CN105272900B - Bisindole derivative and preparation method and application - Google Patents
Bisindole derivative and preparation method and application Download PDFInfo
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- CN105272900B CN105272900B CN201510037124.1A CN201510037124A CN105272900B CN 105272900 B CN105272900 B CN 105272900B CN 201510037124 A CN201510037124 A CN 201510037124A CN 105272900 B CN105272900 B CN 105272900B
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- JYDCZYPUERLHOZ-GFOWMXPYSA-N OCCc1c([C@@H](C(CO)O)c2cnc3c2cccc3)[nH]c2c1cccc2 Chemical compound OCCc1c([C@@H](C(CO)O)c2cnc3c2cccc3)[nH]c2c1cccc2 JYDCZYPUERLHOZ-GFOWMXPYSA-N 0.000 description 1
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Abstract
The invention discloses a kind of bisindole derivatives and preparation method and application.Bisindole alkaloid derivative provided by the present invention, structural formula as shown in formula I and formula II,
Description
Technical field
The present invention relates to biomedicine fields, and in particular to a kind of bisindole derivative and preparation method thereof and this spread out
The medical usage of biology.
Background technology
With the abuse of antibiotic, the appearance of superbacteria so that bacterium infection is to endanger the principal disease of human health
One of.Research and develop the important research content that new antibiotic is always field of medicaments.In recent years, natural products is increasingly becoming
The important sources of human research's effective active composition, during new drug development, the on the one hand natural products with excellent activity
It can be used directly to clinic；On the other hand, using active skull cap components as lead compound, pass through organic synthesis, structure of modification
The methods of find and develop new high-efficiency low-toxicity drug, be one of approach for being proved most effective developing new drug.
Due to the particularity of the marine eco-environment, the biosynthesis pathway and enzyme of marine organisms generation secondary metabolite are anti-
System is answered to have huge difference compared with terrestrial life, cause marine organisms tend to generate some chemical constitutions it is novel,
The significant marine drug lead compound of diverse biological activities, activity, a large amount of pattern knot is provided for new drug research and exploitation
Structure and prodrug.However, although Chinese Marine Biology Resources are enriched, but extremely have for the medicine resource of new drug development
Limit, sustainable use potentiality are also little.
As the important composition in marine ecosystems, it is various that marine microorganism is similarly long-term adaptation existence generation
Enzyme and many novel reactive compounds.Research shows that marine microorganism has abundant bio-diversity, type up to 1
Hundred million kinds or more, but study be less than the 1% of marine microorganism total amount with authenticated marine microorganism at present, it means that sea
Foreign microorganism provides an infinite resource of approximation for the research of marine drug.Distribution of the microorganism in ocean is very wide
It is general, with the presence of microorganism in extreme environment, a portion be in marine animal and plant grow nonparasitically upon another plant altogether, commensalism, parasitism or
The microorganism to grow nonparasitically upon another plant is known as symbiotic and epiphyte microorganism.It is pointed out in many document reports, it is by plant and without vertebra that many, which has previously been thought that,
The active material that animal generates is actually to be generated by the microorganism to grow nonparasitically upon another plant altogether with it.Therefore, ocean symbiotic and epiphyte microorganism is being just
Paid attention to by more and more researchers, be found that type is various and has from the symbiotic and epiphyte microorganism of ocean so far
The significant biological active agents of activity.
Invention content
The object of the present invention is to provide a kind of bisindole derivatives and preparation method thereof.
Bisindole derivative provided by the present invention, structural formula are formula I or the compound of formula II：
The present invention also provides the preparation methods of above-mentioned bisindole derivative, include the following steps：1) fermented and cultured is micro-
Biology；2) by the zymotic fluid after organic solvent extracts, 30 DEG C of reduced pressures obtain primary extract；3) it is the conversion product is residual
Slag uses methanol-water binary system gradient elution with reverse phase mesolow chromatogram purification, the column purification, collects and merges component；4)
The component with reversed-phase high performance liquid chromatography is purified, obtains product.
Wherein, above method step 1) microorganism be actinomyces, bacillus rubidus (Rubrobacter
radiotolerans)。
Extractant is conventional type organic solvent in above method step 2), ethyl acetate.
The preferred eluent for collecting the elution of 50% methanol of reverse phase mesolow chromatogram purification in above method step 3).
Reversed-phase high performance liquid chromatography purifies optimum condition in above method step 4)：Methanol-water (35:65, V/V), flow velocity
For 1.0mL/min.Detection wavelength is 220nm, and isolated structural formula is formula I (retention time 57mins) and formula II (during reservation
Between 108mins) compound.
It is a further object of the present invention to provide bisindole derivative formulas I of the present invention and the purposes of the compound of formula II.
The present invention experiments prove that, bisindole derivative of the invention have good antibacterial activity, can conduct
The active constituent of antibacterials.
The active constituent of these antibacterials can be one kind or several in the compound that structural formula is formula I or formula II
Kind.
Using above compound as can also be added in the drug of active constituent, when needs it is one or more pharmaceutically
Acceptable carrier.The carrier includes the diluent of pharmaceutical field routine, excipient, filler, adhesive, wetting agent, collapses
Agent, sorbefacient, surfactant, absorption carrier, lubricant etc. are solved, it can be according to the conventional method system of pharmaceutical field
It is standby.
The present invention utilizes microbial fermentation, purification technique, the actinomyces (Rubrobacter to grow nonparasitically upon another plant altogether to ocean ascidian
Radiotolerans secondary metabolite) has carried out system separation, obtains a new class of bisindole derivative, passes through
In vitro Bactericidal Experiments confirm that these compounds have preferable antibacterial activity, can have as the active constituent of antibacterials
Extensive purposes.
Description of the drawings
Fig. 1 purifies chromatogram for formula I and II compound RP-HPLC of formula.
Specific embodiment
Embodiment 1, the preparation that structural formula is II compound of formula I and formula
The present invention uses microbial fermentation, extracts, purifying and etc., to prepare the compounds of this invention.It is wherein used
Bacterial strain is bacillus rubidus.It is isolated in this bacterial strain Yu Haiyang ascidian, it is the symbiotic and epiphyte microorganism of ocean ascidian, is positioned over 20%
In glycerine water solution, preserved in subzero 80 DEG C of refrigerators.Selected culture medium is Gause I culture medium.
The preparation of Gause I culture medium：Weigh 2% soluble starch, 1% potassium nitrate, 0.05% sodium chloride, 0.05%
Dipotassium hydrogen phosphate, 0.05% magnesium sulfate, 0.001% ferrous sulfate are dissolved in 1000mL artificial seawaters, sterilize 30 at 121 DEG C
Minute.2% agar is added in liquid medium when preparing solid medium.30.0g sea salt is wherein dissolved in 1000ml certainly
To be configured to artificial seawater in aqueous solution.
The preparation (LB culture mediums) of bacteria culture media：5.0g yeast extracts, 10.0g are added in per 1000mL fluid nutrient mediums
Peptone, 10.0g NaCl, is dissolved in water, and adjusts pH value to 7.0.Solid slope culture medium is prepared to add in liquid medium again
1.5% agar.
The process of particular compound is as follows：
1) it ferments and extracts
Bacillus rubidus (Rubrobacter radiotolerans) is accessed into 2 250mL triangular flasks and (100mL Gao Shi are housed
No.1 culture medium) in, as seed liquor.Shaken cultivation is drawn after 3 days with Sterile pipette at 160rpm on shaking table, 28 DEG C
The seed liquor of 25mL is added in 20 1000mL shaking flasks (equipped with 500mL Gause Is culture medium).After shaken cultivation 14 days,
It is extracted 2 times with isometric ethyl acetate, extract liquor is concentrated under reduced pressure into dry, obtains conversion product residue about 6.0g.
2) reverse phase mesolow chromatography
Proper amount of methanol is dissolved in by residue obtained, adds to the chromatographic column equipped with 120g reverse phase silica gels (120 angstroms, 30-50 mesh), is used
Methanol-water system gradient elution (30%-100% methanol), every 10 percentage is a gradient, per gradient elution liquid
Product 1000ml collects the eluent of 50% methanol elution, concentration.
3) reversed-phase high performance liquid chromatography purifies
By the eluent rp-hplc analysis of step 3) collection, purifying.Analysis condition is：Chromatographic column
Hedera C18A-5 μm, 4.6mm I.D × 250mm (Jiangsu Chinese nation science and technology), elution system is methanol-water isocratic elution, specifically
Condition：Methanol-water (35:65, V/V), flow velocity 1.0mL/min.Detection wavelength is 220nm, 25 DEG C of column temperature, 20 μ L of sample size,
Structural formula is obtained as formula I (retention time, 57mins) or the compound of formula II (retention time, 108mins), as shown in Figure 1.
Chemical compounds I,
3-(3-(2-hydroxyethyl)-1H-indol-2-yl)-3-(1H-indol-3-yl)propane-1,2-
Diol, Yellow amorphous powder：
(+)-HRESIMS m/z 373.1526(calcd for C21H22N2O3Na,373.1528)。
Its1H-NMR and13C-NMR data are as shown in table 1.
Compound ii,
2-(2-(3-hydroxy-1-(1H-indol-3-yl)-2-methoxypropyl)-1H-indol-3-yl)
Acetic acid, Yellow amorphous powder：
(+)-HRESIMS m/z 401.1481(calcd for C22H22N2O4Na,401.1477)。
Its1H-NMR and13C-NMR data are as shown in table 1.
1. chemical compounds I of table, the hydrogen spectrum of compound ii and carbon modal data (CD3OD)
The above result shows that gained compound structure is correct.
The antibacterial activity of 2 the compounds of this invention I of embodiment and compound ii
1) experiment material
Instrument and reagent：CO2Incubator；Microplate reader (Bio-TEK ELx800)；(Shanghai bioengineering is limited for LB culture mediums
Company).
Pathogenic bacteria strain used in test：Enterobacter cloacae (enterobacter cloacae), Escherichia coli
(Escherichia coli), Klebsiella aerogenes (Klebsiella), Pseudomonas aeroginosa (Pseudomonas aeruginosa),
Salmonella typhimurium (salmonella typhimurium), Staphylococcus aureus (staphylococcus aureus),
It is purchased from institute of microbiology of the Chinese Academy of Medical Sciences.
Test sample：Actinomyces bacillus rubidus secondary metabolite chemical compounds I and compound ii, purity is more than 90%；
Meanwhile it is positive control medicine to choose tetracycline, each compound dilutes after being dissolved with DMSO.
2) experimental method
LB culture solutions are configured, sterilize at 121 DEG C 25 minutes it is spare, will be configured in bacterium solution 96 orifice plates of addition that have diluted, often
Hole adds in 180 μ l, and compound 1 and 2 is configured to certain density DMSO solution, addition is diluted step by step with multiple proportion and contains bacterium
In the micropore of liquid, its ultimate density is made to be followed successively by 64,32,16,8,4,2,1,0.5,0.25,0.125,0.0625 μ g/ml, in 37
It is cultivated 24 hours in DEG C incubator, absorbance is read at 600nm with microplate reader, wherein tetracycline is used as positive control, 180
The DMSO mixed solutions of μ l blank cultures and 20 μ l are blank control.Experiment is repeated 3 times.Each given the test agent is calculated to cause the mankind
The minimum inhibitory concentration (MIC value) of germ.
3) experimental result, the results are shown in Table 2.
2. test sample antibacterial activity in vitro the selection result of table
The result shows that the compound of the present invention I and II has good spectrum antibacterial activity, it can be as antibacterials
Active constituent.
Claims (4)
1. the bisindole derivative with II structure of formula I or formula:
2. the preparation method of bisindole derivative, includes the following steps described in claim 1：
1) fermented and cultured ocean ascidian symbiotic and epiphyte microorganism, the microorganism are the bacterial strain that bacillus rubidus belongs to；
2) zymotic fluid obtained by step 1) through ethyl acetate is extracted, obtains ethyl acetate primary extract；
3) by ethyl acetate extract obtained by step 2) by mesolow efficient liquid phase column chromatography, the column chromatography using methanol-
Aqueous two phase system gradient elution is collected and merges component；
4) component with reversed-phase high performance liquid chromatography is purified, obtains bisindole derivative of the structural formula for formula I and formula II
Product.
3. application of the bisindole derivative in anti-bacterial drug is prepared described in claim 1.
4. a kind of anti-bacterial drug, it is characterised in that contain one kind in bisindole derivative as described in claim 1 or several
Kind.
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| CN201510037124.1A CN105272900B (en) | 2015-01-21 | 2015-01-23 | Bisindole derivative and preparation method and application |
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| CN201510037124.1A CN105272900B (en) | 2015-01-21 | 2015-01-23 | Bisindole derivative and preparation method and application |
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| CN109651352B (en) * | 2017-10-12 | 2022-02-15 | 中国科学院上海药物研究所 | Dimeric indole alkaloid compounds, preparation method thereof and application thereof in preparation of antibacterial drugs |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1699341A (en) * | 2005-05-12 | 2005-11-23 | 苏州大学 | Process for synthesizing bis-indolyl alkyl compounds |
| CN102399221A (en) * | 2011-09-23 | 2012-04-04 | 江苏省中国科学院植物研究所 | Application of diindoloquinazoline alkaloid in preparation of antitumor drugs and antifungal drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2004196678A (en) * | 2002-12-17 | 2004-07-15 | Dainippon Pharmaceut Co Ltd | Pyrazole-based derivative |
| ATE497762T1 (en) * | 2004-12-30 | 2011-02-15 | Bioresponse Llc | USE OF DIINDOLYLMETHANE-RELATED INDOLES FOR THE TREATMENT AND PREVENTION OF DISEASES RELATED TO THE RESPIRATORY SYNCYTIAL VIRUS |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1699341A (en) * | 2005-05-12 | 2005-11-23 | 苏州大学 | Process for synthesizing bis-indolyl alkyl compounds |
| CN102399221A (en) * | 2011-09-23 | 2012-04-04 | 江苏省中国科学院植物研究所 | Application of diindoloquinazoline alkaloid in preparation of antitumor drugs and antifungal drugs |
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Effective date of registration: 20190710 Address after: No. 9, Nantong City, Jiangsu, Jiangsu Patentee after: Center for technology transfer, Nantong University Address before: No. 9, Nantong City, Jiangsu, Jiangsu Patentee before: Nantong University |
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Effective date of registration: 20191121 Address after: No.1, floor 3, No.319, zhanggongshan Road, Yuhui District, Bengbu City, Anhui Province Patentee after: Bengbu guijiu Intellectual Property Service Co., Ltd Address before: 226019 Jiangsu city of Nantong province sik Road No. 9 Patentee before: Center for technology transfer, Nantong University |
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Effective date of registration: 20211130 Address after: 314000 04, No. 5, tongerbao street, No. 1, Nanmen Gongnong Road, Chongfu Town, Tongxiang City, Jiaxing City, Zhejiang Province Patentee after: Jiaxing Zhuoshi Biotechnology Co.,Ltd. Address before: 233000 No.1, third floor, No.319, zhanggongshan Road, Yuhui District, Bengbu City, Anhui Province Patentee before: Bengbu guijiu Intellectual Property Service Co.,Ltd. |