CN108929293B - Preparation method and application of butenolide compound - Google Patents
Preparation method and application of butenolide compound Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, in particular to butenolide compounds, a preparation method thereof and application thereof in type II diabetes and alpha glucosidase inhibitors. The compound is produced by fermenting Aspergillus terreus, has a chemical structure shown in the specification, has strong alpha glucosidase inhibition activity, and provides a new candidate compound for developing a medicament for treating type II diabetes, obesity and complications thereof.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to three butenolide compounds separated and purified from Aspergillus terreus and application thereof in preparing alpha glucosidase inhibitors, II type diabetes drugs and obesity drugs.
Background
Alpha-glucosidase is a hydrolase located at the brush border of the intestinal chorion and is mainly involved in the digestion and absorption of carbohydrates in the body. The main function is to hydrolyze glucosidic bonds to release glucose, and the enzyme is an indispensable enzyme in carbohydrate metabolism pathways of organisms. The alpha-glucosidase inhibitor can effectively inhibit the increase of postprandial blood sugar of patients with type II diabetes, obese overweight people, hyperinsulinemia and the like by competitively inhibiting the alpha-glucosidase on the brush border of the small intestine and delaying the process of converting oligosaccharide or polysaccharide into absorbable monosaccharide, thereby stably and slowly maintaining the blood sugar at a certain level. Alpha-glucosidase inhibitors do not stimulate beta cells to secrete insulin but can reduce postprandial insulin levels, suggesting that they may increase insulin sensitivity. Currently there are mainly three α -glucosidase inhibitors used clinically: acarbose, voglibose and miglitol.
Disclosure of Invention
The invention aims to provide three novel butenolide compounds separated and purified from Aspergillus terreus and application thereof in preparing alpha glucosidase inhibitors, type II diabetes drugs and obesity drugs.
In a first aspect of the invention, three butenolide compounds (-) -aspertetal D, (+) -aspertetal D and aspertetal E are provided, the chemical structures of which are shown in formula (I):
in a second aspect of the present invention, there is provided a process for the preparation of the above butenolide compounds (-) -aspertetal D, (+) -aspertetal D and aspertetal E, said compounds being isolated from the fermentation culture of Aspergillus terreus (Aspergillus terreus).
Preferably, the preparation method comprises the following steps:
a. fermenting, preparing Aspergillus terreus fermentation culture, collecting fermentation broth, filtering with gauze to separate mycelium from the fermentation broth, extracting the fermentation broth with equal volume of ethyl acetate for 3 times, mixing the extracts, and concentrating to obtain ethyl acetate extract part;
b. separating the ethyl acetate extract with Sephadex LH-20 gel column chromatography, and separating with CH2Cl2Eluting with MeOH 1:1 as solvent to obtain components Fr.A-Fr.D; Fr.C is separated by silica gel column chromatography under reduced pressure, eluted with dichloromethane-methanol gradient, combined according to TLC analysis results to obtain components Fr.C1-Fr.C6, Fr.C2 by reversed-phase medium-pressure and reversed-phase semi-preparative high performance liquid (45% acetonitrile water, flow rate 3.0mL/min, detection wavelength 254,210nm) to obtain a pair of racemates, which are separated by hand column (Daicel, Chiralcel OJ-R150X 4.6mm, 45% CH)3CN,0.5mL/min) to yield the compounds (-) -aspertetal D and (+) -aspertetal D; and performing reverse-phase medium-pressure separation on the Fr.D to obtain a component Fr. D1-Fr.D7, and performing reverse-phase semi-preparative high performance liquid separation (42% acetonitrile water, the flow rate is 3.0mL/min, and the detection wavelength is 254,210nm) on the Fr.D to obtain a compound aspertetal E.
Preferably, the method for preparing an Aspergillus terreus (Aspergillus terreus) fermentation culture of step a comprises the steps of: inoculating activated Aspergillus terreus (Aspergillus terreus) into seed culture medium, shaking for 72 hr at 28 deg.C and 220rpm to obtain seed liquid, inoculating the seed liquid into fermentation culture medium at 10% of inoculation amount, shaking for 10 days at 28 deg.C and 220rpm, and obtaining fermentation culture of the strain.
Preferably, the formula of the seed culture medium and the fermentation culture medium is that each liter of the culture medium contains: 20g of mannitol, 20g of maltose and CaCO315g, 10g of glucose, 10g of sodium glutamate, 3g of yeast extract, 1g of corn steep liquor and KH2PO40.5g、MgSO4·7H20.3g of O, 30g of sea salt and 1L of distilled water.
In a third aspect of the present invention, there is provided a use of (-) -aspertetal D, (+) -aspertetal D or aspertetal E, or a pharmaceutically acceptable salt thereof, in the preparation of an α -glucosidase inhibitor, a type ii diabetes drug or an obesity drug.
The invention carries out in-vitro alpha glucosidase inhibition activity evaluation on the obtained butenolide compounds, and the structure shows that the compounds have strong alpha glucosidase inhibition activityIC50The values are respectively 9.98 +/-0.68 mu M,8.65 +/-0.24 mu M and 13.36 +/-0.82 mu M, and the alpha glucosidase inhibitor can be used for preventing and treating type II diabetes, obesity and complications thereof.
In a fourth aspect of the invention, there is provided a class of α -glucosidase inhibitors, type ii diabetes drugs or obesity drugs comprising an effective amount of (-) -aspertetal D, (+) -aspertetal D or aspertetal E, or a pharmaceutically acceptable salt thereof as an active ingredient. The medicine can also comprise a pharmaceutically acceptable carrier.
In a fifth aspect of the invention, there is provided the use of Aspergillus terreus (Aspergillus terreus) in the preparation of butenolide compounds (-) -aspertetal D, (+) -aspeter D or aspeter E represented by formula (I).
Aspergillus terreus (Aspergillus terreus) according to the present invention was purchased from ATCC under number 10690.
The invention has the advantages that:
the compound of the invention shows strong alpha glucosidase inhibition activity, and provides a new candidate compound for developing drugs for treating type II diabetes, obesity and complications thereof.
Drawings
FIG. 1 measured and calculated CD curves for the compounds (-) -aspertetal D and (+) -aspertetal D.
Detailed Description
The following examples are provided to illustrate specific embodiments of the present invention.
EXAMPLE 1 preparation and isolation of Compounds of the invention
1. Preparing extract
(1) Fermentation: inoculating activated Aspergillus terreus (ATCC 10690) into a 250mL triangular flask containing 100mL of seed culture medium, shaking for 72h at 28 ℃ and 220rpm to obtain a seed solution, inoculating the seed solution into a 1L triangular flask containing 500mL of fermentation medium at an inoculation amount of 10%, shaking for 10 days at 28 ℃ and 220rpm in total, and obtaining a fermentation culture of the strain. The formula of the seed culture medium and the fermentation culture medium is that each liter of culture medium contains: sweet taste20g of mannitol, 20g of maltose and CaCO315g, 10g of glucose, 10g of sodium glutamate, 3g of yeast extract, 1g of corn steep liquor and KH2PO40.5g、 MgSO4·7H20.3g of O, 30g of sea salt and 1L of distilled water.
(2) And (3) extraction: collecting fermentation liquid, filtering with gauze to separate mycelium from the fermentation liquid, extracting the fermentation liquid with ethyl acetate of the same volume for 3 times, mixing the extracts, and concentrating to obtain ethyl acetate extract part.
2. Separating and purifying
Separating the ethyl acetate extract with Sephadex LH-20 gel column chromatography, and separating with CH2Cl2MeOH 1:1 as solvent, elution was carried out to give components fr.a-fr.d. Fr.c was separated by reduced pressure silica gel column chromatography using methylene chloride-methanol from 100:0, 100:5, 100:10, 100:20, 100: 50, 0: 100, and according to the results of TLC analysis by thin layer chromatography, combining to obtain components Fr.C1-Fr. C6, Fr.C2, and performing reversed-phase medium-pressure and reversed-phase semi-preparative high performance liquid chromatography (45% acetonitrile water, flow rate of 3.0mL/min, detection wavelength of 254,210nm, retention time t)R30min) to give a pair of racemates, and separating with a manual column (Daicel, Chiralcel OJ-R150X 4.6mm, 45% CH)3CN,0.5mL/min) to yield the novel compound of the invention, (-) -aspertetal D (retention time t)R29min) and (+) -aspertetal D (retention time t)R34 min). Fr.D is separated by reversed phase and medium pressure to obtain components Fr.D1-Fr.D7, Fr.D3 is separated by reversed phase semi-preparative high performance liquid chromatography (42% acetonitrile water, flow rate 3.0mL/min, detection wavelength 254 and 210nm, retention time tR22min) to yield the novel compound aspertetal E.
3. Structural identification
The chemical structure of the compound is determined to be shown in the formula (I) through various modern spectral technologies such as NMR, HRESIMS, IR, UV and the like.
The compounds (-) -aspertetal D and (+) -aspertetal D: a colorless oily substance,
((–)-asperteretal),
(c 0.1MeCN)((+)-asperteretal D)。UV (MeOH)λmax(logε):203(2.6),284(1.8)nm。IR(KBr)νmax:3358,1740,1610,1515, 1438,1386,1262,1181,1036,838cm-1。ECD(MeCN)λmax(Δε)(–)-asperteretal: 210(-18.3),280(-18.5)nm；(+)-asperteretal D:212(+10.2),280(+10.7)nm。 (+)-HRESIMS m/z 381.1714[M+H]+(calcd for C23H25O5,381.1702). The data of the nuclear magnetic resonance spectrum are shown in Table 1.
Compound aspertetal E: a light yellow oily substance,
UV(MeCN)λmax(logε):204(2.5),300(1.6)nm。IR(KBr)νmax:3312,2975,2930,1728,1609,1518, 1497,1388,1257,1235,1158,1120,839cm-1。(+)-HRESIMS m/z 367.1544 [M+H]+(calcd for C22H23O5,367.1545). The data of the nuclear magnetic resonance spectrum are shown in Table 1.
TABLE 1 Hydrogen (600MHz) and carbon (125MHz) spectra data for compounds (. + -.) aspertetal D and aspertetal E
The method for calculating CD by using quantum chemistry determines that the absolute configuration of the compound (-) -aspertetal D is 4-R, the absolute configuration of the compound (+) -aspetal D is 4-S, and the actually measured CD curve and the calculated CD curve of the compounds (-) -aspetal D and (+) -aspetal D are shown in figure 1.
Example 2 alpha glucosidase inhibitory activity assay of compounds of the invention:
experiments on the in vitro inhibition of alpha glucosidase activity were performed on 3 compounds of the invention. The reaction is carried out by adopting a PBS buffer system (0.01M, pH6.8), sequentially adding PBS, 15uL sample (2mM) and 15uL alpha-glucosidase (0.2u/mL) into a 96-well plate, carrying out shaking table reaction at 37 ℃ for 8min, then adding substrate PNPG (20 uL/well) with a certain concentration, carrying out shaking table reaction at 37 ℃ for 15min, and adding 0.2M Na2CO3The reaction was stopped (80 uL/well) and absorbance was measured at 405 nm. In the reaction, acarbose was used as a positive drug control, and a blank control group (no sample), an α -glucosidase control group (no α -glucosidase), and a PNPG control group (no PNPG) were set, each group having 3 parallel wells. Half effective inhibition concentration IC of 3 compounds on alpha glucosidase50The values are shown in Table 2.
TABLE 2 half-effective alpha glucosidase inhibitory concentration IC of the compounds50Value (μ M)
As can be seen from Table 2, 3 compounds, (+) -aspertetal D and aspertetal E, have significant inhibitory activity on α -glucosidase, IC50The values are respectively 9.98 +/-0.68 mu M,8.65 +/-0.24 mu M and 13.36 +/-0.82 mu M, which are superior to positive control acarbose (320 +/-8.3 mu M), the invention provides a new lead compound for developing new type II diabetes mellitus treatment medicaments, and has the potential of being developed into type II diabetes mellitus treatment medicaments as an alpha glucosidase inhibitor.
While the preferred embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that the invention is not limited thereto, and that various changes and modifications may be made without departing from the spirit of the invention, and the scope of the appended claims is to be accorded the full range of equivalents.
Claims (5)
1. Butenolide compounds (-) -aspertetal D, (+) -aspertetal D and aspertetal E, the chemical structure of which is shown in formula (I):
2. a process for the preparation of the butenolide compounds (-) -aspertetal D, (+) -aspeter D and aspeter E according to claim 1, wherein the butenolide compounds are isolated from the fermentation culture of Aspergillus terreus ATCC10690, said process comprising the steps of:
A. preparing extract:
(1) fermentation: inoculating activated aspergillus terreus ATCC10690 into a 250mL triangular flask containing 100mL of seed culture medium, performing shake culture at 28 ℃ and 220rpm for 72h to obtain a seed solution, inoculating the seed solution into a 1L triangular flask containing 500mL of fermentation culture medium by 10% of inoculation amount, performing shake culture at 28 ℃ and 220rpm for 10 days in total, and obtaining a fermentation culture of the strain; the formula of the seed culture medium and the fermentation culture medium is that each liter of culture medium contains: 20g of mannitol, 20g of maltose and CaCO315g, 10g of glucose, 10g of sodium glutamate, 3g of yeast extract, 1g of corn steep liquor and KH2PO4 0.5g、MgSO4·7H20.3g of O, 30g of sea salt and 1L of distilled water; (2) and (3) extraction: collecting fermentation liquor, filtering with gauze to separate mycelium from the fermentation liquor, extracting the fermentation liquor with ethyl acetate of the same volume for 3 times, mixing the extracts, and concentrating to obtain ethyl acetate extract part;
B. separation and purification:
separating the ethyl acetate extract with Sephadex LH-20 gel column chromatography, and separating with CH2Cl2Eluting with MeOH 1:1 as solvent to obtain components Fr.A-Fr.D; fr.c was separated by reduced pressure silica gel column chromatography using methylene chloride-methanol from 100:0, 100:5, 100:10, 100:20, 100: 50,0: 100, and performing gradient elution sequentially according to TLC analysis result to obtain components Fr.C1-Fr.C6, Fr.C2 by reversed phase medium pressure neutralizationReversed phase semi-preparation of high performance liquid phase: 45% acetonitrile water, flow rate of 3.0mL/min, detection wavelength of 254,210nm, retention time tR30min to obtain a pair of racemates, separating with a manual column, Daicel, Chiralcel OJ-R150X 4.6mm, 45% CH3CN,0.5mL/min, to give the compound (-) -aspertetal D, retention time tR29min, and (+) -aspertetal D, retention time tR34 min; and (3) performing reverse phase medium pressure separation on the Fr.D to obtain a component Fr.D1-Fr.D7, and performing reverse phase semi-preparative high performance liquid separation on the Fr.D3: 42% acetonitrile water, flow rate 3.0mL/min, detection wavelengths 254 and 210nm, retention time tR22min to obtain compound aspertetal E.
3. Use of the butenolide compounds (-) -aspertetal D, (+) -aspertetal D or aspertetal E according to claim 1, or a pharmaceutically acceptable salt thereof for the preparation of alpha glucosidase inhibitors, type II diabetes drugs or obesity drugs.
4. An alpha glucosidase inhibitor, a type II diabetes drug or an obesity drug, which comprises an effective amount of the butenolide compound (-) -aspertetal D, (+) -aspertetal D or aspertetal E, or a pharmaceutically acceptable salt thereof as an active ingredient, according to claim 1.
5. Use of aspergillus terreus ATCC10690 for the preparation of the butenolide compound (-) -aspertetal D, (+) -aspeter D or aspeter E according to claim 1.
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| CN111393421B (en) * | 2020-04-07 | 2021-08-31 | 自然资源部第三海洋研究所 | Butenolide derivative and preparation method and application thereof |
| CN116041292A (en) * | 2022-12-20 | 2023-05-02 | 周口师范学院 | Alpha, beta-disubstituted butenolide derivative and preparation method and application thereof |
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| WO2014099415A1 (en) * | 2012-12-20 | 2014-06-26 | Danisco Us Inc. | Method of using alpha-amylase from aspergillus terreus and pullulanase for saccharification |
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