CN108558817A - A kind of isocoumarin analog derivative and its preparation method and application - Google Patents
A kind of isocoumarin analog derivative and its preparation method and application Download PDFInfo
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- CN108558817A CN108558817A CN201810288455.6A CN201810288455A CN108558817A CN 108558817 A CN108558817 A CN 108558817A CN 201810288455 A CN201810288455 A CN 201810288455A CN 108558817 A CN108558817 A CN 108558817A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
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- A61P39/06—Free radical scavengers or antioxidants
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention discloses a kind of isocoumarin analog derivative and its preparation method and application, feature is the structural formula of the isocoumarin analog derivative as shown in I, and it is CCTCC No that preparation methods steps, which include by preserving number,:The marine fungi fermented and cultured of M2014086 obtains the fermentate containing isocoumarin analog derivative, then methanol is added and impregnates ultrasound filtration, it is evaporated, it is evaporated after being extracted with ethyl acetate again, obtain coarse extract, by the extract through depressurizing silica gel column chromatography, reverse phase medium pressure column chromatography, last half preparative high-performance liquid chromatographic of reverse phase isolates and purifies to obtain, the isocoumarin analog derivative has antioxidation, advantage, which is compound I, has Scavenging ability, is possibly used for the morbidity of delay Alzheimer disease and helps to alleviate its symptom.
Description
Technical field
The present invention relates to a kind of isocoumarin analog derivatives, more particularly, to a kind of isocoumarin analog derivative and its preparation
Method and purposes.
Background technology
There is isocoumarin analog derivative anticancer, antibacterial, protease to inhibit and physiology and the bioactivity such as anti-oxidant.This hair
A person of good sense is total to epiphytic fungi to spongeAspergillus ustus（It is preserved in China typical culture collection center, deposit number
For：CCTCC No: M2014086）The ethyl acetate extract of solid fermentation has carried out anti-oxidant experiment, it is found that it is anti-oxidant it has
Activity then studies its active constituent, a kind of isolated new isocoumarin analog derivative.Have not yet to see this
The chemical constitution of compound and its report of antioxidant activity, therefore in the market also there is not yet drug related to this.
Invention content
Technical problem to be solved by the invention is to provide a kind of isocoumarin analog derivative with antioxidant activity and
Preparation method and use.
Technical solution is used by the present invention solves above-mentioned technical problem：A kind of isocoumarin analog derivative, an unusually sweet smell
The structural formula of legumin analog derivative is as shown in I：
（I）.
The preparation method of above-mentioned isocoumarin analog derivative, specifically comprises the following steps：
（1）Fermenting and producing：It is CCTCC No by preserving number:The aspergillus ustus of M2014086（Aspergillus ustus）Scribing line
It brings back to life, then chooses a single bacterium colony and be inoculated into PDB fluid nutrient mediums, under the conditions of 28 DEG C, 150rpm, conduct after culture 5 days
Seed liquor；The ratio of seed liquor 5-20% by volume is inoculated into rice medium again, in 28 DEG C, is left to ferment 30 days；
（2）The acquisition of coarse extract：Methanol is added into the conical flask after fermentation, by solid immersion, ultrasound 15 minutes is stood overnight
Afterwards, methanol extract liquid filtered through gauze is removed into solid residue；Solid residue is repeated after extracting 3-5 times, by methanol extract liquid
It is evaporated removing methanol after merging, then uses water dissolution, adds and repeats extraction 5 times with the isometric ethyl acetate of aqueous solution, close
And be concentrated under reduced pressure after extract liquor and remove ethyl acetate, obtain coarse extract；
（3）Compound isolates and purifies：After coarse extract dichloromethane and methanol mixed solvent dissolving, add 200-300 mesh silicon
Glue mixes sample, uses volume ratio for 2:1 petrol ether/ethyl acetate is eluant, eluent, and decompression silica gel column chromatography is carried out to coarse extract, is received
Collect elution fraction；It uses dichloromethane and methanol mixed solvent for eluant, eluent, gel filtration chromatography is carried out to elution fraction（LH-
20）, collect elution fraction；By elution fraction using compression leg chromatographic isolation in reverse phase, use first alcohol and water for eluant, eluent, gradient
It is from volume fraction 30% methanol linear elution to 100% methanol, elution time is 120 minutes, and flow velocity 20mL/min is collected out
The flow point that peak time is 80-90 minutes, finally partly preparation reversed-phase high performance liquid chromatography isolates and purifies to obtain an unusually sweet smell beans flow point warp
Plain analog derivative, structure are shown in formula I：
（I）.
The formula of the PDB fluid nutrient mediums is as follows：Potato 200g, glucose 20g, sea crystal 35g and distillation
Water 1L；The formula of the rice medium is as follows：Rice 100g, sea crystal 3.5g and 100 mL of distilled water.
The volume ratio of dichloromethane and methanol is 1 in the dichloromethane and methanol mixed solvent：1.
Described half eluent for preparing reversed-phase high performance liquid chromatography is acetonitrile and water by volume 28:72 mix.
The application of above-mentioned isocoumarin analog derivative, the isocoumarin analog derivative is in terms of preparing antioxidant
Purposes.
Compared with the prior art, the advantages of the present invention are as follows：A kind of isocoumarin analog derivative of the present invention and its preparation side
Method and purposes obtain the fermentate of the aromatic compounds containing chlorine by microbial fermentation culture, then by fermentate methanol
Impregnate, ethyl acetate extraction, obtain coarse extract, by the coarse extract through depressurize silica gel column chromatography, gel filtration chromatography, medium pressure column chromatography and
Half preparative high-performance liquid chromatographic of reverse phase isolates and purifies to obtain, which can be as with antioxidation
New drug ingredient or lead compound；The present invention obtains isocoumarin analog derivative by microbial fermentation, and operating procedure is simple, raw
The production period is short, product cost is low feature and environmentally safe.
Above-mentioned aspergillus ustus（Aspergillus ustus）, which is DJ003 bacterial strains, and deposit number is CCTCC No.
M2014086, China typical culture collection center was preserved on 03 14th, 2014, and preservation address is the China Wuhan military
Chinese university.
Description of the drawings
Fig. 1 is that chemical compounds I removes DPPH free radicals with concentration dependant manner.Chemical compounds I or vitamin C（VitC）To refer to
Determine concentration to be added in 0.2mM DPPH solution 20 minutes, DPPH free radicals are measured by evaluating the absorbance at 517nm
Content, data indicate the average value ± SEM individually tested three times；Relative to control group * * p<0.01（ANOVA and Duncet examinations
It tests）.
Specific implementation mode
Below in conjunction with attached drawing embodiment, present invention is further described in detail.
Embodiment 1
A kind of isocoumarin analog derivative structural formula is as shown in I：
（I）.
Embodiment 2
The preparation method of isocoumarin analog derivative as shown in I formulas, steps are as follows：
（1）Fermenting and producing：It is CCTCC No by preserving number:The aspergillus ustus of M2014086（Aspergillus ustus）Scribing line
It brings back to life, then chooses a single bacterium colony and be inoculated into PDB fluid nutrient mediums, under the conditions of 28 DEG C, 150rpm, conduct after culture 5 days
Seed liquor；The ratio of seed liquor 5-20% by volume is inoculated into rice medium again, in 28 DEG C, is left to ferment 30 days；Its
The formula of middle PDB fluid nutrient mediums is as follows：Potato 200g, glucose 20g, sea crystal 35g and distilled water 1L；Described is big
The formula of rice culture medium is as follows：Rice 100g, sea crystal 3.5g and 100 mL of distilled water；
（2）The acquisition of coarse extract：Methanol is added into the conical flask after fermentation, by solid immersion, ultrasound 15 minutes is stood overnight
Afterwards, methanol extract liquid filtered through gauze is removed into solid residue；Solid residue is repeated after extracting 3-5 times, by methanol extract liquid
It is evaporated removing methanol after merging, then uses water dissolution, adds and repeats extraction 5 times with the isometric ethyl acetate of aqueous solution, close
And be concentrated under reduced pressure after extract liquor and remove ethyl acetate, obtain coarse extract；
（3）Compound isolates and purifies：After coarse extract dichloromethane and methanol mixed solvent dissolving, add 200-300 mesh silicon
Glue mixes sample, uses volume ratio for 2:1 petrol ether/ethyl acetate is eluant, eluent, and decompression silica gel column chromatography is carried out to coarse extract, is received
Collect elution fraction；It uses dichloromethane and methanol mixed solvent for eluant, eluent, gel filtration chromatography is carried out to elution fraction（LH-
20）, collect elution fraction；By elution fraction using compression leg chromatographic isolation in reverse phase, use first alcohol and water for eluant, eluent, gradient
It is from volume fraction 30% methanol linear elution to 100% methanol, elution time is 120 minutes, and flow velocity is 20mL/min, is collected
The flow point that appearance time is 80-90 minutes, finally partly preparation reversed-phase high performance liquid chromatography isolates and purifies to obtain an unusually sweet smell flow point warp
Legumin analog derivative, structure are shown in formula I：
（I）.
The volume ratio of dichloromethane and methanol is 1 wherein in dichloromethane and methanol mixed solvent：1；Half prepares reverse phase height
The eluent of effect liquid phase chromatogram is acetonitrile and water by volume 28:72 mix.
The chemical compounds I aubergine powder, molecular formula C14H18O5, [α]=-23.83 (c 0.2, CHCl3), cation
HRESIMS m/z：284.1490[M+NH4]+,1H and13C-NMR data are shown in Table 1.
1 chemical compounds I of table1H and13C NMR datas (600 and 150MHz, in DMSO-d6)a
Note：This table signals assignment be based on DEPT,1H-1H COSY, HSQC and HMBC spectrum analysis results.Hydrogen signal multiplicity point
It Yong not s (singlet), d (doublet), t (triplet) and m (multiplet) table.
Embodiment 3
The test of antioxidation activity in vitro（Free-radical scavenging activity is tested）
（1）Laboratory sample
The preparation of sample solution：Test sample is the chemical compounds I sterling isolated and purified in above-described embodiment 2, and precision weighs
Appropriate amount of sample, for surveying activity.
（2）Experimental method
The antioxidant properties for determining chemical compounds I are measured by DPPH radicals scavengings.The drug of various concentration is added to DPPH
Methanol solution（0.2mM）In.By mixture（200 holes μ L/）It is added in 96 orifice plates, and shakes 20 minutes at room temperature.Use enzyme
Mark instrument measures absorbance at 517nm.Use vitamin C as positive control.DPPH free radical scavenging activities are calculated using following formula：
DPPH free radical scavenging activities（%）=[（The absorbance of absorbance-sample of control）The absorbance of/control] × 100.
（3）Experimental result
In the test that chemical compounds I removes free radical.Chemical compounds I or vitamin C（VitC）It is added to 0.2mM with prescribed concentration
20 minutes in DPPH solution, the content of DPPH free radicals is measured by evaluating the absorbance at 517nm.As shown in Figure 1, chemical combination
The content for reducing to I concentration dependent of object DPPH free radicals shows that chemical compounds I may be used as effective antioxidant, tables of data
Show the average value ± SEM individually tested three times, relative to control group * * p<0.01（ANOVA and Duncet experiments）.Chemical compounds I
Effective antioxidation may be due to its hydroxyl.Many antioxidants potentially contribute to postpone such as vitamin C and vitamin E
Alzheimer disease（AD）Morbidity and help to alleviate its symptom.Therefore, chemical compounds I, which is used as, has strong radicals scavenging
The isocoumarin analog derivative of energy, it can also be used to the treatment of AD.
Above description is not limitation of the present invention, and the present invention is also not limited to the example above.The art it is common
Technical staff is in the essential scope of the present invention, the variations, modifications, additions or substitutions made, and should also belong to the protection of the present invention
Range.
Claims (6)
1. a kind of isocoumarin analog derivative, it is characterised in that the structural formula of the isocoumarin analog derivative is as shown in I：
（I）.
2. a kind of preparation method of isocoumarin analog derivative according to claim 1, it is characterised in that specifically include as
Lower step：
（1）Fermenting and producing：It is CCTCC No by preserving number:The aspergillus ustus of M2014086（Aspergillus ustus）Scribing line
It brings back to life, then chooses a single bacterium colony and be inoculated into PDB fluid nutrient mediums, under the conditions of 28 DEG C, 150rpm, conduct after culture 5 days
Seed liquor；The ratio of seed liquor 5-20% by volume is inoculated into rice medium again, in 28 DEG C, is left to ferment 30 days；
（2）The acquisition of coarse extract：Methanol is added into the conical flask after fermentation, by solid immersion, ultrasound 15 minutes is stood overnight
Afterwards, methanol extract liquid filtered through gauze is removed into solid residue；Solid residue is repeated after extracting 3-5 times, by methanol extract liquid
It is evaporated removing methanol after merging, then uses water dissolution, adds and repeats extraction 5 times with the isometric ethyl acetate of aqueous solution, close
And be concentrated under reduced pressure after extract liquor and remove ethyl acetate, obtain coarse extract；
（3）Compound isolates and purifies：After coarse extract dichloromethane and methanol mixed solvent dissolving, add 200-300 mesh silicon
Glue mixes sample, uses volume ratio for 2:1 petrol ether/ethyl acetate is eluant, eluent, and decompression silica gel column chromatography is carried out to coarse extract, is received
Collect elution fraction；It uses dichloromethane and methanol mixed solvent for eluant, eluent, gel filtration chromatography is carried out to elution fraction, collection is washed
De- component；By elution fraction using compression leg chromatographic isolation in reverse phase, use first alcohol and water for eluant, eluent, gradient is from volume point
For several 30% methanol linear elutions to 100% methanol, elution time is 120 minutes, flow velocity 20mL/min, collects appearance time and is
80-90 minutes flow points, finally partly preparation reversed-phase high performance liquid chromatography isolates and purifies to obtain isocoumarin class derivative flow point warp
Object, structure are shown in formula I：
（I）.
3. a kind of preparation method of isocoumarin analog derivative according to claim 2, it is characterised in that the PDB liquid
The formula of body culture medium is as follows：Potato 200g, glucose 20g, sea crystal 35g and distilled water 1L；The rice culture
The formula of base is as follows：Rice 100g, sea crystal 3.5g and distilled water 100mL.
4. a kind of preparation method of isocoumarin analog derivative according to claim 2, it is characterised in that the dichloro
The volume ratio of dichloromethane and methanol is 1 in methane and methanol mixed solvent：1.
5. the preparation method of isocoumarin analog derivative according to claim 2, it is characterised in that：Described half prepares anti-
The eluent of phase high performance liquid chromatography is acetonitrile and water by volume 28:72 mix.
6. a kind of application of isocoumarin analog derivative according to any one of claims 1-5, it is characterised in that：It is described
Purposes of the isocoumarin analog derivative in terms of preparing antioxidant.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483467A (en) * | 2019-07-11 | 2019-11-22 | 宁波大学 | Dihydroiso-coumarin analog derivative and its preparation method and application |
| CN111592989A (en) * | 2020-06-28 | 2020-08-28 | 曲靖师范学院 | Aspergillus sp.G12 and method for preparing isocorydine alkali by fermenting Aspergillus sp.G12 |
| CN113061631A (en) * | 2021-03-31 | 2021-07-02 | 华中科技大学 | Isochroman derivative and enzymatic synthesis method and application thereof |
| CN116178390A (en) * | 2021-11-26 | 2023-05-30 | 北京中医药大学东直门医院 | Dihydrothiophene heterozygous isocoumarin compound with circularly polarized fluorescence and application thereof |
| CN116650475A (en) * | 2023-04-24 | 2023-08-29 | 福建中医药大学 | Application of isocoumarin derivative diaorthothin in preparation of medicine with neuroprotective function |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483467A (en) * | 2019-07-11 | 2019-11-22 | 宁波大学 | Dihydroiso-coumarin analog derivative and its preparation method and application |
| CN110483467B (en) * | 2019-07-11 | 2023-01-03 | 宁波大学 | Dihydroisomerin derivative and preparation method and application thereof |
| CN111592989A (en) * | 2020-06-28 | 2020-08-28 | 曲靖师范学院 | Aspergillus sp.G12 and method for preparing isocorydine alkali by fermenting Aspergillus sp.G12 |
| CN113061631A (en) * | 2021-03-31 | 2021-07-02 | 华中科技大学 | Isochroman derivative and enzymatic synthesis method and application thereof |
| CN116178390A (en) * | 2021-11-26 | 2023-05-30 | 北京中医药大学东直门医院 | Dihydrothiophene heterozygous isocoumarin compound with circularly polarized fluorescence and application thereof |
| CN116178390B (en) * | 2021-11-26 | 2024-05-14 | 北京中医药大学东直门医院 | Dihydrothiophene heterozygous isocoumarin compound with circularly polarized fluorescence and application thereof |
| CN116650475A (en) * | 2023-04-24 | 2023-08-29 | 福建中医药大学 | Application of isocoumarin derivative diaorthothin in preparation of medicine with neuroprotective function |
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Effective date of registration: 20221115 Address after: 276000 Shangye Town Industrial Park, Fei County, Linyi City, Shandong Province (north of the expressway exit) Patentee after: DOUHUANGJIN FOOD Co.,Ltd. Address before: Room 2202, 22 / F, Wantong building, No. 3002, Sungang East Road, Sungang street, Luohu District, Shenzhen City, Guangdong Province Patentee before: Shenzhen dragon totem technology achievement transformation Co.,Ltd. Effective date of registration: 20221115 Address after: Room 2202, 22 / F, Wantong building, No. 3002, Sungang East Road, Sungang street, Luohu District, Shenzhen City, Guangdong Province Patentee after: Shenzhen dragon totem technology achievement transformation Co.,Ltd. Address before: 315211, Fenghua Road, Jiangbei District, Zhejiang, Ningbo 818 Patentee before: Ningbo University |