CN106167494A - Halogenation II type polyketide compound, preparation method and applications - Google Patents
Halogenation II type polyketide compound, preparation method and applications Download PDFInfo
- Publication number
- CN106167494A CN106167494A CN201610390757.5A CN201610390757A CN106167494A CN 106167494 A CN106167494 A CN 106167494A CN 201610390757 A CN201610390757 A CN 201610390757A CN 106167494 A CN106167494 A CN 106167494A
- Authority
- CN
- China
- Prior art keywords
- compound
- halogenation
- preparation
- polyketide compound
- type polyketide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- 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
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of halogenation II type polyketide compound, it is characterised in that structure is:The technical problem to be solved in the present invention is to provide the halogenation II type polyketide compound of a kind of stronger overriding resistance staphylococcus aureus.
Description
Technical field
The present invention relates to microorganism field, be specifically related to a kind of halogenation II type polyketide compound, preparation method
And application.
Background technology
Antibiotic has played vital effect in terms of the treatment disease such as microorganism infection and tumor, but due to anti-
Many reasons such as the abuse of raw element, the pathogenic bacteria resistance to drugs problem found clinically is increasingly severe.Such as, the world is each in recent years
There is multiple " superbacteria " in ground, and they all produce drug resistance to most antibiotics, to diseases such as pathogenic bacterial infections clinically
Treatment bring huge challenge.At present, the mankind in the serious threat such as bacterial resistance, superinfection, untoward reaction, anaphylaxis
Health, if taken action the most as early as possible, this may be to the mankind's bringing on a disaster property consequence.Therefore, in view of the most increasingly serious
Antibacterial situation, strengthens antibiotic R&D intensity, and exploring and research and develop antibiotics becomes the task of top priority.
Summary of the invention
The technical problem to be solved in the present invention is to provide the halogenation II type of a kind of stronger overriding resistance staphylococcus aureus
Polyketide compound.
In order to solve above-mentioned technical problem, the present invention provides following technical scheme: halogenation II type polyketide chemical combination
Thing, structure is:
This compound has the structural framework type of Anthrabenzoxocinones type.This compound is by streptomycete
Streptomyces sp.FJS31-2 bacterial strain (bacterial strain preserving number: CGMCC 4.7321) fermentation isolated, to gram sun
Property antibacterial such as staphylococcus aureus and fastbacteria thereof have the highest inhibitory activity, are expected to become overriding resistance Staphylococcus aureus
Bacterium medicine and lead compound thereof and there is good medicinal DEVELOPMENT PROSPECT.
Another technical scheme that the present invention provides, the preparation method of halogenation II type polyketide compound, include
CGMCC registration number is the streptomycete of CGMCC 4.7321.
Another technical scheme that the present invention provides, the application of halogenation II type polyketide compound, as overriding resistance
Staphylococcus aureus.
Accompanying drawing explanation
Fig. 1 is the infrared spectrogram of the compounds of this invention；
Fig. 2 is the high resolution mass spectrum figure of the compounds of this invention；
Fig. 3 is that the compounds of this invention is in MeOH-d41H-NMR spectrum；
Fig. 4 is that the compounds of this invention is in MeOH-d413C-NMR spectrogram；
Fig. 5 is the compounds of this invention DEPT spectrogram in MeOH-d4；
Fig. 6 is the compounds of this invention hsqc spectrum figure in MeOH-d4；
Fig. 7 is the compounds of this invention HMBC spectrogram in MeOH-d4；
Fig. 8 is the compounds of this invention H-H COSY spectrogram in MeOH-d4；
Fig. 9 is the compounds of this invention ROESY spectrogram in MeOH-d4；
Figure 10 is the compounds of this invention CD spectrum in MeOH-d4；
Figure 11 is the overriding resistance staphylococcus aureus activity pictorial diagram of compound.
The depositary institution of streptomycete used: China Committee for Culture Collection of Microorganisms of Pekinese common micro-organisms center
(CGMCC)；
Deposit number: CGMCC 4.7321；
The preservation time: on 06 02nd, 2016.
Detailed description of the invention
Halogenation natural product has the feature of novel structure, makes halogenated products patent medicine potentiality increase, it has been found that to have
More than 6000 plant the halogenation natural product with various structures.They have the activity of antibiotic greatly.Due to halogenation
Product has bigger clinical practice potentiality in terms of antagonism drug-fast bacteria infection, such as anti-infective vancomycin clinically, impersonates and draws
Peaceful and U.S. FDA approval listing in 2014 antimicrobial agent infects antibiotic new drug dalbavancin, oritavancin and safe ground azoles
Amine, they broadly fall into halogenation natural product.
From a streptomycete Streptomyces sp., (this streptomycete is preserved in Pekinese China Microbiological bacterium to the present inventor
Kind of preservation administration committee common micro-organisms center (CGMCC), registration number is: CGMCC 4.7321) in secondary metabolite point
From an Anthrabenzoxocinones class antibiotic, through ultraviolet spectra, infrared spectrum, high resolution mass spectrum, circular dichroism spectra and
The spectral datas such as nuclear magnetic resonance, NMR carefully analyze, and are defined as the new chlorizate of Anthrabenzoxocinones class.
CGMCC 4.7321 streptomycete:
1), name biology, classification foundation:
Primer (27f/1492r) amplification, order-checking online comparison analysis and reference strain is guarded through 16S rRNA
The homology of Streptomyces sparsogenes strain NBRC 13086 is 99%, and preliminary classification is streptomycete.
Named: streptomycete Streptomyces sp.
2), depositary institution: China Committee for Culture Collection of Microorganisms of Pekinese common micro-organisms center (CGMCC)；
3), deposit number: CGMCC 4.7321；
4), the preservation time: on 06 02nd, 2016；
5), preservation place: Yard 1, BeiChen xi Road, Chaoyang District, Beijing City 3: Institute of Microorganism, Academia Sinica；
6), feature:
I. aerial hyphae is flourishing, ecru bacterium colony, and edge roughness has gauffer；Spore number is on the low side；Mol%G+C=
73%.
Isolation medium:
Ii. solid GYM (ISP2): glucose 4g, Fructus Hordei Germinatus extract 4g, yeast powder 10g, calcium carbonate 2g, agar powder 18g,
Add water to 1000 milliliters, sterilizing.
Iii. condition of culture is advised:
Solid GYM culture medium: the suitableeest cultivation temperature 28 DEG C, it is proposed that incubation time: 4 days.
Iv.16s RNA sequence is:
TGCAGTCGAACGATGAAGCCGCTTCGGTGGTGGATTAGTGGCGAACGGGTGAGTAACACGTGGGCAATCTGCCCTGC
ACTCTGGGACAAGCCCTGGAAACGGGGTCTAATACCGGATATGACCTGGTGAGGCATCTTACTGGGTGGAAAGCTCC
GGCGGTGCAGGATGAGCCCGCGGCCTATCAGCTTGTTGGTGGGGTGATGGCCTACCAAGGCGACGACGGGTAGCCGG
CCTGAGAGGGCGACCGGCCACACTGGGACTGAGACACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGC
ACAATGGGCGAAAGCCTGATGCAGCGACGCCGCGTGAGGGATGACGGCCTTCGGGTTGTAAACCTCTTTCAGCAGGG
AAGAAGCGCAAGTGACGGTACCTGCAGAAGAAGCGCCGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGGCG
CAAGCGTTGTCCGGAATTATTGGGCGTAAAGAGCTCGTAGGCGGCTTGTCACGTCGGATGTGAAAGCCCGGGGCTTA
ACCCCGGGTCTGCATTCGATACGGGCAGGCTAGAGTTCGGTAGGGGAGATCGGAATTCCTGGTGTAGCGGTGAAATG
CGCAGATATCAGGAGGAACACCGGTGGCGAAGGCGGATCTCTGGGCCGATACTGACGCTGAGGAGCGAAAGCGTGGG
GAGCGAACAGGATTAGATACCCTGGTAGTCCACGCCGTAAACGTTGGGAACTAGGTGTGGGCGACATTCCACGTTGT
CCGtGCCGCAGCTAACGCATTAAGTTCCCCGCCTGGGGAGTACGGCCGCAAGGCTAAAACTCAAaGgAATTGACGGG
GGCCCGCACAAGCGGCGGAGCATGTGGCTTAATTCGACGCAACGCGAAGAACCTTACCAAGGCTTGACATACATCGG
AAACATCCAGAGATGGGTGCCCCCTTGTGGTCGGTGTACAGGTGGTGCATGGCTGTCGTCAGCTCGTGTCGTGAGAT
GTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTGTTCTGTGTTGCCAGCATGCCCTTCGGGGTGATGGGGACTCACA
GGAGACTGCCGGGGTCAACTCGGAGGAAGGTGGGGACGACGTCAAGTCATCATGCCCCTTATGTCTTGGGCTGCACA
CGTGCTACAATGGCCGGTACAATGAGCTGCGATACCGCGAGGTGGAGCGAATCTCAAAAAGCCGGTCTCAGTTCGGA
TTGGGGTCTGCAACTCGACCCCATGAAGTCGGAGTCGCTAGTAATCGCAGATCAGCATTGCTGCGGTGAATACGTTC
CCGGGCCTTGTACACACCGCCCGTCACGTCACGAAAGTCGGTAACACCCGAAGCCGGTGGCCCAACCCCTTGTGGAG
GGAGTC。
7), place is separated:
Fanjing Mountain Nature Reserve in Guizhou Province (height above sea level 800m, east longitude 108 ° 47 ' 50 ", north latitude 27 ° 56 ' 32 ").With
It it is down the determination confirming and applying of the concrete preparation method of Antibiotique composition of the present invention, compound.
It it is below the determination confirming and applying of the concrete preparation method of Antibiotique composition of the present invention, compound.
One, the preparation method of the Antibiotique composition of the present invention is:
1, fermentation culture
The streptomycete Streptomyces sp.FJS31-2 inoculation on growth inclined-plane is trained in seed culture medium, seed
Foster base is GYM solid medium, and (preparation method of GYM solid medium is: with glucose 4g, Fructus Hordei Germinatus extract 4g, yeast powder
10g, calcium carbonate 2g, trace element premix liquid 0.5mL and 1.8% agar powder (w/v), add deionized water constant volume to 1.0L, 121
DEG C autoclaving 30min makes), cultivate 48 hours, be then seeded into fermentation medium (formula and seed culture medium phase for 28 DEG C
With), cultivate 17 days at 28 DEG C.
2, separation is extracted
Being smashed to pieces together with thalline by above-mentioned fermentation medium, it is little that addition ethyl acetate extracts 24 at rotary shaker (160rpm)
Time, extract three times continuously, utilize Rotary Evaporators to reclaim ethyl acetate solvent at 45 DEG C, obtain fermented product crude extract 32g.
Fermented product crude extract 32g, normal phase silicagel column layer (silica gel 100-200 mesh, 1.5Kg silica gel particle), eluting solvent chlorine
Imitative: acetone (100%, 95%, 90%, 80%, 67%, 50%, 33%, 0%) eluting successively, is 80% (v/ by chloroform-acetone
V) elution fraction is again through polydextran gel Sephadex LH-20 column chromatography, the components I that 100% methanol-eluted fractions obtains warp again
Cross silica gel column chromatography (100-200 mesh), petroleum ether: ethyl acetate (v/v) eluting, eluting the most in the above sequence, petroleum ether: second
The elution fraction of acetoacetic ester (v/v)=10:1 is prepared into compound through HPLC 95% methanol isocratic elution again.
Two, the Structural Identification of compound
For buff powder, it is soluble in the organic solvents such as methanol, dimethyl sulfoxide, as it is shown in figure 1, the infrared spectrum of compound
Display, its INFRARED ABSORPTION 3385cm-1And 1609cm-1Show this compound with the presence of hydroxyl and carbonyl group, INFRARED ABSORPTION in addition
Peak 1421-1Cm and 1384cm-1, this compound is possibly together with benzene ring structure；
As in figure 2 it is shown, the high resolution mass spectrum of compound shows, its high-resolution anion peak charge-mass ratio 527.0658 He
529.0652, imply that this compound has molecular formula to be C27H22Cl2O7, degree of unsaturation is 16.
As shown in Fig. 4, Fig. 5, Fig. 6,13Showing in C NMR and DEPT spectrum and hsqc spectrum, this compound has three benzene
Ring, the sub-absorption signal of its carbonaceous is respectively 160.6, and 157.7,152.6,151.8,150.7,150.7,150.4,141.2,
133.4,122.5,117.2,115.7,113.6,113.6,111.2,107.2,106.3 and 101.7；In addition this compound is also
Containing a carbonyl group, its signal is 189.7；One methylene (δC: 39.4)；Quaternary carbon atom (δC: 38.1,98.4)；As
Shown in Fig. 3, in conjunction with13In H NMR nuclear-magnetism spectrum, compound has three phenyl ring unimodal Hydrogen Proton signal [δH: 6.82 (1H, s), 6.57
(1H,s),6.17(1H,s)]；Four methyl peak-to-peak signals [2.41 (3H, s), 1.51 (3H, s), 1.45 (3H, s), 1.36 (3H,
s)]；Show that this compound has ABX poly-type skeleton in conjunction with literature survey.This compound is different from ABX skeleton to be, its phenyl ring
On two Hydrogen Proton be substituted by a chlorine atom both.
As shown in Figure 7, Figure 8, in HMBC spectrum and H-H COSY spectrogram, hydrogen signal 6.82 (1H, s) with carbon signal 111.2 and
122.5 are correlated with, it was demonstrated that this proton is connected to the C-8 position of ABX skeleton；δH6.57 (1H, s) and δC106.3 it is relevant.
As it is shown in figure 9, on ROSEY spectrogram, δH6.57 (1H, s) He two methyl hydrogen proton signal 1.36 and 1.45 phases
Pass may determine that this Hydrogen Proton is attached to C-10 position；δH6.17 (1H, s) and δC113.6,115.7,133.4,150.7 Hes
152.6 are correlated with, it was demonstrated that (1H s) is connected on C-4 position for proton 6.17；(1H s) has a key to last proton signal 6.10
Coherent signal, it is relevant to carbon signal 98.4 determines that this proton is connected on C-16 position.Comprehensive information above, it may be determined that chlorine is former
Son the position of substitution on phenyl ring, 2 chlorine atoms instead of the hydrogen atom on 4 and 12 respectively, has obtained the flat of this compound
Face structure.
As shown in Figure 10, be may determine that by CD spectrogram the absolute configuration of compound, CD spectrogram show at 239nm and
283nm has the most positive Cotton effect, according to the report of Chen Haiyan et al., shows that this compound C-16 and C-6 is configured as S,
The structure thereby determining that this compound is:With compound NMR data in MeOH-d4
As shown in table 1.This compound of systematic naming method is: (6s, 16s)-4,12-dichloro anthrabenzoxocinone, due to
This compound is the discovery first of the present inventor, and therefore, secondary Compound nomenclature is zunyimycin B by inventor.Its two dimension is vertical
Body surface is shown as:
Table 1
Three, the application of compound determines
Paper disk method is used this compound of named zunyimycin B to be carried out antibacterial activity test, with drug resistance Bao Man not
Lever bacterium, antibiotic-resistance E. coli, drug resistance klebsiella pneumoniae, resistant Staphylococcus aureus are for surveying viable bacteria, methanol and acetone
For negative control.As shown in figure 11,2 is the compound of the present invention to result, and 1,3 is other two kinds of compounds；4 is acetone；5 is first
Alcohol, shows, the compound of the present invention is all inhibited to resistant Staphylococcus aureus, and antibacterial circle diameter is 1.3mm.
For a person skilled in the art, on the premise of without departing from technical solution of the present invention, it is also possible to if making
Dry deformation and improving, these also should be considered as protection scope of the present invention, these all without affect effect that the present invention implements with
Practical applicability.
Claims (3)
1. halogenation II type polyketide compound, it is characterised in that structure is:
The preparation method of halogenation II type polyketide compound the most according to claim 1, it is characterised in that: include
The streptomycete having CGMCC registration number to be CGMCC 4.7321.
The application of halogenation II type polyketide compound the most according to claim 1 and 2, it is characterised in that: it is used as
Overriding resistance staphylococcus aureus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610390757.5A CN106167494B (en) | 2016-06-03 | 2016-06-03 | Halogenation II type polyketides compound, preparation method and applications |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610390757.5A CN106167494B (en) | 2016-06-03 | 2016-06-03 | Halogenation II type polyketides compound, preparation method and applications |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106167494A true CN106167494A (en) | 2016-11-30 |
| CN106167494B CN106167494B (en) | 2018-08-31 |
Family
ID=57359186
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610390757.5A Expired - Fee Related CN106167494B (en) | 2016-06-03 | 2016-06-03 | Halogenation II type polyketides compound, preparation method and applications |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106167494B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110526925A (en) * | 2019-07-16 | 2019-12-03 | 遵义市第一人民医院 | A kind of separation method of 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative and its application |
| CN115054597A (en) * | 2022-06-30 | 2022-09-16 | 延安大学 | Application of halogenated II type polyketone compound in intervention of Alzheimer's disease |
-
2016
- 2016-06-03 CN CN201610390757.5A patent/CN106167494B/en not_active Expired - Fee Related
Non-Patent Citations (2)
| Title |
|---|
| HAIYAN CHEN ET AL.: "Isolation of an anthrabenzoxocinone 1.264-C from Streptomyces sp. FXJ1.264 and absolute configuration determination of the anthrabenzoxocinones", 《TETRAHEDRON: ASYMMETRY》 * |
| YUHONG LÜ ET AL.: "Molecular Genetic Characterization of an Anthrabenzoxocinones Gene Cluster inStreptomyces Sp. FJS31-2 for the Biosynthesis of BE-24566B and Zunyimycin Ale", 《MOLECULES》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110526925A (en) * | 2019-07-16 | 2019-12-03 | 遵义市第一人民医院 | A kind of separation method of 25 β--23 β of secondary cyclobutenyl-isobutyl acyloxy mibemycin derivative and its application |
| CN110526925B (en) * | 2019-07-16 | 2021-10-12 | 遵义市第一人民医院 | Separation method and application of 25 beta-sec-butenyl-23 beta-isobutyryloxymilbemycin derivative |
| CN115054597A (en) * | 2022-06-30 | 2022-09-16 | 延安大学 | Application of halogenated II type polyketone compound in intervention of Alzheimer's disease |
| CN115054597B (en) * | 2022-06-30 | 2023-08-25 | 延安大学 | Application of halogenated type II polyketide in intervention of Alzheimer's disease |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106167494B (en) | 2018-08-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106432262A (en) | Streptomyces-derived halogenated polyketide compound, preparation method and application | |
| CN104402899B (en) | Citrinin compounds penicitrinol L coming from Aspergillus citrimum and its preparation method and application | |
| CN102977082B (en) | Isocoumarin compound as well as preparation method and application thereof | |
| CN108017655A (en) | A kind of II type halogenation polyketides of chlorine substitution and preparation method and application | |
| CN106167495B (en) | A kind of halogenation II type polyketides compound, preparation method and applications | |
| CN106167494B (en) | Halogenation II type polyketides compound, preparation method and applications | |
| CN112300243B (en) | Cyclopeptide compound and preparation method and application thereof | |
| CN109106702A (en) | Derived from application of 4-4 ' the isomerization secalonic acid D in terms of colon cancer of penicillium oxalicum | |
| CN103145740B (en) | Sulfoxide alkaloid compound as well as preparation method and application for same | |
| CN114213428B (en) | Indole alkaloid compound and preparation method and application thereof | |
| CN1923825B (en) | Novel antibiotic Chemomycin A and preparation method thereof | |
| CN105399721B (en) | Noval chemical compound and preparation method thereof and the application in antibacterial antineoplastic is prepared | |
| CN109988129A (en) | Compound and its preparing the application in antituberculotic | |
| CN113248513B (en) | Novel cytochalasin compound with function of antagonizing clinically drug-resistant bacteria and preparation method thereof | |
| CN114621092A (en) | Phenolic compound in mangrove plant-derived fungi and preparation method thereof | |
| CN108441427B (en) | Arthriospora fungi and pyridone alkaloid compound produced by same | |
| CN108727169A (en) | A kind of preparation method of the biphenyl ether compound in marine fungi source and the application as antiseptic | |
| CN105837590A (en) | Compound with anti-Candida albicans activity, preparation method and application thereof | |
| CN100387609C (en) | Novel antibiotic preparing process | |
| CN107973803B (en) | Seven-membered lactonofuran derivative and preparation method and application thereof | |
| CN110172410A (en) | A kind of aphthopyrans ketone compound in marine fungi source, preparation method and applications | |
| CN103265522B (en) | Lactone derivative derived from trichoderma citrinoviride and application thereof | |
| CN103980285B (en) | A kind of pyrans naphthoquinones class microbiotic and Synthesis and applications thereof | |
| CN109111422A (en) | Macrolides compound and its application in preparation prevention and treatment plant-pathogenic pathogenic bacteria drug | |
| CN103880824B (en) | Isocoumarin class microbiotic and agromycin (Hetiamacin) B, C, D and Synthesis and applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180831 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |