CN110015991A - bipyridine compound and preparation method and application thereof - Google Patents
bipyridine compound and preparation method and application thereof Download PDFInfo
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- CN110015991A CN110015991A CN201910426803.6A CN201910426803A CN110015991A CN 110015991 A CN110015991 A CN 110015991A CN 201910426803 A CN201910426803 A CN 201910426803A CN 110015991 A CN110015991 A CN 110015991A
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- -1 bipyridine compound Chemical class 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- 238000010898 silica gel chromatography Methods 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 229940088710 antibiotic agent Drugs 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- 241000187180 Streptomyces sp. Species 0.000 claims description 5
- 102000018690 Trypsinogen Human genes 0.000 claims description 5
- 108010027252 Trypsinogen Proteins 0.000 claims description 5
- 238000002270 exclusion chromatography Methods 0.000 claims description 5
- 239000000499 gel Substances 0.000 claims description 5
- 238000011534 incubation Methods 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000002953 preparative HPLC Methods 0.000 claims description 4
- 229940041514 candida albicans extract Drugs 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- 239000012138 yeast extract Substances 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 229920001503 Glucan Polymers 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims description 2
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 claims 1
- 238000001228 spectrum Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 2
- 229940124350 antibacterial drug Drugs 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000001963 growth medium Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
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- 229930014626 natural product Natural products 0.000 description 3
- 238000011218 seed culture Methods 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical class N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000187747 Streptomyces Species 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
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- 229960000988 nystatin Drugs 0.000 description 2
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 2
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241001655322 Streptomycetales Species 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
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- 238000011081 inoculation Methods 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
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- 239000006228 supernatant Substances 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- 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
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
- C12P17/165—Heterorings having nitrogen atoms as the only ring heteroatoms
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Microbiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a bipyridine compound and a preparation method and application thereof, belonging to the field of medicines. The bipyridyl compound has good antibacterial activity, can be used for preparing antibacterial drugs, and has the structural formula:
Description
Technical field
The present invention relates to field of medicaments, in particular to a kind of Bipyridine compound and its preparation method and application.
Background technique
Natural product chemistry is the important branch of organic chemistry, is the research biologic artifact metabolite from molecular level
And its science of changing rule.Rich and varied organism is the source of natural products discovery, Structures of Natural Products in the Nature
It is the important sources of Development of New Drugs with diversity, complexity.Interior raw microorganism is considered as bioactivity and the new chemical combination of chemistry
The abundant and reliable sources of object have the potentiality to be exploited of extensive medical treatment, agricultural and industrial circle.Almost it is tellurian each
Plant has interior raw microorganism.In general, it can be isolated from one plant of plant and count to hundreds of endophytes.It is worth noting
, have nearly 300,000 kinds of plants on the earth, each plant is considered as one or more endophytic hosts, it is this in
Plant can create huge bio-diversity.In recent years, endophyte causes more and more people to new medicinal
The concern of product.By the end of the year 2010, more than 33500 kinds bioactive compounds are obtained from microorganism.Wherein 40% is
It is generated by actinomyces, especially the excellent production bacterium of streptomycete (Streptomyces) category.
Summary of the invention
The purpose of the present invention is to provide a kind of Bipyridine compound and its preparation method and application, this bipyridyl chemical combination
Object, structure novel, and have good antibacterial activity, it can be used for preparing antibacterials, there is wide prospect in medicine.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
A kind of Bipyridine compound, structural formula are shown in formula I:
A kind of preparation method of Bipyridine compound comprising:
The strain of isolated streptomycete Streptomyces sp.Kib H017C is subjected to fermented and cultured, obtains culture solution；
After the culture solution is extracted with ethyl acetate, silica gel column chromatography, the MCI gel column-efficient liquid of preparative are successively used
Phase chromatography, exclusion chromatography and semi-preparative high performance liquid chromatography are separated.
Further, in preferred embodiments of the present invention, the condition of above-mentioned fermented and cultured are as follows: 25-30 DEG C of cultivation temperature,
Incubation time 5-10 days.
Further, in preferred embodiments of the present invention, the culture medium of above-mentioned fermented and cultured includes: 0.2-0.8%'s
Trypsinogen, the yeast extract of 0.2-0.8%, the soluble starch of 0.5-1.5%, 0.5-1.5% D-Glucose,
The glycerol of 0.5-1.5% and the CaCO of 0.1-0.5%3。
Further, in preferred embodiments of the present invention, above-mentioned the step of being separated with silica gel column chromatography include: by
The acetic acid ethyl ester extract obtained after the culture solution is extracted with ethyl acetate and carries out silica gel column chromatography separation, with petroleum ether-second
Acetoacetic ester mixed solvent system and methanol are eluant, eluent, obtain component A, B component and component C；
Preferably, the volume ratio of petroleum ether and ethyl acetate is successively in the petroleum ether-ethyl acetate mixed solvent system
For 80-95:10,40-60:50 and 0-10:90-100.
Further, above-mentioned to use MCI gel column-preparative high performance liquid chromatography in preferred embodiments of the present invention
The step of being separated includes: to carry out ladder using the methanol aqueous solution that flow velocity is 10-14mL/min for after the B component loading
Degree elution, obtains B-3 component.
Further, above-mentioned that the B-3 group is separated using the exclusion chromatography in preferred embodiments of the present invention
Point, packing material is glucan SephadexLH-20.
A kind of application of above-mentioned Bipyridine compound in preparation antibacterials.
A kind of antibacterials comprising above-mentioned Bipyridine compound and pharmaceutically acceptable auxiliary material.
A kind of pharmaceutical composition, active constituent include above-mentioned Bipyridine compound.
Compared with prior art, the invention has the benefit that
This Bipyridine compound provided by the invention, molecular formula C13H13N3O2S, structure novel, and have fine
Antibacterial activity, especially antifungal activity can be used for preparing antibacterials.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described.
Fig. 1 is the nuclear magnetic resonance spectroscopy (DMSO-d of compound of formula I6,600MHz)；
Fig. 2 is the carbon-13 nmr spectra (DMSO-d of compound of formula I6,600MHz)；
Fig. 3 is that the nuclear magnetic resonance H-H COSY of compound of formula I composes (DMSO-d6,600MHz)；
Fig. 4 is the nuclear magnetic resonance hsqc spectrum (DMSO-d of compound of formula I6,600MHz)；
Fig. 5 is that the nuclear magnetic resonance HMBC of compound of formula I composes (DMSO-d6,600MHz)。
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
Present embodiment provides a kind of Bipyridine compound (specially 2,2 '-Bipyridine compounds), structural formula such as Formulas I
It is shown:
The preparation method of this Bipyridine compound shown in formula I, comprising the following steps:
Step S1, the preparation of fermentation liquid:
The strain of isolated streptomycete Streptomyces sp.Kib H017C is subjected to fermented and cultured, obtains culture solution；
Wherein, the bacterial strain of streptomycete Streptomyces sp.Kib H017C is by Northeast Agricultural University's Life Science College
It provides.(Genbank is logged in the 16S rRNA gene order (Genbank accession number MK049995) and streptomyces S8 of the bacterial strain
Number CP015362) with 99% homology.
Further, the condition of above-mentioned fermented and cultured are as follows: 25-30 DEG C of cultivation temperature, or be 27-29 DEG C；Incubation time
5-10 days, or be 7-9 days.
Further, the culture medium of above-mentioned fermented and cultured includes: the ferment of the trypsinogen of 0.2-0.8%, 0.2-0.8%
Female extract, the soluble starch of 0.5-1.5%, the D-Glucose of 0.5-1.5%, 0.5-1.5% glycerol and 0.1-0.5%
CaCO3。
Alternatively, the culture medium of above-mentioned fermented and cultured include: the trypsinogen of 0.4-0.6%, 0.3-0.7% yeast mention
Take object, the soluble starch of 0.7-1.2%, the D-Glucose of 0.7-1.2%, the glycerol of 0.7-1.2% and 0.2-0.4%
CaCO3。
Step S2, the preparation of compound of formula I:
After the culture solution is extracted with ethyl acetate, silica gel column chromatography, the MCI gel column-efficient liquid of preparative are successively used
Phase chromatography, exclusion chromatography and semi-preparative high performance liquid chromatography are separated.
This 2 of present embodiment offer, 2 '-Bipyridine compounds can be administered orally or without mouth, and dosage is because of medicine
Object is different and has nothing in common with each other, and for adult, daily 1-100mg is proper.
When oral administration, make the compound and conventional medicinal adjuvant such as excipient, disintegrating agent, binder, profit first
Lubrication prescription, coating agent, colorant, aromatic, surfactant etc. mixing, be made into the forms such as granule, capsule, tablet to
Medicine, when non-oral administration, can be administered in the form of injection, infusion solution or suppository etc..When preparing above-mentioned preparation, routine can be used
Preparation technique.
Feature and performance of the invention are described in further detail with reference to embodiments:
Embodiment 1
The present embodiment provides a kind of Bipyridine compound, preparation method includes:
1. fermented and cultured:
The strain of isolated streptomycete Streptomyces sp.Kib H017C is inoculated in seed culture medium.Seed
Culture medium is prepared in 250 milliliters of baffle conical flasks.Each flask fill 50ml Triptic soya soup (30g/L,
PH is not adjusted), and cultivated 48 hours on 28 DEG C of rotary shaker (200rpm).
Fermented and cultured is carried out in 1000 milliliters of baffle conical flasks, 250 milliliters of culture medium is injected in each flask,
Including 0.5% trypsinogen, 0.5% yeast extract, 1% soluble starch, 1% D-Glucose, 1%
Glycerol and 0.3% CaCO3(pH is adjusted to 7.0).Each fermentation flask is inoculated with 10mL seed culture medium, in 28 DEG C of rotation
It is cultivated 7 days on shaking table (200rpm), obtains culture solution.
2. compound separates:
After culture solution (15L) is centrifuged (4000rpm, 20 minutes), aqueous supernatant liquid is extracted with ethyl acetate (6 × 5L),
Mycelium is extracted with acetone (3 × 0.5L), is added water after vacuum concentration with ethyl acetate (2 × 0.5L) extraction.Merge two second
Evaporative removal solvent after acetoacetic ester phase, (1.5 grams) progress silica gel column chromatographies of residue.
It is eluted with petroleum ether-ethyl acetate (90:10,50:50 and 0:100v/v) and methanol, generates three A to C components.
B component (1.0g) is further separated on MCI column using preparation HPLC, the MeOH-H for the use of flow velocity being 12ml/min2O (methanol
Percentage by volume successively are as follows: 25%, 50%, 75% and 100%) elute, isolated B-1 to B-4 component.With
B-3 is further separated into B-3-1 to B-3-3 component by SephadexLH-20 chromatography (MeOH is eluant, eluent).It is made using half
The standby HPLC 35% methanol aqueous solution Isocratic clution that flow velocity is 3mL/min, obtains compound I (4.0mg).
3, the Structural Identification of compound I:
Character: white powder is soluble in DMSO, molecular formula C13H13N3O2S。
HRESI-MS:m/z 276.0808 [M+H]+(calcd C13H13N3O2S for 276.0801)
1 nuclear magnetic spectrogram of compound is as Figure 1-Figure 5, and NMR (DMSO) data are shown in Table 1.
NMR (DMSO) data of 1 noval chemical compound 1 of table
It is identified by above-mentioned spectral data, compound I is 2,2 '-Bipyridine compounds, and structural formula is shown in formula I:
4, determination of activity:
(1) antibacterial activity
For plate diffusion analysis, the compound I of 20 μ g is dissolved in acetone and drips on paper disc (diameter 5mm, thickness
0.5mm).It aseptically dries, places it in and be inoculated on the agar plate of test organisms that (experimental bacteria includes two kinds of fungal bacterial strains
With two kinds of bacterium bacterial strains.Two kinds of fungal bacterial strains: saccharomyces cerevisiae and penicillium decumbens ATCC 10436；Two kinds of bacterium bacterial strains: large intestine
Bacillus ATCC 8099 and staphylococcus aureus ATCC 6538).Culture plate is cultivated 12 hours or 28 DEG C under 37 DEG C (bacterium)
(fungi) is cultivated 48 hours, and measures inhibition zone.Respectively with kanamycins (10 μ g/disk) and nystatin (10 μ g/disk)
As the positive control of bacterium and fungi, each test is carried out four times.
Antibacterial activity evaluation is carried out to compound I, the results are shown in Table 2, and concentration is 20 μ g/disk, to saccharomyces cerevisiae table
Reveal antifungal activity, for the diameter of inhibition zone between 10-11mm, effect is slightly below positive reference substance nystatin (10 μ g/
disk)。
Table 2: the antibacterial activity of compound 1
(2) cellular cytoxicity activity
With MTS method measurement compound I to people's myeloid leukemia (HL-60), liver cancer (SMMC-7721), lung cancer (A-549),
The cytotoxicity of the tumor cell lines such as breast cancer (MCF-7) and colon cancer (SW480).Cis-platinum (sigma, purity 99%) and purple
China fir alcohol (taxol, sigma, purity 97%) is used as positive control.
The culture in RPMI1640 the or DMEM culture medium (Hyclone, Logan, UT, USA) by all cells, at 37 DEG C
Contain 5%CO2Humidified ambient in add 10% fetal calf serum (Hyclone, USA).Cell is with every hole 1 × 104Cell inoculation
In 96 porocyte culture plates, 37 DEG C incubation 12-24 hours.By the change of various concentration (0.064,0.32,1.6,8.0,40 μm)
It closes and is cultivated 48 hours in object I 96 orifice plates of addition.Then 20 μ L MTS, 37 DEG C of incubation 4h are added in every hole.Finally, being used at 492nm
Multiskan FC microplate reader (Thermo Scientific, USA) measurement optical density simultaneously calculates IC50 value.
Cellular cytoxicity activity is carried out to isolated compound I, the results are shown in Table 3.Thus illustrate, compound I
(i.e. 2,2 '-Bipyridine compounds) are to 5 kinds of cancer cell line (IC50> 40 μm) without apparent antiproliferative effect.
Table 3: cellular cytoxicity activity (IC of the compound I to 5 kinds of tumor cell lines50, μm)
Embodiment 2:
Tablet: by embodiment 1 gained compound I 10mg, lactose 180mg, starch 55mg, magnesium stearate 5mg, lactose and
Starch mixes, and is uniformly moistened with water, the mixture after moistening is sieved and is dried, re-sieving, magnesium stearate is added, then will mix
Close object tabletting, every slice weight 250mg, compound I content 10mg.
Embodiment 3:
Ampulla: 1 gained compound I 2mg of embodiment, sodium chloride 10mg are dissolved in suitable water for injection, mistake
Acquired solution is filtered, is aseptically fitted into ampoule bottle.
Embodiment 4:
Injection is freeze-dried: by embodiment 1 gained compound I 10mg, sodium bicarbonate 2mg, mannitol 252mg.
Preparation method: sodium bicarbonate, mannitol are dissolved in water for injection, and add activated carbon adsorption 30min depyrogenation, mistake
Deactivation charcoal is filtered out, compound is added in filtrate, ultrasonic treatment makes to dissolve, and adjusting PH with 1N hydrochloric acid is 5.0-7.0, micropore
Filter membrane filtration, add water for injection, dispense, freeze-drying, top plug, roll lid to get.
Embodiment 5:
Capsule: by embodiment 1 gained compound I 10mg, lactose 187mg, magnesium stearate 3mg；Preparation method: will change
It closes object or its salt and cosolvent mixes, sieving uniformly mixes, and obtained mixture is packed into hard gelatin capsule, each capsule weight
200mg, active component content 10mg.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of Bipyridine compound, structural formula are shown in formula I:
2. a kind of preparation method of Bipyridine compound as described in claim 1, characterized in that it comprises:
The strain of isolated streptomycete Streptomyces sp.Kib H017C is subjected to fermented and cultured, obtains culture solution；
After the culture solution is extracted with ethyl acetate, silica gel column chromatography, MCI gel column-preparative high-efficient liquid phase color are successively used
Spectrum, exclusion chromatography and semi-preparative high performance liquid chromatography are separated.
3. the preparation method of Bipyridine compound according to claim 2, which is characterized in that the condition of the fermented and cultured
Are as follows: 25-30 DEG C of cultivation temperature, incubation time 5-10 days.
4. the preparation method of Bipyridine compound according to claim 3, which is characterized in that the culture of the fermented and cultured
Base includes: the trypsinogen of 0.2-0.8%, the yeast extract of 0.2-0.8%, the soluble starch of 0.5-1.5%, 0.5-
The CaCO of 1.5% D-Glucose, the glycerol of 0.5-1.5% and 0.1-0.5%3。
5. the preparation method of Bipyridine compound according to claim 2, which is characterized in that divided with silica gel column chromatography
From the step of include: that the acetic acid ethyl ester extract that obtains after the culture solution will be extracted with ethyl acetate to carry out silica gel column chromatography point
From obtaining component A, B component and component C using petroleum ether-ethyl acetate mixed solvent system and methanol as eluant, eluent；
Preferably, the volume ratio of petroleum ether and ethyl acetate is followed successively by 80- in the petroleum ether-ethyl acetate mixed solvent system
95:10,40-60:50 and 0-10:90-100.
6. the preparation method of Bipyridine compound according to claim 5, which is characterized in that use MCI gel column-preparation
The step of type high performance liquid chromatography is separated includes: the first for the use of flow velocity being 10-14mL/min by after the B component loading
Alcohol solution carries out gradient elution, obtains B-3 component.
7. the preparation method of Bipyridine compound according to claim 6, which is characterized in that use the exclusion chromatography
The B-3 component is separated, packing material is glucan Sephadex LH-20.
8. a kind of application of Bipyridine compound as described in claim 1 in preparation antibacterials.
9. a kind of antibacterials, which is characterized in that it includes Bipyridine compound as described in claim 1, and pharmaceutically
Acceptable auxiliary material.
10. a kind of pharmaceutical composition, which is characterized in that its active constituent includes Bipyridine compound as described in claim 1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0912550A (en) * | 1995-06-30 | 1997-01-14 | House Foods Corp | 2,2'-bipyridine derivative, its production and antineoplastic agent containing the same |
| CN108484699A (en) * | 2016-11-15 | 2018-09-04 | 中国海洋大学 | Bipyridyliums alkaloid, preparation method and use |
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2019
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0912550A (en) * | 1995-06-30 | 1997-01-14 | House Foods Corp | 2,2'-bipyridine derivative, its production and antineoplastic agent containing the same |
| CN108484699A (en) * | 2016-11-15 | 2018-09-04 | 中国海洋大学 | Bipyridyliums alkaloid, preparation method and use |
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