CN106565639A - Tetrahydrofuran compound and preparation method and application thereof - Google Patents
Tetrahydrofuran compound and preparation method and application thereof Download PDFInfo
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- CN106565639A CN106565639A CN201610901163.6A CN201610901163A CN106565639A CN 106565639 A CN106565639 A CN 106565639A CN 201610901163 A CN201610901163 A CN 201610901163A CN 106565639 A CN106565639 A CN 106565639A
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- tetrahydrofurans
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- ethyl acetate
- dichloromethane
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- C—CHEMISTRY; METALLURGY
- 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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- C—CHEMISTRY; METALLURGY
- 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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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a tetrahydrofuran compound and a preparation method and application thereof. The invention is characterized in that the structural formula of the tetrahydrofuran compound is as shown in the formula I. The preparation method comprises the following steps: acquiring a fermented substance containing a novel tetrahydrofuran compound by fermental cultivation of aspergillus versicolor with the preservation number of CCTCC No. M2014089; immersing the fermented substance with methanol and extracting with ethyl acetate so as to obtain a crude extract; and separating and purifying the crude extract by reduced pressure silica-gel column chromatography and semi-preparative reversed phase high-performance liquid chromatography. The tetrahydrofuran compound has an antifungal effect and can be used as a novel medicine component or lead compound with an antifungal effect.
Description
Technical field
The present invention relates to a kind of tetrahydrofurans, tetrahydrofuran derivatives are prepared more particularly, to one kind with marine fungi
The method of compound and such compound are preparing the application of antifungal drug.
Background technology
Marine fungi due to abundance, growing environment is various, metabolic pathway is special the features such as, many can be produced
Structure is novel, and the secondary metabolite with notable antifungal activity, some of them compound is expected to enter one through structure of modification
Step is developed into new antibiotic.The present inventor studies and learns, marine fungiAspergillus versicolor DJ013（Protect
China typical culture collection center is hidden in, deposit number is：CCTCC No: M2014089）Solid fermentation ethyl acetate
Extract has preferably antimycotic bacterium activity, and its active component is studied then.Have not yet to see the chemistry of the compound
The report of structure and antifungal activity, therefore also there is not yet medicine related to this on market.
The content of the invention
The technical problem to be solved be to provide a kind of tetrahydrofurans with antifungal activity and
Preparation Method And The Use.
The present invention solve the technical scheme that adopted of above-mentioned technical problem for：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 includes following steps：
（1）Fermenting and producing
By the aspergillus versicolor that preserving number is CCTCC No. M2014089（Aspergillus versicolor DJ013）Line
Bring back to life, be inoculated on PDA solid slope culture mediums, after cultivating 5 days in 28 DEG C of incubators；The bacterium colony that inclined-plane culture is obtained is complete
Portion is inoculated in solid medium, and in 28 DEG C, standing for fermentation culture 40 days obtains fermentate；
（2）The acquisition of medicinal extract
Above-mentioned fermentate is soaked 3 times with 4L methyl alcohol, then methanol extract concentration is evaporated, redissolved with the water of 1L, then use 1L
Ethyl acetate repeats extraction 3 times, merges three extraction gained extracts, and extract reduced pressure concentration is removed into ethyl acetate, obtains
CE；
（3）The separation and purification of compound
After by above-mentioned CE dichloromethane and methanol mixed solvent dissolving, plus 200-300 mesh silica gel mixed samples, using oil
Ether/ethyl acetate is with volume ratio 10:1 gradient is eluted for eluant, eluent, and to CE decompression silica gel column chromatography is carried out, and collection is washed
De- component, then carry out isolating and purifying obtaining tetrahydrofurans through partly preparing RPLC, its structure is such as
Shown in Formulas I：
（I）.
The compound method of described solid medium is as follows：80g rice is dissolved in into 120ml seawater, after soaked overnight, in
121 DEG C of autoclaving 20min.
Dichloromethane and the volume ratio of methyl alcohol are 1 in described dichloromethane and methanol mixed solvent：1.
The described eluent for partly preparing RPLC is acetonitrile and water by volume 45:55 ratio is mixed
Close.
The application of above-mentioned tetrahydrofurans, described tetrahydrofurans are used to prepare antifungal object space
The purposes in face.
Compared with prior art, it is an advantage of the current invention that：A kind of tetrahydrofurans of the present invention and its preparation side
Method and purposes, the fermentate containing new tetrahydrofurans is obtained by fermentable culture, then uses fermentate
Methyl alcohol immersion, ethyl acetate are extracted, and obtain CE, and prepared by CE Jing decompression silica gel column chromatographies and anti-phase half into efficient liquid phase
Chromatographic separation and purification is obtained, and the tetrahydrofurans have antifungic action, can be used as the novel drugs of antifungic action
Composition or lead compound.
Above-mentioned aspergillus versicolor（Aspergillus versicolor）, the bacterium is DJ013 bacterial strains, and deposit number is CCTCC
No. M2014089, China typical culture collection center was preserved on 03 14th, 2014, and preservation address is China. and it is military
The Chinese. Wuhan University.
Specific embodiment
The present invention is described in further 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 the tetrahydrofurans as shown in I formulas, specifically includes following steps：
（1）Fermenting and producing
By the aspergillus versicolor that preserving number is CCTCC No. M2014089（Aspergillus versicolor DJ013）Line
Bring back to life, be inoculated on PDA solid slope culture mediums, after cultivating 5 days in 28 DEG C of incubators；The bacterium colony that inclined-plane culture is obtained is complete
Portion is inoculated into solid medium（80g rice is dissolved in into 120ml seawater, after soaked overnight, is in 121 DEG C of autoclaving 20min
Can）In, in 28 DEG C, standing for fermentation culture 40 days obtains fermentate；
（2）The acquisition of medicinal extract
Above-mentioned fermentate is soaked 3 times with 4L methyl alcohol, then methanol extract concentration is evaporated, redissolved with the water of 1L, then use 1L
Ethyl acetate repeats extraction 3 times, merges three extraction gained extracts, and extract reduced pressure concentration is removed into ethyl acetate, obtains
CE；
（3）The separation and purification of compound
By above-mentioned CE dichloromethane and methanol mixed solvent（Dichloromethane：Methyl alcohol=1:1,v/v）After dissolving, plus 200-
300 mesh silica gel mixed samples, adopt petroleum ether-ethyl acetate with volume ratio as 10:1 gradient is eluent, and CE is carried out
Decompression silica gel column chromatography, collects elution fraction, then carries out isolated tetrahydrofuran through partly preparing RPLC
Class compound, its structure is shown in formula I：
（I）.
The chemical compounds I is faint yellow wax-like, molecular formula C16H26O4, cation HRESIMSm/z：300.2172 [M + NH4
]+,1H and13C-NMR data are shown in Table 1.
The chemical compounds I of table 11H 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, and precision is weighed
Appropriate amount of sample, with DMSO the solution of desired concn is configured to, for surveying activity.The indicator bacteria that the experiment is used be neogenesis cryptococcus and
Candida albicans.
（2）Experimental technique
The antimycotic method of testing of 96 orifice plates：By testing compound stepwise dilution in 20%DMSO/ salt solution, and shift 10 L to 96
In the flat bottom microtiter plate of hole.Under aerobic conditions, two bacterium indicator strains are trained under the conditions of 30 DEG C in sabouraud's agar (SDA)
Foster 16-20 hours.A series of compound for adding variable concentrations is placed in RPMI1640 culture mediums, and inoculated fungi bacterial strain, newly
Raw cryptococcus is 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 positive control,
DMSO solution is used as negative control.The concentration of testing compound is respectively 1 μ g/ml, 2 μ g/ml, 4 μ g/ml, 8 μ g/ml.Culture knot
Shu Hou, determines light absorption value under 600nm, and according to equation below inhibiting rate is calculated.Inhibiting rate（%）=(ODR-OD)/(ODR-ODB)
ODR：Bacterium solution control wells light absorption value；ODB：Blank absorbency；OD：Sample determination hole light absorption value.
（3）Experimental result
In the antimycotic test of 96 orifice plates, the chemical compounds I of variable concentrations is to neogenesis cryptococcus and Candida albicans histamine result point
It is not shown in Table 2.
Inhibiting rate of the chemical compounds I of the variable concentrations of table 2 to pathomycete（%）
As seen from the above table chemical compounds I has the effect of significant anti-neogenesis cryptococcus and Candida albicans, can be used as antifungal
The research of thing or lead compound.
Described above not limitation of the present invention, the present invention is also not limited to the example above.The art it is common
In the essential scope of the present invention, change, remodeling, addition or the replacement made should also belong to the protection of the present invention to technical staff
Scope.
Claims (6)
1. a kind of tetrahydrofurans, it is characterised in that：The structural formula of the tetrahydrofurans is as shown in I：
（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
By the aspergillus versicolor that preserving number is CCTCC No. M2014089（Aspergillus versicolor）Line brings back to life, and connects
Plant on PDA solid slope culture mediums, after cultivating 5 days in 28 DEG C of incubators；The bacterium colony that inclined-plane culture is obtained all is inoculated with
To in solid medium, in 28 DEG C, standing for fermentation culture 40 days obtains fermentate；
（2）The acquisition of medicinal extract
Above-mentioned fermentate is soaked 3 times with 4L methyl alcohol, then methanol extract concentration is evaporated, redissolved with the water of 1L, then use 1L
Ethyl acetate repeats extraction 3 times, merges three extraction gained extracts, and extract reduced pressure concentration is removed into ethyl acetate, obtains
CE；
（3）The separation and purification of compound
After by above-mentioned CE dichloromethane and methanol mixed solvent dissolving, plus 200-300 mesh silica gel mixed samples, using oil
Ether/ethyl acetate is with volume ratio 10:1 gradient is eluted for eluant, eluent, and to CE decompression silica gel column chromatography is carried out, and collection is washed
De- component, then carry out isolating and purifying obtaining tetrahydrofurans through partly preparing RPLC, its structure is such as
Shown in Formulas I：
（I）.
3. a kind of preparation method of tetrahydrofurans according to claim 2, it is characterised in that step（1）It is described
Solid medium compound method it is as follows：80g rice is dissolved in into 120ml seawater, after soaked overnight, in 121 DEG C of autoclavings
20min.
4. the preparation method of a kind of tetrahydrofurans according to claim 2, it is characterised in that：Step（3）Institute
Dichloromethane and the volume ratio of methyl alcohol are 1 in the dichloromethane stated and methanol mixed solvent：1.
5. the preparation method of a kind of tetrahydrofurans according to claim 2, it is characterised in that：Step（3）Institute
The eluent for partly preparing RPLC stated is acetonitrile and water by volume 45:55 ratio mixing.
6. a kind of application of tetrahydrofurans according to claim 1, it is characterised in that：Described tetrahydrofuran
Class compound is used to prepare the purposes in terms of antifungal drug.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109942524A (en) * | 2019-03-29 | 2019-06-28 | 广州医科大学 | A kind of phthalein compounds and its extracting method |
| CN110003152A (en) * | 2019-03-07 | 2019-07-12 | 宁波大学 | 2 (5H)-furanone based derivatives of one kind and its preparation method and application |
Citations (3)
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|---|---|---|---|---|
| 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 |
|---|
| DAVID A. EVANS ET AL.: ""Total Synthesis of the Polyether Antibiotic X-206"", 《J. AM. CHEM. SOC》 * |
| 柳俊灵: ""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"", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110003152A (en) * | 2019-03-07 | 2019-07-12 | 宁波大学 | 2 (5H)-furanone based derivatives of one kind and its preparation method and application |
| CN110003152B (en) * | 2019-03-07 | 2022-12-13 | 宁波大学 | 2 (5H) -furanone derivative and preparation method and application thereof |
| CN109942524A (en) * | 2019-03-29 | 2019-06-28 | 广州医科大学 | A kind of phthalein compounds and its extracting method |
| CN109942524B (en) * | 2019-03-29 | 2021-10-08 | 广州医科大学 | Phthalein compound and extraction method thereof |
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| CN106565639B (en) | 2018-09-21 |
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