CN106565639B - A kind of tetrahydrofurans and its preparation method and application - Google Patents
A kind of tetrahydrofurans and its preparation method and application Download PDFInfo
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- CN106565639B CN106565639B CN201610901163.6A CN201610901163A CN106565639B CN 106565639 B CN106565639 B CN 106565639B CN 201610901163 A CN201610901163 A CN 201610901163A CN 106565639 B CN106565639 B CN 106565639B
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- tetrahydrofurans
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- 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
- C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
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Abstract
The invention discloses a kind of tetrahydrofurans and its preparation method and application, feature is the structural formula of the tetrahydrofurans as shown in I, preparation methods steps include obtaining the fermentate containing new tetrahydrofurans by preserving number for the aspergillus versicolor fermented and cultured of CCTCC No.M2014089, then fermentate is impregnated with methanol, ethyl acetate extracts, obtain coarse extract, the coarse extract is isolated and purified to obtain through depressurizing silica gel column chromatography and half preparative high-performance liquid chromatographic of reverse phase, the tetrahydrofurans have antifungic action, advantage is can be as the novel drugs ingredient or lead compound of antifungic action.
Description
Technical field
The present invention relates to a kind of tetrahydrofurans, and tetrahydrofuran derivatives are prepared with marine fungi more particularly, to a kind of
The method of compound and such compound are in the application for preparing antifungal drug.
Background technology
Marine fungi can generate many due to having the characteristics that abundance, growing environment are various, metabolic pathway is special
Structure novel, the secondary metabolite with notable antifungal activity, some of compounds are expected to by structure of modification into one
Step is developed into new antibiotic.The present inventor studies and learns, marine fungiAspergillus versicolor DJ013（It protects
It is hidden in China typical culture collection center, deposit number is：CCTCC No: M2014089）Solid fermentation ethyl acetate
Extract has preferable antimycotic bacterium activity, is studied then its active constituent.Have not yet to see the chemistry of the compound
The report of structure and antifungal 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 tetrahydrofurans with antifungal activity and
Preparation method and use.
Technical solution is used by the present invention solves above-mentioned technical problem：A kind of tetrahydrofurans, the tetrahydrochysene
The structural formula of furfuran compound is as shown in I：
（I）.
The preparation method of above-mentioned tetrahydrofurans, specifically comprises the following steps：
（1）Fermenting and producing
By the aspergillus versicolor that preserving number is CCTCC No. M2014089（Aspergillus versicolor DJ013）
Scribing line is brought back to life, and is inoculated into PDA solid slope culture mediums, after being cultivated 5 days in 28 DEG C of incubators；The bacterium that inclined-plane culture is obtained
It falls and is all inoculated into solid medium, in 28 DEG C, standing for fermentation culture 40 days obtains fermentate；
（2）The acquisition of medicinal extract
Above-mentioned fermentate 4L methanol is impregnated 3 times, then methanol extract concentration is evaporated, is redissolved with the water of 1L, then
Extraction 3 times is repeated with 1L ethyl acetate, merges extraction gained extract liquor three times, extract liquor is concentrated under reduced pressure and removes ethyl acetate,
Obtain coarse extract；
（3）The separation and purification of compound
After above-mentioned coarse extract dichloromethane and methanol mixed solvent dissolving, add 200-300 mesh silica gel mixed samples, using stone
Oily ether/ethyl acetate is with volume ratio 10:1 gradient is that eluant, eluent is eluted, and carries out decompression silica gel column chromatography to coarse extract, collects
Elution fraction prepares reversed-phase high performance liquid chromatography using half and is isolated and purified to obtain tetrahydrofurans, structure
Shown in formula I：
（I）.
The preparation method of the solid medium is as follows：80g rice is dissolved in 120ml seawater, after soaked overnight, in
121 DEG C of high pressure sterilization 20min.
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 45:55 ratio is mixed
It closes.
The application of above-mentioned tetrahydrofurans, the tetrahydrofurans are used to prepare antifungal object space
The purposes in face.
Compared with the prior art, the advantages of the present invention are as follows：A kind of tetrahydrofurans of the present invention and its preparation side
Method and purposes obtain the fermentate containing new tetrahydrofurans by microbial fermentation culture, then use fermentate
Methanol impregnates, ethyl acetate extracts, and obtains coarse extract, which is partly prepared efficient liquid phase through depressurizing silica gel column chromatography and reverse phase
Chromatographic separation and purification obtains, which has antifungic action, can be as the novel drugs of antifungic action
Ingredient or lead compound.
Above-mentioned aspergillus versicolor（Aspergillus versicolor）, which is DJ013 bacterial strains, deposit number CCTCC
No. M2014089, China typical culture collection center was preserved on 03 14th, 2014, and preservation address is China military
Chinese Wuhan Universitys.
Specific implementation mode
Present invention is further described in detail with reference to embodiments.
Embodiment 1
A kind of tetrahydrofurans structural formula is as shown in I：
（I）.
Embodiment 2
The preparation method of tetrahydrofurans, specifically comprises the following steps as shown in I formulas：
（1）Fermenting and producing
By the aspergillus versicolor that preserving number is CCTCC No. M2014089（Aspergillus versicolor DJ013）
Scribing line is brought back to life, and is inoculated into PDA solid slope culture mediums, after being cultivated 5 days in 28 DEG C of incubators；The bacterium that inclined-plane culture is obtained
It falls and is all inoculated into solid medium（80g rice is dissolved in 120ml seawater, after soaked overnight, in 121 DEG C of high pressure sterilization 20min
）In, in 28 DEG C, standing for fermentation culture 40 days obtains fermentate；
（2）The acquisition of medicinal extract
Above-mentioned fermentate 4L methanol is impregnated 3 times, then methanol extract concentration is evaporated, is redissolved with the water of 1L, then
Extraction 3 times is repeated with 1L ethyl acetate, merges extraction gained extract liquor three times, extract liquor is concentrated under reduced pressure and removes ethyl acetate,
Obtain coarse extract；
（3）The separation and purification of compound
By above-mentioned coarse extract dichloromethane and methanol mixed solvent（Dichloromethane：Methanol=1:1,v/v）After dissolving, add
200-300 mesh silica gel mixed samples use petroleum ether-ethyl acetate with volume ratio for 10:1 gradient is eluent, to coarse extract
Decompression silica gel column chromatography is carried out, elution fraction is collected, preparing reversed-phase high performance liquid chromatography using half carries out isolated tetrahydrochysene
Furfuran compound, structure are shown in formula I：
（I）.
The chemical compounds I is faint yellow wax-like, molecular formula C16H26O4, cationic HRESIMSm/z：300.2172 [M + NH4
]+,1H and13C-NMR data are shown in Table 1.
1 chemical compounds I of table1H and13C NMR datas（600 and 150MHz, in CDCl3）
Embodiment 3
The test of extracorporeal antifungal activity（96 orifice plate bacteriostatic methods）
（1）Laboratory sample
The preparation of sample solution：Test sample is the chemical compounds I sterling isolated and purified in above-described embodiment 1, accurate
Appropriate amount of sample is weighed, the solution of required concentration is configured to DMSO, for surveying activity.The indicator bacteria that the experiment uses is newborn hidden ball
Bacterium and Candida albicans.
（2）Experimental method
The antimycotic test method of 96 orifice plates：Untested compound is diluted in step by step in 20%DMSO/ brine, and shifts 10 μ L
Into 96 hole flat bottom microtiter plates.Under aerobic conditions, by two bacterium indicator strains under the conditions of 30 DEG C in sabouraud's agar
(SDA) it cultivates 16-20 hours.A series of compound that various concentrations are added is placed in RPMI1640 culture mediums, and inoculated fungi
Bacterial strain, neogenesis cryptococcus are cultivated 70 hours at 35 DEG C, and Candida albicans is cultivated 46 hours at 35 DEG C.8 μ g/ml Fluconazoles are used as sun
Property control, DMSO solution is as negative control.The concentration of untested compound is respectively 1 μ g/ml, 2 μ g/ml, 4 μ g/ml, 8 μ g/
ml.After culture, light absorption value under 600nm is measured, inhibiting rate is calculated according to following formula.Inhibiting rate（%）=(ODR-OD)/
(ODR-ODB)
ODR：Bacterium solution control wells light absorption value；ODB：Blank absorbency；OD：Sample measures hole light absorption value.
（3）Experimental result
In the antimycotic test of 96 orifice plates, the chemical compounds I of various concentration inhibits knot to neogenesis cryptococcus and Candida albicans
Fruit is shown in Table 2 respectively.
Inhibiting rate of the chemical compounds I of 2 various concentration of table to pathomycete（%）
Chemical compounds I has the function of significant anti-neogenesis cryptococcus and Candida albicans as seen from the above table, can be used as anti-true
The research of bacterium drug or lead compound.
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 (5)
1. a kind of tetrahydrofurans, it is characterised in that：The structural formula of the tetrahydrofurans is as shown in I：
2. a kind of preparation method of tetrahydrofurans according to claim 1, it is characterised in that specifically include as
Lower step：
(1) fermenting and producing
The aspergillus versicolor (Aspergillus versicolor) that preserving number is CCTCC No.M2014089 is crossed and is brought back to life, is connect
In kind to PDA solid slope culture mediums, after being cultivated 5 days in 28 DEG C of incubators；The bacterium colony that inclined-plane culture is obtained all is inoculated with
Into solid medium, in 28 DEG C, standing for fermentation culture 40 days obtains fermentate；
(2) acquisition of medicinal extract
Above-mentioned fermentate 4L methanol is impregnated 3 times, then methanol extract concentration is evaporated, is redissolved with the water of 1L, then use 1L
Ethyl acetate repeats extraction 3 times, merges extraction gained extract liquor three times, extract liquor is concentrated under reduced pressure and removes ethyl acetate, is obtained
Coarse extract；
(3) separation and purification of compound
After above-mentioned coarse extract dichloromethane and methanol mixed solvent dissolving, add 200-300 mesh silica gel mixed samples, using volume ratio
It is 10:1 petrol ether/ethyl acetate is that eluant, eluent is eluted, and carries out decompression silica gel column chromatography to coarse extract, collects elution group
Point, it prepares reversed-phase high performance liquid chromatography using half and is isolated and purified to obtain tetrahydrofurans, structure such as Formulas I institute
Show：
The eluent that wherein described half prepares reversed-phase high performance liquid chromatography is acetonitrile and water by volume 45:55 ratio is mixed
It closes.
3. a kind of preparation method of tetrahydrofurans according to claim 2, it is characterised in that step (1) is described
Solid medium preparation method it is as follows：80g rice is dissolved in 120ml seawater, after soaked overnight, in 121 DEG C of high pressure sterilizations
20min.
4. a kind of preparation method of tetrahydrofurans according to claim 2, it is characterised in that：Step (3) institute
The volume ratio of dichloromethane and methanol is 1 in the dichloromethane and methanol mixed solvent stated：1.
5. a kind of application of tetrahydrofurans according to claim 1, it is characterised in that：The tetrahydrofuran
Class compound is used to prepare the purposes in terms of antifungal drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110003152B (en) * | 2019-03-07 | 2022-12-13 | 宁波大学 | 2 (5H) -furanone derivative and preparation method and application thereof |
| CN109942524B (en) * | 2019-03-29 | 2021-10-08 | 广州医科大学 | Phthalein compound and extraction method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1122134A (en) * | 1993-04-30 | 1996-05-08 | 先灵公司 | Process for preparing intermediates for the synthesis of antifungal agents |
| FR2826007A1 (en) * | 2001-06-13 | 2002-12-20 | Entomed | New tetrasubstituted polycationic tetrahydrofuran derivatives having antibacterial and antifungal activity for use in man, animals and plants |
| CN105503531A (en) * | 2015-12-04 | 2016-04-20 | 深圳大学 | Extract of fungus culture as well as preparation method and application of extract |
-
2016
- 2016-10-14 CN CN201610901163.6A patent/CN106565639B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1122134A (en) * | 1993-04-30 | 1996-05-08 | 先灵公司 | Process for preparing intermediates for the synthesis of antifungal agents |
| FR2826007A1 (en) * | 2001-06-13 | 2002-12-20 | Entomed | New tetrasubstituted polycationic tetrahydrofuran derivatives having antibacterial and antifungal activity for use in man, animals and plants |
| CN105503531A (en) * | 2015-12-04 | 2016-04-20 | 深圳大学 | Extract of fungus culture as well as preparation method and application of extract |
Non-Patent Citations (2)
| Title |
|---|
| "Total Synthesis of the Polyether Antibiotic X-206";David A. Evans et al.;《J. Am. Chem. SOC》;19881231;第110卷(第8期);第2506-2526页 * |
| "海洋微生物产生的四氢呋喃类化合物农药活性及抑菌机理的研究";柳俊灵;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20140715(第07期);B016-414 * |
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