relates to the technical field of natural medicine and medicine, and discloses natural active compound moenofuran prepared from moenothera biennis, and preparation and application thereof. The invention firstly separates and obtains the nocardiopsis ZHD001 from the sediment collected in the sea area around the boat and the mountain, and further separates and researches the fermentation product nocardiopsis ZHD001. The invention determines the chemical structure of the new compound moenofuran by analyzing the high-resolution mass spectrum HRESIMS, hydrogen spectrum, carbon spectrum, HMQC spectrum and HMBC spectrum of the moenofuran. A series of researches show that the moenofuran can remarkably accumulate lipid in a HepG2 cell lipid model, has the biological activity of reducing blood fat, can be used for preparing blood fat-reducing medicines or blood fat-reducing health-care foods, and has good development and application prospects.

Description

Natural active compound moenofuran and preparation method and application thereof
Technical Field
The invention belongs to the technical field of natural medicine and medicine, and particularly relates to a natural active compound moenofuran, and a preparation method and application thereof.
Background
The incidence and mortality of cardiovascular disease is still in the ascending phase. Cardiovascular disease burden is becoming more and more severe and has become a major public health problem. It has been confirmed that hyperlipidemia is one of the major factors responsible for cardiovascular disease, and reducing blood lipid levels significantly improves the quality of life of patients suffering from cardiovascular disease and effectively reduces the incidence of cardiovascular disease.
At present, statin drugs are the first drugs clinically used for treating hyperlipidemia, but long-term administration of statin drugs can cause toxic and side effects such as blood sugar rise, muscular soreness, rhabdomyolysis, hepatorenal toxicity and the like in a significant part of patients. Therefore, the novel safe and effective hypolipidemic drug has important application value. Natural products are an important source of new drugs, while marine organisms are far more diverse than land, 80% of organisms on earth are in the ocean, and the abundant biodiversity is equal to the abundant chemical structure diversity. Thus the ocean will likely become the main battlefield for new drug discovery.
The marine organism medicine is extracted from marine animals and plants, and the marine animals and the marine organisms are abundant in the sea, so that not only are a large number of foods provided for human beings, but also a large number of medicines are provided for the human beings, and the marine medicine has the advantages of remarkable curative effect, low price and unique effect, so that the research of the marine medicine has very important significance. And marine microbial natural products are an important source of marine pharmaceuticals. Marine actinomycetes as an important component of marine microorganisms provide a rich lead compound for the development of marine pharmaceuticals, such as the proteasome inhibitor NPI-0052 derived from marine actinomycetes Salinispora tropica CNB-392, which has been approved by the FDA as an orphan for the treatment of multiple myeloma. The secondary metabolite of marine actinomycetes has rich structure types, mainly polyketides, polyethers, quinones, alkaloids, macrolides, peptides and the like.
Therefore, the invention takes nocardia pseudolaris as a research object to search for novel compounds with hypolipidemic activity and a preparation method thereof.
Disclosure of Invention
In order to provide a marine natural active compound with blood lipid reducing effect, the invention provides a new compound, namely, moenofuran prepared from moenosis, as well as a preparation method and application thereof. The novel pseudo-norfuran compound which is a marine microorganism source can obviously inhibit lipid accumulation in a HepG2 cell lipid model, and is used for preparing hypolipidemic drugs or hypolipidemic health-care foods.
The specific scheme of the invention is as follows:
in one aspect, the invention provides a compound, moenofuran, the chemical structure of which is determined by analyzing the high resolution mass spectrum HRESIMS, hydrogen spectrum, carbon spectrum, HMQC spectrum and HMBC spectrum of the moenofuran. The chemical structural formula is as follows:
the compound provided by the invention is quasi-norfuran as a new compound. A series of researches show that the moenofuran can remarkably accumulate lipid in a lipid model of HepG2 cells and has the biological activity of reducing blood fat. The invention provides a novel compound which can be applied to the preparation of hypolipidemic drugs.
In another aspect, the invention provides a method for preparing the compound moenofuran. The preparation method of the moenofuran comprises the following steps: (1) Fermenting nocardia in a liquid culture medium to obtain a fermentation liquor containing a compound nocarpus; (2) Extracting the fermentation liquor by an organic solvent to obtain an organic extracting solution; (3) Concentrating the organic extract, separating and purifying to obtain the moenofuran.
The Nocardia is named ZHD001 and is preserved in China Center for Type Culture Collection (CCTCC) in 2022, wherein the microorganism preservation number is CCTCC NO: m2022921 the microorganism classification is designated Nocardiopsis sp. The strain is isolated from sediment collected in the sea area around the boat and the mountain for the first time by the applicant, and no public literature is reported on the strain at present. The applicant found through research that strain ZHD001 has excellent inhibitory activity on lipid accumulation of HepG2 cells after fermentation, and strain ZHD001 has blood lipid lowering biological activity. Further studies have shown that strain ZHD001 produces the previously described compound moenofuran after fermentation.
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 a high-first liquid culture medium.
Preferably, in the step (2), the organic solvent is an ester organic solvent. Further preferably, the organic solvent is ethyl acetate.
Specifically, the organic extract concentration method described in step (3) is preferably: part of the solvent was removed by drying under reduced pressure.
Specifically, the separation and purification steps in the step (3) are 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 moenofuran; (b) The obtained components are separated and purified by adopting a preparative high performance liquid chromatography to obtain the moenofuran, and the preparative high performance liquid chromatography separation method comprises the following steps: the Agilent pursis C18 chromatographic column 21.2X105 mm,10 μm, detection wavelength 210nm, gradient elution with methanol-water system of 20-100% volume percentage, and collecting the eluent for 24.2-25.3 min. Preferably, in the step (a), the gradient of the mixed solvent of dichloromethane and methanol is 80-100:1, 40-70:1, 25-35:1, 15-20:1, 8-12:1, 4-7:1, 1-3:1 and 0-0.5:1.
The novel compound moenofuran has the following effects:
(1) In order to further test the biological activity of the moenofuran obtained by separation, the lipid-lowering activity of the HepG2 cell is evaluated in vitro. Experiments show that the simulated norfuran obtained by separation of the invention can remarkably accumulate lipid in a HepG2 cell lipid model and has the biological activity of reducing blood fat.
(2) The reduction of the blood lipid level can obviously improve the life quality of patients with cardiovascular diseases and effectively reduce the incidence rate of the cardiovascular diseases, and the moenofuran can be used for preparing blood lipid-lowering medicaments or blood lipid-lowering health-care foods and is a human health assistance.
(3) The moenofuran is a new natural product compound with hypolipidemic activity, and has important application value for discovering safe and effective novel hypolipidemic drugs.
Drawings
FIG. 1 is a high resolution mass spectrum of moenofuran;
FIG. 2 is a hydrogen diagram of a moenofuran;
FIG. 3 is a carbon diagram of a moenofuran;
FIG. 4 is a HSQC diagram of moenofuran;
FIG. 5 is an HMBC diagram of normimetic furan;
fig. 6 is data from the blood lipid lowering activity of moenofuran.
Detailed Description
The invention is further described below with reference to examples.
Example 1
1. Acquisition of strain ZHD001 nocardia mimetic strain ZHD001 was isolated from sediment collected in the sea area surrounding the boat mountain. The microbial preparation is preserved in China Center for Type Culture Collection (CCTCC) in 2022, 06 and 20 days, and the microbial preparation number is CCTCC NO: m2022921 the microorganism classification is designated Nocardiopsis sp.
2. Preparation of Nocardiopsis sp.ZHD001 fermentation broth
Taking a proper amount of nocardia pseudolaris strain ZHD, inoculating to a solid culture medium of Gao's No. one, standing in a 37 ℃ incubator, and performing activation culture for 5 days. Single colonies of the activated Nocardia mimetic strain ZHD001 were inoculated into 500mL Erlenmeyer flasks, each containing 250mL of liquid medium of Gao's first type, and cultured in shaking table at 28℃for 10 days with shaking at 180rpm, to obtain fermentation broth. The formula of the solid culture medium of Gaoshi No. 1 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 liquid culture medium of Gaoshi No. 1 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 moenofuran
The fermentation broth was extracted 3 times with an equal volume of ethyl acetate, and the ethyl acetate solvent was removed by distillation under reduced pressure using a rotary evaporator to obtain a concentrated solution. Separating the obtained concentrated solution by silica gel column chromatography, gradient eluting with mixed solvents of dichloromethane and methanol with mixing gradient of 100:1, 80:1, 50:1, 30:1, 20:1, 10:1,5:1,1:1 and 0:1, collecting eluate, detecting each component by thin layer chromatography, and combining the components containing moenofuran.
The obtained fraction containing the moenofuran is separated and purified by a preparative Shimadzu LC-20AP high performance liquid chromatograph, an Agilent purset C18 chromatographic column is 21.2x250 mm, the detection wavelength is 210nm, a methanol-water system with the volume percentage of 20% -100% is adopted, gradient elution is carried out for 40 minutes at 10mL/min, and the eluent with the volume percentage of 24.2-25.3 minutes is collected to obtain the compound moenofuran.
4. Structure confirmation of moenofuran
Pseudo-norfuran, yellow oil, 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 The high resolution mass spectrum of the moenofuran is shown in figure 1. As shown in fig. 2 to 5, the hydrogen spectrum, the carbon spectrum, the HMQC spectrum and the HMBC spectrum of the moenofuran are respectively, and the chemical structure of the natural active compound moenofuran is determined as a new compound by analyzing the data of the spectra.
The nuclear magnetic resonance data for moenofuran are shown in Table 1.
TABLE 1 Norofuran mimetic 13 C (150 MHz) and 1 h (600 MHz) NMR data (deuterated methanol-d as solvent) 4 )
The chemical structure of the natural active compound moenofuran is as follows:
4. hypolipidemic activity of moenofurans
HepG2 cells were cultured in DMEM medium containing 10% Fetal Bovine Serum (FBS) at 37℃with a volume fraction of 5% CO 2 Cells were digested with 0.25% trypsin every 3 days, passaged 1:3, cells were suspended in log phase, plated in 24 well plates, incubated for 24h, and the experiments were divided into 4 groups: (1) blank control group: culturing in DMEM medium containing 10% FBS for 24 hr; (2) model group: culturing in DMEM medium containing 1mM oleic acid for 24 hours; (3) positive control group: 1mM oleic acid and simvastatin (10. Mu.M) in DMEM medium for 24h; (4) sample group: 1mM oleic acid and moenofuran (10. Mu.M) in DMEM medium for 24h.
The culture solution is removed from each group, the PBS is washed 3 times, after 80 mu L of 4% paraformaldehyde is added into each hole for fixing for 40min, the PBS is washed 3 times, after the mixture is treated by 60% isopropanol/water for 10 min, 50 mu L of oil red working solution (the working solution is prepared by 0.3g/100mL of oil red/isopropanol mother solution and water volume ratio of 3:2) is added for 20min, the oil red working solution is removed, the PBS is washed 3 times, and the intracellular lipid drop staining condition is observed by an inverted microscope. After dissolving the stained lipid droplets with 80. Mu.L of isopropanol, the OD was measured at a wavelength of 520nm in an ELISA reader. The experimental results are shown in fig. 6 (compared with the model group, p <0.001; < 0.001;). The results show that the moenofuran can significantly inhibit 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 unless specified otherwise; the methods used in the present invention are conventional in the art unless otherwise specified.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and any simple modification, variation and equivalent transformation of the above embodiment according to the technical substance of the present invention still fall within the scope of the technical solution of the present invention.

Claims (10)

1. A natural active compound moenofuran, which is characterized by the chemical structural formula:
2. use of the natural active compound moenofuran according to claim 1 for the preparation of a hypolipidemic medicament.
3. A process for the preparation of the natural active compound moenofuran as claimed in claim 1, characterized in that it comprises the following steps:
(1) Inoculating a nocardia pseudolaris strain into a liquid culture medium for fermentation to obtain a fermentation liquor containing a compound nocarpus pseudolaris; the Nocardia pseudonymph ZHD001 is preserved in China center for type culture Collection (China center for type culture Collection) in 2022, and the microorganism preservation number is CCTCC NO: m2022921, microorganism classification designated Nocardiopsis sp;
(2) Extracting the fermentation liquor by an organic solvent to obtain an organic extracting solution;
(3) Concentrating the organic extract, separating and purifying to obtain the moenofuran.
4. The method according to claim 3, 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 moenofuran;
(b) The obtained components are separated and purified by adopting a preparative high performance liquid chromatography to obtain the moenofuran, and the preparative high performance liquid chromatography separation method comprises the following steps: adopting Agilent pursis C18 chromatographic column 21.2mm×250mm×10μm, and adopting methanol-water system gradient elution with volume percentage of 20-100%; collecting the eluent for 24.2-25.3 min; the detection wavelength was 210nm.
5. The process of claim 4, wherein in step (a), the gradient of the mixed solvent of dichloromethane and methanol is 80-100:1, 40-70:1, 25-35:1, 15-20:1, 8-12:1, 4-7:1, 1-3:1 and 0-0.5:1.
6. The process according to claim 3, wherein in the step (1), the fermentation is carried out at a temperature of 28 to 32 ℃.
7. The method according to claim 3, wherein in the step (1), the fermentation time is 10 to 12 days.
8. The method according to claim 3, wherein in the step (2), the organic solvent is an ester-type organic solvent.
9. The method of claim 8, wherein the organic solvent is ethyl acetate.
10. The method according to claim 3, wherein in the step (3), the concentration of the organic extract is performed by drying under reduced pressure.
CN202210820329.7A 2022-07-12 2022-07-12 Natural active compound moenofuran and preparation method and application thereof Active CN115385878B (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101074234A (en) * 2007-03-30 2007-11-21 云南大学 Antitumor antibiotics and its production
CN101942406A (en) * 2010-08-12 2011-01-12 淮海工学院 Marine nocardiopsissp.HY-G and beta-glucosidase produced by same
CN102822154A (en) * 2009-12-07 2012-12-12 味之素株式会社 Heteroarylcarboxylic acid ester derivative
CN104877929A (en) * 2014-12-30 2015-09-02 中国科学院新疆生态与地理研究所 Nocardiopsis for producing ansamycin P-3 and 15-hydroxyl derivatives as well as preparation method and application of nocardiopsis
CN114081103A (en) * 2021-11-25 2022-02-25 福建汇盛生物科技有限公司 Preparation process and device of composite cellulase preparation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020133009A1 (en) * 2001-03-13 2002-09-19 Lambrou George N. Method for opening potassium channels

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101074234A (en) * 2007-03-30 2007-11-21 云南大学 Antitumor antibiotics and its production
CN102822154A (en) * 2009-12-07 2012-12-12 味之素株式会社 Heteroarylcarboxylic acid ester derivative
CN101942406A (en) * 2010-08-12 2011-01-12 淮海工学院 Marine nocardiopsissp.HY-G and beta-glucosidase produced by same
CN104877929A (en) * 2014-12-30 2015-09-02 中国科学院新疆生态与地理研究所 Nocardiopsis for producing ansamycin P-3 and 15-hydroxyl derivatives as well as preparation method and application of nocardiopsis
CN114081103A (en) * 2021-11-25 2022-02-25 福建汇盛生物科技有限公司 Preparation process and device of composite cellulase preparation

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