CN104311525A - Use of marine fungus-derived Azaphilone compound in preparation of antituberculosis drugs - Google Patents
Use of marine fungus-derived Azaphilone compound in preparation of antituberculosis drugs Download PDFInfo
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- CN104311525A CN104311525A CN201410465631.0A CN201410465631A CN104311525A CN 104311525 A CN104311525 A CN 104311525A CN 201410465631 A CN201410465631 A CN 201410465631A CN 104311525 A CN104311525 A CN 104311525A
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- azaphilone
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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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- 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
- C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
Abstract
The invention discloses a use of a marine fungus-derived Azaphilone compound in preparation of antituberculosis drugs. The Azaphilone compound is shown in the structural formula (I). The Azaphilone compound has activity of substantially inhibiting mycobacterium tuberculosis tyrosine phosphatase (mPTPB), has an IC50 value of 3.99+/-0.34 micromoles per liter, can be used for preparation of novel antituberculosis drugs and has wide application prospects.
Description
Technical field
The present invention relates to medical compounds field, specifically, relate to a class Azaphilone compounds as the application in antitubercular agent.
Background technology
Occupy ocean that earth surface amasss 70% and breed ten hundreds of and active diversified marine microorganism.In order to survive under the extreme environments such as high salinity, high pressure, low nutrition, marine microorganism has developed unique metabolic way.Thalassiomycetes, among particular surroundings, has developed unique metabolic way, can produce novel structure, the significant all kinds of secondary metabolite of physiologically active.Its meta-bolites has the multiple pharmaceutical uses such as antibacterial, antitumor, immunomodulatory, enzyme level.At present, from the marine microorganism comprising thalassiomycetes, the focus that new medicine source has become international and domestic research is found.
Tuberculosis is the communicable disease of the serious harm human health caused by mycobacterium tuberculosis (Mycobacterium tuberculosis).The health of the mankind and the development of society are directly connected to the research of tuberculosis mechanism and the development of antituberculosis drug carried out for special target spot.By the important virulence factor that the tyrosine phosphatase (mPTPB) of mycobacterium tuberculosis secretory is mycobacterium tuberculosis, be cause phthisical major reason.MPTPB is entered in scavenger cell after mycobacterium tuberculosis secretory, stop the startup of host immune system, regulates the survival of bacillus in host.MPTPB is that tubercular drugs screens new target spot.Suppress the mPTPB of tubercule bacillus secretion, tubercule bacillus can be stoped to produce restraining effect to host immune, contribute to host and immunity is produced to tubercule bacillus, thus reach treatment object lungy.
Summary of the invention
The object of this invention is to provide above-mentioned Azaphilone compounds and preparing the application in antitubercular agent.
Above-mentioned purpose of the present invention is achieved by the following technical programs:
One birdss of the same feather flock together its structural formula of ketones derivant as shown in (I):
The preparation method of Azaphilone compounds of the present invention comprises the steps:
(1) bacterial strain of thalassiomycetes aspergillus Aspergillussp.HNY16-5C is accessed seed culture medium from slant medium, shaking table is cultivated, (depositary institution of described thalassiomycetes aspergillus Aspergillussp.HNY16-5C is China typical culture collection center to obtain seed culture fluid, preservation address is Wuhan University of Wuhan, China city, preserving number is CCTCC M 2012358, and preservation date is on September 19th, 2012);
(2) seed culture fluid is accessed in fermention medium, quiescent culture;
(3) tunning filtration is obtained thalline, thalline methyl alcohol soaks, and concentrating under reduced pressure obtains medicinal extract, then through chromatographic separation, obtains polyketone analog derivative 1.
As a kind of preferred version, in above-mentioned preparation method, the component of step (1) described seed culture medium is: glucose 40g, peptone 4g, yeast extract paste 4g, sea salt 5g, water 2L.
As a kind of preferred version, in above-mentioned preparation method, the component of step (2) described fermention medium is: glucose 2000g, peptone 200g, yeast extract paste 200g, sea salt 250g, water 100L.
As a kind of preferred version, in above-mentioned preparation method, the described shaking table culture condition of step (1) is: rotating speed 200rpm, temperature 28 DEG C, incubation time 72h.
As a kind of preferred version, in above-mentioned preparation method, the described quiescent culture temperature of step (2) is 25 DEG C, and incubation time is 28 days.
As a kind of preferred version, in above-mentioned preparation method, the described medicinal extract silica gel column chromatography of step (3) is separated, and is separated the ethyl acetate/petroleum ether gradient elution with 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 100%.
As a kind of preferred version, in above-mentioned preparation method, described 30% ethyl acetate--sherwood oil elution fraction is through dextrane gel Sephadex LH-20 chromatography, and eluent is methyl alcohol: chloroform=1:1 (volume ratio), more repeatedly recrystallization obtains compound 1.
Azaphilone compounds of the present invention 1 pair of tubercule bacillus tyrosine phosphatase (mPTPB) has restraining effect, can be used for preparing antitubercular agent.
Compared with prior art, the present invention has following beneficial effect: Azaphilone compounds 1 of the present invention derives from South Sea mangrove fungi Aspergillussp.HNY16-5C, simple, with low cost from the method for fungi extraction and isolation; Azaphilone compounds 1 pair of tubercule bacillus tyrosine phosphatase (mPTPB) has remarkable inhibiting activity, has a extensive future.
Embodiment
Explain the present invention further below in conjunction with embodiment, but embodiment does not limit in any form to the present invention.
Embodiment 1:
Compound of the present invention, can be separated and obtain from the thalline of thalassiomycetes aspergillus Aspergillussp.HNY16-5C.Thalassiomycetes aspergillus Aspergillussp.HNY16-5C is separated to obtain from the leaf of marine site, Haikou Mangrove Sonneratia apetala Buch. Ham S.apetala.Concrete steps are as follows:
1. seed culture:
(1) seed culture medium is prepared: glucose 40g, peptone 4g, yeast extract paste 4g, sea salt 5g, tap water 2000mL, average mark is loaded on 8 500mL Erlenmeyer flasks, and 121 DEG C go out 30 minutes.
(2) cultivation of seed: by the bacterial strain of thalassiomycetes aspergillus Aspergillussp.HNY16-5C access seed culture medium, at the temperature of 28 DEG C, put with the rotating speed of 200rpm on shaking table, cultivate 72 hours to obtain seed culture fluid.
2. fermentation culture:
(1) fermention medium is prepared: glucose 2000g, peptone 200g, yeast extract paste 200g, sea salt 250g, tap water 100L, 121 DEG C go out 30 minutes.
(2) fermentation culture: seed liquor 5mL access is equipped with in the Erlenmeyer flask of fermention medium, in 25 DEG C of quiescent culture 28 days by aseptic technique.
3. extraction and isolation:
Fermented product filters to obtain thalline, and thalline methyl alcohol soaks, and soak solution concentrating under reduced pressure at lower than 50 DEG C obtains medicinal extract 18.5g.This medicinal extract is separated through silica gel column chromatography, uses 5% respectively, and 10%, 20%, 30%, 40%, 50%, 60%, the ethyl acetate-light petrol gradient elution of 70%, 100%, wherein 30% ethyl acetate--sherwood oil elution fraction is through Sephadex LH-20 gel column, with methyl alcohol--chloroform (1:1) is eluent, repeatedly obtains compound 1 after chromatography and recrystallization.
Embodiment 2: carry out structural analysis test to the compound in embodiment 1, obtains following physico-chemical property data:
Compound 1: yellow crystals, fusing point 213-214 DEG C (thermometer does not correct), EI-MS (m/z): 382 [M]
+.
The NMR data of compound 1 are in table 1.
The NMR data (100MHz/400MHz, TMS, ppm) of table 1 compound 1
Embodiment 3: mycobacterium tuberculosis tyrosine phosphatase (mPTPB) Inhibition test is carried out to the compound 1 in embodiment 1:
Adopt p-nitrophenyl phosphoric acid (pNPP) to be substrate, carry out in 3, the 3-dimethylated pentanedioic acid damping fluids (25 DEG C, pH 7.0) of 50mM.PNPP is p-NP by mPTPB enzymolysis, to measure the change of its absorbancy and calculate the activity of enzyme with ultraviolet-visible spectrophotometer at 405nm wavelength place.Reaction initial system 200 μ L, wherein comprises the enzyme of 5 μ L, the substrate pNPP of 2.5mM, the inhibitor of different concns.Reaction adds NaOH (concentration the is 5mol/L) termination reaction of 50 μ L after starting 5min immediately, then in transferase 12 00 μ L to 96 orifice plate, measures the light absorption value at 405nm wavelength place.
Enzymic activity is calculated: inhibiting rate (%)=[(A with following formula
0– A)/A
0] × 100%, wherein A
0the absorbancy changing value of blank, A is the absorbancy changing value of sample.Measure the sample of 5 concentration, draw dosage--inhibiting rate curve, draw its IC
50value.Each sample replication three times, result mean value ± standard deviation represents.
It is inhibited that result records compound 1 pair of mycobacterium tuberculosis tyrosine phosphatase (mPTPB), its IC
50it is 3.99 ± 0.34 μMs.
Claims (3)
1. the Azaphilone compounds in thalassiomycetes source, is characterized in that structural formula is as shown in formula I:
。
2. Azaphilone compounds described in claim 1 is preparing the application in mycobacterium tuberculosis tyrosine phosphatase enzyme inhibitors.
3. the application of Azaphilone compounds according to claim 2, is characterized in that described mycobacterium tuberculosis tyrosine phosphatase enzyme inhibitors is for preventing and treating tuberculosis.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410465631.0A CN104311525A (en) | 2014-09-13 | 2014-09-13 | Use of marine fungus-derived Azaphilone compound in preparation of antituberculosis drugs |
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| CN201410465631.0A CN104311525A (en) | 2014-09-13 | 2014-09-13 | Use of marine fungus-derived Azaphilone compound in preparation of antituberculosis drugs |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104987316A (en) * | 2015-04-27 | 2015-10-21 | 中山大学 | Marine fungus-derived polyketone compound and application thereof in treatment of type 2 diabetes |
| WO2018141263A1 (en) * | 2017-02-04 | 2018-08-09 | 扬州蓝色生物医药科技有限公司 | Penicilones derivative and application thereof as anti-resistant bacteria drug |
| CN108503585A (en) * | 2017-02-28 | 2018-09-07 | 扬州蓝色生物医药科技有限公司 | The amino acid derivativges of PeniciloneB and its application as antibacterials |
| CN110776518A (en) * | 2019-11-28 | 2020-02-11 | 云南大学 | Azaphilone spiro compounds and preparation method and application thereof |
| CN115872966A (en) * | 2022-08-29 | 2023-03-31 | 中国科学院南海海洋研究所 | Xanthone compound and preparation method and application thereof |
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| WO2009049098A2 (en) * | 2007-10-09 | 2009-04-16 | Indiana University Research & Technology Corporation | Materials and methods for regulating the activity of phosphatases |
| CN102911040A (en) * | 2012-10-22 | 2013-02-06 | 中山大学 | Sesquiterpenoids from marine fungi source as well as preparation method and application thereof |
| CN103694209A (en) * | 2013-06-07 | 2014-04-02 | 中山大学 | Marine fungus-derived acetophenone compounds and preparation method and application thereof |
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2014
- 2014-09-13 CN CN201410465631.0A patent/CN104311525A/en active Pending
Patent Citations (3)
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| WO2009049098A2 (en) * | 2007-10-09 | 2009-04-16 | Indiana University Research & Technology Corporation | Materials and methods for regulating the activity of phosphatases |
| CN102911040A (en) * | 2012-10-22 | 2013-02-06 | 中山大学 | Sesquiterpenoids from marine fungi source as well as preparation method and application thereof |
| CN103694209A (en) * | 2013-06-07 | 2014-04-02 | 中山大学 | Marine fungus-derived acetophenone compounds and preparation method and application thereof |
Non-Patent Citations (2)
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104987316A (en) * | 2015-04-27 | 2015-10-21 | 中山大学 | Marine fungus-derived polyketone compound and application thereof in treatment of type 2 diabetes |
| CN104987316B (en) * | 2015-04-27 | 2017-04-19 | 中山大学 | Marine fungus-derived polyketone compound and application thereof in treatment of type 2 diabetes |
| WO2018141263A1 (en) * | 2017-02-04 | 2018-08-09 | 扬州蓝色生物医药科技有限公司 | Penicilones derivative and application thereof as anti-resistant bacteria drug |
| CN108503585A (en) * | 2017-02-28 | 2018-09-07 | 扬州蓝色生物医药科技有限公司 | The amino acid derivativges of PeniciloneB and its application as antibacterials |
| CN108503585B (en) * | 2017-02-28 | 2019-10-25 | 扬州蓝色生物医药科技有限公司 | The amino acid derivativges of Penicilone B and its application as antibacterials |
| CN110776518A (en) * | 2019-11-28 | 2020-02-11 | 云南大学 | Azaphilone spiro compounds and preparation method and application thereof |
| CN115872966A (en) * | 2022-08-29 | 2023-03-31 | 中国科学院南海海洋研究所 | Xanthone compound and preparation method and application thereof |
| CN115872966B (en) * | 2022-08-29 | 2024-05-07 | 中国科学院南海海洋研究所 | Xanthone compound and preparation method and application thereof |
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Application publication date: 20150128 |