CN102406637A - Application of japonicone A in preparation of tumor necrosis factor (TNF) inhibitor drugs - Google Patents
Application of japonicone A in preparation of tumor necrosis factor (TNF) inhibitor drugs Download PDFInfo
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- CN102406637A CN102406637A CN2011103617993A CN201110361799A CN102406637A CN 102406637 A CN102406637 A CN 102406637A CN 2011103617993 A CN2011103617993 A CN 2011103617993A CN 201110361799 A CN201110361799 A CN 201110361799A CN 102406637 A CN102406637 A CN 102406637A
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Abstract
The invention provides an application of japonicone A (chemical structural formula I) in preparation of tumor necrosis factor (TNF) inhibitor drugs. The japonicone A is inula japonica extract. In the invention, by adopting a reverse docking technology for virtual screening, the result shows that TNF-alpha is potential binding protein of the japonicone A; by adopting a BIACORE technology, the result shows that the japonicone A can be directly combined with TNF-alpha coupled on a chip, and can inhibit the combination of the TNF-alpha and the TNF-R (receptor) coupled on a sensor chip; and furthermore, an experiment confirms that the japonicone A can be directly combined with the TNF-alpha and can inhibit the interaction of the TNF-alpha and the TNF-R, thus the japonicone A can be used for preparing TNF inhibitor drugs. The drug provided by the invention is a pharmaceutical composition prepared from a medicinal carrier and the japonicone A used as an active ingredient. The pharmaceutical composition can be used for treating TNF-related diseases such as osteoarthropathy, asthma, bronchitis, allergic rhinitis and the like, thereby providing a new way for treating the diseases and obtaining greater clinical application values.
Description
Technical field
The present invention relates to medicine, be specifically related to the application of Flos Inulae extract in pharmacy, relate in particular to the application of bispin Flos Inulae lactone first in preparation tumor necrosis factor inhibitors medicine.
Background technology
Caswell in 1975 etc. at first give injected in mice with bacillus calmette-guerin vaccine and endotoxin, in its serum, find to be called tumor necrosis factor (tumor necrosis factor) by a kind of material that can make mouse tumor generation hemorrhagic necrosis.TNF is a kind of protein that the mononuclear phagocyte system cell produces, and not only the kinds of tumor cells to people and animal has cytotoxicity and the static effect of cell, and is body inflammatory and immune important regulatory factor.It and organism fever, shock, dyscrasia etc. substantial connection arranged, therefore receive people's pay attention to day by day and attention.
TNF is produced by monocyte/macrophage; Have the multiple biological activity relevant with rheumatic arthritis and osteoarthritis pathogeny; At first can promote the leukocytic accumulation of all types with expression of adhesion molecules and discharge secondary chemotaxis kytoplasm, like interleukin 8 through stimulating endothelial; Secondly, TNF can stimulate the intraarticular cell, and is synthetic and express derivable cyclooxygenase and derivable NO synthase.The product of these enzymes, prostaglandin and NO all are main media of pain and inflammation; Once more, also possibly be the most important, TNF is as interleukin-11, can the activation chondrocyte, the extracellular matrix of himself of degrading, and suppress to cause cartilage matrix composition synthetic of cartilage destruction.Except these effects, TNF plays pivotal role in the adjusting of other kytoplasm productions.
Tumor necrosis factor-alpha (TNF-α) is a kind of multiple bioactive cytokine that has; Have effects such as the inflammation of causing, trigger cell necrosis and neovascularization, participate in the pathogenic process and the disease progression process of multiple complicated inflammation such as rheumatic arthritis, allergic dermatitis, asthma and even liver cirrhosis, diabetes, coronary heart disease or immune disease.Reduce in-house TNF-alpha levels or block its pathological effect these treatment of diseases are had important value.In recent years, make substantial progress with anti-TNF-Alpha antibodies treatment autoimmune inflammation disease clinically, prove that further it is a kind of efficacious therapy means that this proinflammatory cytokine is blocked in the extracellular.Because biological product such as TNF-Alpha antibodies cost an arm and a leg and necessary drug administration by injection, the long-acting TNF-α micromolecular inhibitor that exploitation can be oral is paid close attention in current more research.Yet with respect to biological preparation such as TNF-α monoclonal antibodies, the basic and applied research of the micromolecule antagonist of TNF-α is made slow progress.At present the micromolecule TNF antagonist of report be limited to the tumor necrosis factor invertase (TACE, a kind of participation TNF synthetic with excretory key enzyme) the not clear TNF-alpha active inhibitor of inhibitor, TNF-alpha expression inhibitor that mechanism is not clear, the mechanism analyzed based on cellular level and the various intracellular signaling pathway inhibitor (comprise NF-kB, AP-1 and JNK/p38 pathway inhibitor) relevant with activity etc. with the TNF-alpha expression.And be that the micromolecular inhibitor of target is merely SCIENCE in 2005 and reports 1 example [Science 2005 with the TNF-alpha molecule directly; 310:1022].
Inula (Inula L.) plant is that one in the Compositae (Compositae) belongs to, and the whole world has 100 kinds approximately, respectively at Asia, Europe And Africa, is main with Mediterranean Region.In kind surplus state-owned 20, this genus has the various plants hyoscine, can be used as like Radix Inulae (I.helenium) to be good for the stomach, diuresis, to eliminate the phlegm and anthelmintic; Inula Britannica (I.britannica) has effects such as expectorant, the therapeutic method to keep the adverse QI flowing downwards, softening the hard mass, row water.Sesquiterpenoids is the characteristic chemical constituent of this platymiscium, is main with eudesmane-type, germacrane type and guainane type, also comprises pseudo-guainane type, driffractive ring eudesmane-type, olive alkane type, xanthane type and a spot of acyclic sesquiterpene and sesquiterpene dimers.Research shows that the sesquiterpenoids in this platymiscium has anthelmintic parasite killing, antibiotic antitumor, antiviral, immunosuppressant effect.
Flos Inulae (Inula japonica) has another name called Jin Fohua, Herba Inulae (Jiangsu and Zhejiang Provinces), chrysanthemum in June (Hebei).Perennial herb, root stock is short, horizontally walks or tiltedly gives birth to, and sturdy fibrous root is arranged.Be distributed in ground such as NORTH CHINA, northeast, middle part, east, Sichuan, Guangdong, but hyoscine.The root of Flos Inulae and leaf can be treated the knife injury furunculosis; The decoction antitussive of can relievining asthma; Its flower is the expectorant that is good for the stomach, and treats also in the heart that painful abdominal mass is vexed, stomach expansion, belch, cough, vomiting etc. (" Jiangsu Province's medical material will ").Flos Inulae ancient prescription for eliminate the phlegm, dehumidify, sharp intestinal, be the bullate main medicine of harnessing the river again.
Chemical compound bispin Flos Inulae lactone first (Japonicone A) is the extract of Flos Inulae (Bozhou, Anhui), and I is following for its chemical structural formula:
Bispin Flos Inulae lactone first chemical structural formula, method for preparing have been applied for the national inventing patent and the (dimeric sesquiterpene lactone compounds that is authorized; ZL200810038568.7), this patent discloses the method for preparing and the application in preparation antiinflammatory and antitumor drug of above-claimed cpd.
The inventor has carried out the chemical constitution study of system to Flos Inulae, finds that its extract bispin Flos Inulae lactone first has the biological activity of good inhibition tumor necrosis factor, intends and carries out the new indication medicine of deep research and development.
Summary of the invention
Technical problem to be solved by this invention is further to study Flos Inulae extract to the biological activity that tumor necrosis factor suppresses, and designs new application.
The invention provides the application of chemical compound bispin Flos Inulae lactone first in preparation tumor necrosis factor inhibitors medicine.
Bispin Flos Inulae lactone first chemical compound according to the invention can prepare by the ZL200810038568.7 disclosed method.Comprise the following steps:
(1) extract: the aerial parts of Flos Inulae (growing in the Bozhou, Anhui) is dry, pulverize, extract 3～4 times each 12～24 hours with 80～95% ethanol soaking at room temperature; Merge extractive liquid,, the extracting solution concentrating under reduced pressure becomes fluid extract, behind the thin up, earlier with petroleum ether extraction, again with dichloromethane, ethyl acetate, n-butanol extraction, collects the dichloromethane position;
(2) separate: silica gel column chromatography is used at above-mentioned dichloromethane position; With volume ratio is 100: 0～2: 1 methylene chloride system gradient elution, and thin layer chromatography detects, and collects the flow point that contains bispin Flos Inulae lactone first; Again through dextran gel column chromatography; With volume ratio is 1: 1 methylene chloride eluting, after the liquid chromatograph preparation, bispin Flos Inulae lactone first.
Bispin Flos Inulae lactone first of the present invention is a flaky crystal, and by electron spray ion massspectrum signal m/z535 [M-H], high resolution mass spectrometry must the accurate mass number of this chemical compound be 559.2676 [M+Na]
+, calculate that its molecular formula is C
32H
40O
7The structure of chemical compound is passed through
1H-NMR,
13C-NMR, means such as 2D-NMR and X-diffraction are proved conclusively.
The inventor adopts anti-phase docking technique virtual screening; Find that TNF-α (tumor necrosis factor) is the potential conjugated protein of dimeric sesquiterpene lactone constituents bispin Flos Inulae lactone first; Analyze bispin Flos Inulae lactone first through BIACORE technology (interaction of biomacromolecules analytical technology) again and be coupled to the interaction between the sensor chip reorganization TNF-alpha molecule; Proof bispin Flos Inulae lactone first (1.68-10 μ M) can be directly be coupled at chip on TNF-α combine; Bispin Flos Inulae lactone first (1,10 μ m) can suppress combining of TNF-α and the TNF-R that is coupled to sensor chip.And further through the direct interaction of experimental verification bispin Flos Inulae lactone first to TNF-α; Adopt the responsive target cell L929 cell of TNF-α; Detect bispin Flos Inulae lactone first is killed and wounded its target cell to TNF-α active inhibitory action; And set up ELISA systematic analysis bispin Flos Inulae lactone first and TNF-α and incubate the influence of back to itself and TNF receptors bind in advance, the result shows that bispin Flos Inulae lactone first is inhibited to the biological activity of TNF-α, can directly be incorporated into TNF-α; And suppress the interaction of itself and TNF receptor, be a kind of good TNF-alpha inhibitor.Therefore, can be used as active component, be used to prepare the tumor necrosis factor inhibitors medicine.
The pharmaceutical composition that medicine according to the invention is made up of as active component and pharmaceutical carrier bispin Flos Inulae lactone first.
Medicine according to the invention can be used as the new purposes of the disease relevant with treating tumor necrosis factor such as osteoarthritis, asthma, bronchitis, allergic rhinitis etc., for treating these diseases new approach is provided, and bigger clinical value is arranged.
Description of drawings
The 3-D solid structure of the potential conjugated protein TNF-α of Fig. 1 bispin Flos Inulae lactone first.
The interaction sites of Fig. 2 bispin Flos Inulae lactone first and TNF-α.
The coupling of Fig. 3, TNF-α albumen and chip (final coupling 7600RU).
Fig. 4, bispin Flos Inulae lactone first (1.68-10 μ M) directly be coupled at the TNF-α association reaction curve on the chip.
Fig. 5, get reporting point (Time:174.5s, Time Windows=5s), the figure that corresponding again each concentration is done at the equilibrium stage of every curve.
The coupling of Fig. 6, TNF-R albumen and chip (final coupling 3500RU).
Fig. 7, TNF-α are incubated back and the bonded response curve of TNF-R that is coupled to chip separately or with bispin Flos Inulae lactone first (1,10 μ M) in advance;
Article three, curve is followed successively by from top to bottom: TNF-α separately, TNF-α+bispin Flos Inulae lactone first 1 μ M, TNF-α+bispin Flos Inulae lactone first 10 μ M.
Fig. 8, TNF-α are incubated back adding L929 cell, the situation of killing and wounding of pair cell behind the effect 18h separately or with bispin Flos Inulae lactone first in advance;
Picture is followed successively by from top to bottom: blank control group, TNF-α group (200pg/ml), TNF-α+bispin Flos Inulae lactone first 5 μ M, TNF-α+bispin Flos Inulae lactone first 10 μ M, TNF-α+bispin Flos Inulae lactone first 20 μ M.
Fig. 9, each porocyte detect the OD value after with violet staining, and the TNF-α of calculating is to the cytotoxicity of L929 cell;
Four row from left to right are followed successively by: TNF-α group (200pg/ml), TNF-α+bispin Flos Inulae lactone first 5 μ M, TNF-α+bispin Flos Inulae lactone first 10 μ M, TNF-α+bispin Flos Inulae lactone first 20 μ M.
After Figure 10, bispin Flos Inulae lactone first add L929 cytosis 24h separately, the influence of on cell proliferation.
Four row from left to right are followed successively by: bispin Flos Inulae lactone first 0 μ M, bispin Flos Inulae lactone first 5 μ M, bispin Flos Inulae lactone first 10 μ M, bispin Flos Inulae lactone first 20 μ M.
The OD value that Figure 11, ELISA detect and the linear relationship chart of TNF-α concentration.
Figure 12, commercial TNF-α monoclonal antibody (type gram) are to the blocking effect of TNF-α and TNF receptors bind.
Figure 13, bispin Flos Inulae lactone first and TNF-α are incubated the inhibitory action of back to itself and TNF receptors bind in advance.
The specific embodiment
The preparation of embodiment 1 chemical compound bispin Flos Inulae lactone first
The aerial parts of exsiccant Flos Inulae (I.japonica grows in the Bozhou, Anhui, commercially available obtaining) comprises stem, leaf, flower) the 10.0kg powder is pure, and room temperature (25 ℃) is down with 95% ethanol extraction 3 times, each 80L 24,12,12 hours times spent of difference.After gained crude extract 408.7g added suitable quantity of water 10L dilution, use petroleum ether 40L successively, divides four times, dichloromethane 40L divides four times, and ethyl acetate 40L divides four times, and n-butyl alcohol 10L extracts.The dichloromethane extract 42.3g that obtains is separated with 200-300 purpose thin layer silica gel, use CH
2Cl
2-MeOH (100: 0,50: 1,20: 1,10: 1,5: 1,2: 1) carry out gradient elution.Thin layer chromatography detects, and collects wherein to contain bispin Flos Inulae lactone first, adopts Sephadex LH-20 to separate again, uses CH
2Cl
2-MeOH (1: 1) carries out eluting, obtains mixture, and the colour developing of vanillin concentrated sulphuric acid is sesquiterpenoids, adopts preparation HPLC to separate and obtains bispin Flos Inulae lactone first 149mg.(because of the inventor has got bispin Flos Inulae lactone first, see patent ZL200810038568.7,, pass through then so can adopt the contrast of reference substance bispin Flos Inulae lactone first earlier
1H-NMR,
13C-NMR, means such as 2D-NMR are proved conclusively, this chemical compound is consistent with the disclosed bispin Flos Inulae of ZL200810038568.7 lactone first).
The bispin Flos Inulae lactone first that present embodiment makes is used for following experiment.
Reverse molecular docking is calculated and is adopted the INVDOCK software kit.This software kit has obtained United States Patent (USP) (patent No. US6519611).The three dimensional structure of this method input drug molecule through the proteic situation that combines among this drug molecule of computer program simulation and the protein three-dimensional structure data base, thereby is predicted bonded albumen of this drug molecule and bonded avtive spot.Utilize the INVDOCK software kit, the potential target point protein of pharmaceutically active ingredient in can predicting.
In should using; Three dimensional structure input INVDOCK software kit with bispin Flos Inulae lactone first; To NF-κ B (cell transcription factor) signal path (the NF-Kbsignaling pathway among the Biocarta signal path data base; See http://www.biocarta.com/pathfiles/h_nfkbPathway.asp) go up all albumen of known three dimensional structure; Carried out virtual targeting screening, found that TNF-α (tumor necrosis factor) is the potential conjugated protein of dimeric sesquiterpene lactone constituents bispin Flos Inulae lactone first.
Interaction between embodiment 3 BIACORE (interaction of biomacromolecules analyser) analysis confirmation bispin Flos Inulae lactone first and the TNF-α
In order further to verify the direct interaction of bispin Flos Inulae lactone first and TNF-α, adopt Amersham Bioscience company to analyze bispin Flos Inulae lactone first and be coupled to the interaction between the sensor chip reorganization TNF-alpha molecule again based on the biomolecular interaction analysis equipment B IACORE 3000 of the release of surface plasma body resonant vibration (SPR) principle.Experimentation is: earlier with recombinant expressed TNF-α (available from U.S. GeneTex; Inc.; Purity＞98%) with the amino coupled method covalent coupling in the Biacore 3000 control softwares in sensor chip surface, TNF-α coupling amount is 4000 reactons (Response Unit, RU) (Fig. 3); Compound dissolution and is diluted to 1.68 μ M, 2.4 μ M in the phosphate buffer that contains 1 ‰ dimethyl sulfoxide (DMSO); 3.4 μ M, 4.9 μ M, the Concentraton gradient of 7 μ M and 10 μ M; Centrifugal back auto injection, the combination that detects variable concentrations medicine and TNF-α is active.Whether influence the interaction of TNF-α and its receptor in order further to analyze bispin Flos Inulae lactone first; With recombinant expressed free type TNF-α receptor (TNF-R; Available from U.S. GeneTex, Inc., purity＞98%) be coupled on the sensing chip; Whether then TNF-α and bispin Flos Inulae lactone first are mixed before application of sample, detecting bispin Flos Inulae lactone first can antagonism TNF-α and the molecule of its receptors bind.The result prove bispin Flos Inulae lactone first (1.68-10 μ M) can be directly be coupled at chip on TNF-α combine (Fig. 4); The equilibrium stage of every association reaction curve get reporting point (time: 174.5s, time window=5s), corresponding again each concentration mapping, and carry out Fitting Analysis with stable state (Steady State) pattern, the result shows that affinity is 5.55 μ M; (Fig. 5).Further TNF-α receptor is coupled to sensor chip; Detect bispin Flos Inulae lactone first and whether can block combining of TNF-α and its receptor; Find that bispin Flos Inulae lactone first (1,10 μ M) can suppress combine (Fig. 6,7) of TNF-α and the TNF-R that is coupled to sensor chip.
Verified with BIACORE bispin Flos Inulae lactone first can with TNF-α direct interaction after, further adopt the responsive target cell L929 cell of TNF-α, whether detect bispin Flos Inulae lactone first has inhibitory action to the activity that TNF-α kills and wounds its target cell.
Concrete experimental procedure is: the l cell cultivated of going down to posterity is that the L929 cell is suspended in RPMI-1640 complete medium (commercially available, available from Sigma company) after with trypsinization, and the adjustment cell concentration is 1 * 10
5/ ml inoculates 100 μ l in 96 porocyte culture plates, CO
2The incubator overnight incubation.TNF-α is (available from U.S. GeneTex; Inc.) be made into the solution of 200pg/ml with the RPMI-1640 complete medium; The medicine to be measured that adds actinomycin D (2 μ g/ml) and series concentration; Every hole adds 100 μ l in the L929 Tissue Culture Plate, and cell culture wants to hatch 18h, and mirror observation TNF-α down kills and wounds the situation of L929 cell and takes pictures; Abandon supernatant, with violet staining, wash plate and decolouring, survey absorbance in wavelength 570nm place, calculate the cell killing rate, data are the mean ± SD of 3 independent experiments.The result shows: the activity that bispin Flos Inulae lactone first (5-20 μ M) is killed and wounded responsive target cell to TNF-α has the inhibitory action (Fig. 8,9) of dose dependent, and bispin Flos Inulae lactone first does not have direct cytotoxicity and short proliferation function (Figure 10) to the L929 cell separately in same dosage range.The above results shows that bispin Flos Inulae lactone first is inhibited to the biological activity of TNF-α.
In order further to verify the direct interaction of bispin Flos Inulae lactone first and TNF-α; Set up the ELISA detection system of analyzing TNF-α and TNF receptors bind; Be about to free type TNFR1 (20ng/ml is dissolved in the 50mM sodium carbonate liquor of pH9.0); Add enzyme mark version 100 μ l/ holes, 96 hole, encapsulate in 4 ℃ and spend the night; Remove coating buffer morning next day; Add 275 μ L phosphoric acid buffer liquid for plugging (PBS Superblock) (available from U.S. Pierce company) shutoff 60 minutes; The TNF-α that adds series concentration with phosphate buffer (PBS/0.01% Tween 20) the washing back that contains 0.01% polysorbas20; Incubated at room 30min removes unconjugated TNF-α with PBS/0.01% Tween 20 washings; Every hole adds the anti-TNF antibodies (HRP-anti-TNF Ab) of 100 μ l horseradish peroxidase-labeled, and the room temperature jolting is hatched after 30 minutes and removed unconjugated HRP-anti-TNF Ab with PBS/0.01% Tween 20 washings; Add peroxidase substrate (TMB peroxidase substrate) (available from U.S. Pierce company) colour developing 10 minutes, add the phosphoric acid solution color development stopping of 100 μ l 1M, absorbance reaction TNF-R1 in detection 490nm place combines with TNF-α's.The result of Figure 11 shows with the TNF-α amount that adds to be increased, and the OD value that records after the chromogenic reaction increases thereupon, and is linear, y=0.025x+0.1137 (R
2=0.9953); The result of Figure 12 shows after a certain amount of TNF-α (2ng/ml) and the commercial TNF-α monoclonal antibody (type gram) of series concentration are incubated 30min in advance and adds; The OD value that records after the chromogenic reaction is by the TNF-α combined standard curve calculation of Figure 11 and the bonded TNF-α amount of TNF-R, finds that type gram can dose dependent ground inhibition TNF-α and the combining of TNF-R.This system of The above results explanation can be used for detecting the effect of TNF-α and TNF receptors bind and TNF-alpha blocker.Use this detection system and analyze bispin Flos Inulae lactone first and TNF-α and incubate the influence of back to itself and TNF receptors bind in advance, discovery bispin Flos Inulae lactone first can be blocked TNF-α and TNF receptors bind with the mode of dose dependent.This result shows: bispin Flos Inulae lactone first can directly be incorporated into TNF-α, and suppresses the interaction of itself and TNF receptor.
Claims (4)
1. the application of bispin Flos Inulae lactone first in preparation tumor necrosis factor inhibitors medicine is characterized in that the chemical structural formula of said bispin Flos Inulae lactone first is following:
2. application according to claim 1 is characterized in that, said bispin Flos Inulae lactone first prepares through following method:
(1) extract: the aerial parts of Flos Inulae is dry, pulverize, extract 3～4 times each 12～24 hours with 80～95% ethanol soaking at room temperature; Merge extractive liquid,, the extracting solution concentrating under reduced pressure becomes fluid extract, behind the thin up, earlier with petroleum ether extraction, again with dichloromethane, ethyl acetate, n-butanol extraction, collects the dichloromethane extraction position;
(2) separate: silica gel column chromatography is used at above-mentioned dichloromethane extraction position; With volume ratio is 100: 0～2: 1 methylene chloride system gradient elution, and thin layer chromatography detects, and collects the flow point that contains bispin Flos Inulae lactone first; Again through dextran gel column chromatography; With volume ratio is 1: 1 methylene chloride eluting, after the liquid chromatograph preparation, bispin Flos Inulae lactone first.
3. application according to claim 1 is characterized in that, said medicine is the pharmaceutical composition of being made up of as active component and pharmaceutical carrier bispin Flos Inulae lactone first.
4. application according to claim 1 is characterized in that, the said application that is applied as in preparation treatment osteoarthritis, asthma, bronchitis or the allergic rhinitis medicine.
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Cited By (1)
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| WO2017036392A1 (en) * | 2015-08-31 | 2017-03-09 | 山西振东先导生物科技有限公司 | Derivative of inula lineariifolia lactone a |
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Cited By (3)
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| WO2017036392A1 (en) * | 2015-08-31 | 2017-03-09 | 山西振东先导生物科技有限公司 | Derivative of inula lineariifolia lactone a |
| CN107849002A (en) * | 2015-08-31 | 2018-03-27 | 山西振东先导生物科技有限公司 | A kind of inula lineariifolia lactone A derivative |
| CN107849002B (en) * | 2015-08-31 | 2021-07-06 | 山西振东先导生物科技有限公司 | Inula lineariifolia lactone A derivative |
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Application publication date: 20120411 |