CN105272900A - Bis(indolyl) derivatives, preparation method and applications - Google Patents
Bis(indolyl) derivatives, preparation method and applications Download PDFInfo
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- CN105272900A CN105272900A CN201510037124.1A CN201510037124A CN105272900A CN 105272900 A CN105272900 A CN 105272900A CN 201510037124 A CN201510037124 A CN 201510037124A CN 105272900 A CN105272900 A CN 105272900A
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- formula
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- bisindole derivative
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- MQRYPXXPMWCWNO-UHFFFAOYSA-N COC(CO)C(c1c[nH]c2ccccc12)c1c(CC(O)=O)c(cccc2)c2[nH]1 Chemical compound COC(CO)C(c1c[nH]c2ccccc12)c1c(CC(O)=O)c(cccc2)c2[nH]1 MQRYPXXPMWCWNO-UHFFFAOYSA-N 0.000 description 1
- GTKKLIYNQCXJMH-UHFFFAOYSA-N OCCc1c(C(C(CO)O)c2c[nH]c3ccccc23)[nH]c2c1cccc2 Chemical compound OCCc1c(C(C(CO)O)c2c[nH]c3ccccc23)[nH]c2c1cccc2 GTKKLIYNQCXJMH-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses bis(indolyl) derivatives, a preparation method and applications. The structural formulas of the provided bis(indolyl) derivatives are shown in the specification. The technologies of microbial culture, separation purification, structural analysis and the like are utilized, secondary metabolites of marine symbiotic actinomycetes are subjected to detailed analysis and two novel compounds are obtained. In-vitro antibacterial tests prove that the compounds have good broad-spectrum antibacterial activity and can be employed as active components of antibacterial agents and have extensive applications.
Description
Technical field
The present invention relates to biomedicine field, be specifically related to the medicinal use of class double-indole analog derivative and preparation method thereof and this derivative.
Background technology
Along with antibiotic abuse, the appearance of superbacteria, makes bacteriological infection be one of principal disease of harm humans health.Research and develop the important research content that new microbiotic is field of medicaments always.In recent years, natural product becomes the important sources of human research's effective active composition gradually, and in new drug development process, the natural product on the one hand with excellent activity can directly be used to clinical; On the other hand, take active skull cap components as lead compound, being found by the method such as organic synthesis, structure of modification and develop new high-efficiency low-toxicity medicine, is one of approach being proved the most effective developing new drug.
Due to the singularity of the marine eco-environment, the biosynthetic pathway that marine organisms produce secondary metabolite has huge difference with enzymatic reaction system compared with terrestrial life, cause marine organisms often can produce some chemical structure novelties, diverse biological activities, active significant marine drug lead compound, for new drug research and exploitation provide a large amount of mode configurations and prodrug.But, although Chinese Marine Biology Resources is enriched, can be very limited for the medicine resource of new drug development, sustainable use potentiality are also little.
As the important composition in Marine ecosystems, marine microorganism is similarly long-term and adapts to the active compound that existence produces various enzyme and many novelties.Research shows, marine microorganism has abundant species diversity, kind reaches more than 100,000,000 kinds, but at present institute study and is less than 1% of marine microorganism total amount with authenticated marine microorganism, this means that marine microorganism is that the research of marine drug provides one and is similar to infinite resource.The distribution of microorganism in ocean widely, has microorganism to exist in extreme environment, wherein a part and marine animal and plant be in grow nonparasitically upon another plant altogether, commensalism, parasitism or the microorganism that grows nonparasitically upon another plant be called symbiotic and epiphyte microorganism.Point out in a lot of bibliographical information, to think before many that the active substance produced by plant and invertebrates was actually and produce by with its microorganism grown nonparasitically upon another plant altogether.Therefore, ocean symbiotic and epiphyte microorganism is just being subject to the attention of more and more investigator, to have found of a great variety up to now from the symbiotic and epiphyte microorganism of ocean and has had active significant biological active agents.
Summary of the invention
The object of this invention is to provide class double-indole analog derivative and preparation method thereof.
Bisindole derivative provided by the present invention, its structural formula is the compound of formula I or formula II:
Present invention also offers the preparation method of above-mentioned bisindole derivative, comprise the steps: 1) fermentation culture microorganism; 2) by after described fermentation liquor organic solvent extraction, 30 DEG C of concentrating under reduced pressure, obtain primary extract; 3) by described conversion product residue with anti-phase mesolow chromatogram purification, described column purification adopts methanol-water biphasic system gradient elution, collects and merges component; 4) by described component RPLC purifying, product is obtained.
Wherein, aforesaid method step 1) microorganism is actinomycetes, bacillus rubidus (Rubrobacterradiotolerans).
Aforesaid method step 2) in extraction solvent be conventional type organic solvent, ethyl acetate.
Aforesaid method step 3) in anti-phase mesolow chromatogram purification preferably collect the elutriant of 50% methanol-eluted fractions.
Aforesaid method step 4) middle RPLC purifying optimum condition: Jia Chun – water (35:65, V/V), flow velocity is 1.0mL/min.Determined wavelength is 220nm, is separated and obtains the compound that structural formula is formula I (retention time 57mins) and formula II (retention time 108mins).
Another object of the present invention is to provide the purposes of the compound of bisindole derivative formula I of the present invention and formula II.
The present invention confirms by experiment, and bisindole derivative of the present invention has good anti-microbial activity, can as the activeconstituents of antibacterials.
The activeconstituents of these antibacterials can be that to be selected from structural formula be one or more in the compound of formula I or formula II.
In the medicine taking above-claimed cpd as activeconstituents, one or more pharmaceutically acceptable carriers when needs, can also be added.Described carrier comprises the thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant etc. of pharmaceutical field routine, all can prepare according to the ordinary method of pharmaceutical field.
The present invention utilizes fermentable, purification technique, systematic position has been carried out to the secondary metabolite of the actinomycetes (Rubrobacterradiotolerans) that ocean Ascidian grows nonparasitically upon another plant altogether, obtain the bisindole derivative that a class is new, confirmed by In vitro Bactericidal Experiments, these compounds have good anti-microbial activity, can as the activeconstituents of antibacterials, and tool has been widely used.
Accompanying drawing explanation
Fig. 1 is formula I and formula II compound RP-HPLC purifying color atlas.
Embodiment
Embodiment 1, structural formula are the preparation of formula I and formula II compound
The present invention adopts fermentable, and extract, the steps such as purifying, prepare the compounds of this invention.Wherein adopted bacterial strain is bacillus rubidus.Be separated in this bacterial strain Yu Haiyang Ascidian and obtain, be the symbiotic and epiphyte microorganism of ocean Ascidian, be positioned in 20% aqueous glycerin solution, preserve in subzero 80 DEG C of refrigerators.Selected substratum is Gause I substratum.
The preparation of Gause I substratum: take 2% Zulkovsky starch, 1% saltpetre, 0.05% sodium-chlor, 0.05% dipotassium hydrogen phosphate, 0.05% magnesium sulfate, 0.001% ferrous sulfate, is dissolved in 1000mL artificial seawater, sterilizing 30 minutes at 121 DEG C.2% agar is added in liquid medium within during preparation solid medium.Wherein 30.0g sea salt is dissolved in 1000ml polymer solution in water and is configured to artificial seawater.
The preparation (LB substratum) of bacteria culture medium: every 1000mL liquid nutrient medium adds 5.0g yeast extract, 10.0g peptone, and 10.0gNaCl, is dissolved in water, adjust pH to 7.0.Preparation solid slant culture base adds 1.5% agar in liquid medium within again.
The process of particular compound is as follows:
1) fermentation and extraction
Bacillus rubidus (Rubrobacterradiotolerans) is accessed in 2 250mL triangular flasks (100mL Gause I substratum is housed), as seed liquor.On shaking table 160rpm, shaking culture, after 3 days, is drawn the seed liquor of 25mL, is joined in 20 1000mL shaking flasks (500mL Gause I substratum is housed) with Sterile pipette at 28 DEG C.Shaking culture is after 14 days, and with isopyknic extraction into ethyl acetate 2 times, extraction liquid is evaporated to dry, obtains conversion product residue and is about 6.0g.
2) anti-phase mesolow chromatography
Proper amount of methanol is dissolved in by residue obtained, add to and 120g reverse phase silica gel (120 dusts are housed, 30 – 50 orders) chromatographic column, with methanol-water system gradient elution (30%-100% methyl alcohol), every 10 per-cents are a gradient, every gradient eluent volume 1000ml, collects the elutriant of 50% methanol-eluted fractions, concentrated.
3) RPLC purifying
By step 3) elutriant rp-hplc analysis, the purifying collected.Analysis condition is: chromatographic column HederaC
18a-5 μm, 4.6mmI.D × 250mm (Jiangsu Chinese nation science and technology), elution system is Jia Chun – water isocratic elution, and actual conditions: Jia Chun – water (35:65, V/V), flow velocity is 1.0mL/min.Determined wavelength is 220nm, column temperature 25 DEG C, sample size 20 μ L, obtains the compound that structural formula is formula I (retention time, 57mins) or 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:
(+)-HRESIMSm/z373.1526(calcdforC21H22N2O3Na,373.1528)。
Its
1h-NMR and
13c-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) aceticacid, Yellow amorphous powder:
(+)-HRESIMSm/z401.1481(calcdforC22H22N2O4Na,401.1477)。
Its
1h-NMR and
13c-NMR data are as shown in table 1.
The hydrogen spectrum of table 1. chemical compounds I, compound ii and carbon modal data (CD
3oD)
Above result shows, gained compound structure is correct.
The anti-microbial activity of embodiment 2 the compounds of this invention I and compound ii
1) experiment material
Instrument and reagent: CO
2incubator; Microplate reader (Bio-TEKELx800); LB substratum (Shanghai biotechnology company limited).
Test malignant bacteria strain used: Enterobactercloacae (enterobacter cloacae), Escherichiacoli (intestinal bacteria), Klebsiellaaerogenes (klebsiella), Pseudomonasaeroginosa (Pseudomonas aeruginosa), Salmonellatyphimurium (Salmonella typhimurium), Staphylococcusaureus (streptococcus aureus), is purchased from institute of microbiology of the Chinese Academy of Medical Sciences.
Test sample: actinomycetes bacillus rubidus secondary metabolite chemical compounds I and compound ii, purity is more than 90%; Meanwhile, choosing tsiklomitsin is positive control medicine, dilution after each compound all dissolves with DMSO.
2) experimental technique
Configuration LB nutrient solution, at 121 DEG C, sterilizing 25 minutes is for subsequent use, add in 96 orifice plates by configuring the bacterium liquid diluted, every hole adds 180 μ l, compound 1 and 2 is configured to certain density DMSO solution, add in the micropore containing bacterium liquid with multiple proportion stepwise dilution, 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, cultivate 24 hours in 37 DEG C of incubators, absorbancy is read in 600nm place by microplate reader, wherein tsiklomitsin is adopted to be positive control, the DMSO mixing solutions of 180 μ l blank cultures and 20 μ l is blank.Experiment repetition 3 times.Calculate the minimum inhibition concentration (MIC value) of each given the test agent to human disease bacterium.
3) experimental result, result is as shown in table 2.
Sample antibacterial activity in vitro the selection result tested by table 2.
Result shows, chemical compounds I of the present invention and II has good spectrum antibacterial activity, can as the activeconstituents of antibacterials.
Claims (6)
1. there is the bisindole derivative of structure shown in formula I:
2. there is the bisindole derivative of formula II structure:
3. the preparation method of bisindole derivative described in claim 1 or 2, comprises the steps:
1) fermentation culture ocean Ascidian symbiotic and epiphyte microorganism, described microorganism is actinomycetes strain;
2) by step 1) gained fermentation liquor extraction into ethyl acetate, obtain ethyl acetate primary extract;
3) by step 2) gained ethyl acetate extract is through mesolow high performance liquid phase, and described column chromatography adopts methanol-water biphasic system gradient elution, collects and merges component;
4) by described component RPLC purifying, the bisindole derivative products that structural formula is formula I and formula II is obtained.
4. preparation method as claimed in claim 3, is characterized in that described actinomycetes strain is the bacterial strain that bacillus rubidus belongs to.
5. the application of bisindole derivative described in claim 1 or 2 in preparation antibacterials.
6. antibacterials, is characterized in that containing, for example one or more in bisindole derivative described in claim 1 or 2.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651352A (en) * | 2017-10-12 | 2019-04-19 | 中国科学院上海药物研究所 | A kind of dimeric indole alkaloid compound, preparation method and its application in preparation antibacterials |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004196678A (en) * | 2002-12-17 | 2004-07-15 | Dainippon Pharmaceut Co Ltd | Pyrazole-based derivative |
| CN1699341A (en) * | 2005-05-12 | 2005-11-23 | 苏州大学 | Process for synthesizing bis-indolyl alkyl compounds |
| WO2006083458A2 (en) * | 2004-12-30 | 2006-08-10 | Bioresponse Llc | Use of diindolylmethane-related indoles for the treatment and prevention of respiratory syncytial virus associates conditions |
| 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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- 2015-01-23 CN CN201510037124.1A patent/CN105272900B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004196678A (en) * | 2002-12-17 | 2004-07-15 | Dainippon Pharmaceut Co Ltd | Pyrazole-based derivative |
| WO2006083458A2 (en) * | 2004-12-30 | 2006-08-10 | Bioresponse Llc | Use of diindolylmethane-related indoles for the treatment and prevention of respiratory syncytial virus associates conditions |
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651352A (en) * | 2017-10-12 | 2019-04-19 | 中国科学院上海药物研究所 | A kind of dimeric indole alkaloid compound, preparation method and its application in preparation antibacterials |
| 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 |
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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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