CN108785319A - Purposes of the Phenylpropanoid Glycosides glycoside in preparing IDO inhibitor - Google Patents
Purposes of the Phenylpropanoid Glycosides glycoside in preparing IDO inhibitor Download PDFInfo
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Abstract
The invention belongs to drug or field of health care products, and in particular to the purposes of Phenylpropanoid Glycosides glycoside and its pharmaceutically acceptable derivates in preparing IDO inhibitor.The present invention is had found by studying, echinacoside, resupinate woodbetony leaf or root glycosides A and resupinate woodbetony leaf or root glycosides H are superior to inhibitory activity of the positive control drug 1- methyl tryptophans (1-MT) to intracellular IDO to the inhibitory activity of intracellular IDO, inhibitory activity with significant IDO can be used for treating cancer, Alzheimer disease, ankylosing spondylitis, autoimmune disease, bacterium infection, cataract, mood disorder, depressive and anxiety neurosis.
Description
Technical field
The invention belongs to drug or field of health care products, and in particular to purposes of the Phenylpropanoid Glycosides glycoside in preparing IDO inhibitor.
Background technology
The entitled indoleamine 2 of IDO (indoleamine-2,3-dioxygenase) Chinese, 3- is bis- to add oxidizing ferment, be liver with
The rate-limiting enzyme that outer unique catalysis tryptophan is metabolized along kynurenine pathway (kynurenine pathway, KP), can be by color ammonia
Acid is decomposed into a variety of metabolins such as L- kynurenins, pyridine carboxylic acid and quinolinic acid.L-Trp maintains cell to live as in human body
Amino acid necessary to changing and being proliferated, and the indispensable ingredient of protein is constituted, its shortage can cause some important thin
The dysfunction of born of the same parents.Since 1967 are found, IDO inhibits the mechanism of pathogenic microorganism proliferation, IDO by tryptophan of degrading
Relationship between the nervous system disease is gradually elucidated with；And thering is research to confirm, IDO also participates in the reaction of regulatory T-cell, can
Proliferation and activation to T cell generate inhibiting effect, and this inhibiting effect has then mediated expression the immune of IDO tumour cells to escape
Ease phenomenon.Therefore, the expression of IDO or active exception increase, closely related with the pathogenesis of a variety of diseases, be cause it is a variety of
The viruses such as an important factor for disease, such as the tumour, Alzheimer disease, depression, cataract of old people, the AIDS that have been found
Bacterium infections such as infection, Lyme disease and streptococcal infection etc. (can refer to following document：The progress of IDO inhibitor, Kong Linglei
Deng,《Chinese journal of Medicinal Chemistry》, 2009,19 (2)：147-154；Chinese patent literature CN101429151A one kind containing (E) -4-
The IDO inhibitor and preparation method thereof of (Β-bromo vinyl) benzene oxygen acyl group structure, May 13 2009 publication date).Therefore,
IDO inhibitor becomes the medicine of great potential, causes the concern of numerous scholars.
As a kind of completely new target spot, IDO becomes the cancer immunotherapy target of great potential.The IDO of screening efficiently, less toxic
Inhibitor/antibody, and use it for treating above-mentioned disease, become the common demand of researcher.1978, there is researcher
Non-selective competitive IDO inhibitor has been isolated in research, but it inhibits effect faint.In the early 1990s, closing for the first time
(i.e. at tryptophan derivative 1-MT：Indoximod), as with the immediate inhibitor of substrate tryptophan structure, cause
People are for IDO inhibitor more widely concern and interest.The research and development of IDO inhibitor are still in the initial stage of drug development,
Only 2 compounds (epacadostat and indoximod) enter II phase clinic at present, and 1 compound (GDC-0919) enters
I phase is clinical.
Initially the work of searching IDO inhibitor is mainly using chemical synthesis as means, using the substrate tryptophan of IDO as template,
Structural modification is carried out to it on the basis of studying structure-activity relationship, the patent of the article and registration delivered almost covers all energy
The group of modification, but produce little effect.From 2006, domestic and foreign scholars, which attempt to find from natural products, had new construction
The IDO inhibitor of the high activity of skeleton, such as：Brastianos etc. is extracted to obtain from sponge Neopetrosiaexigua
Exiguamine A (value=0.21 μM Ki)；Alban Pereir etc. extracted from seawater Xi obtain Annulin C (Ki values=
0.14μM)；The natural products Brassinin (value=97.7 μM Ki) that the discoveries such as Caspari business can be sold has medium activity；In
State patent document CN101843618A is disclosed：Jamaicin and its derivative also have IDO inhibiting effect.
Phenylpropanoid Glycosides glycosides compound, also known as benzyl carbinol glycoside compound are a kind of phenethyl containing substitution and cinnamoyl
Natural glucosides, be widely present in dicotyledon.Since first Phenylpropanoid Glycosides glycosides compound in 1963 is by since detaching,
The number of such isolated compound is on the increase.With deepening continuously to such compound research, effect experiment table
Bright, Phenylpropanoid Glycosides glycosides compound has extensive and significant biological activity, such as：With antibacterial anti-inflammatory, it is antitumor, antiviral,
The effects that anti-oxidant, liver protecting, base reparation etc..
Currently, being used to prepare IDO inhibitor about Phenylpropanoid Glycosides glycoside there is no report.
Invention content
For this purpose, the technical problem to be solved by the present invention is to be used to prepare IDO inhibitor without Phenylpropanoid Glycosides glycoside in the prior art
The problem of, to provide purposes of the Phenylpropanoid Glycosides glycoside in preparing IDO inhibitor.
In order to solve the above technical problems, the present invention is achieved through the following technical solutions：
The present invention provides the purposes of Phenylpropanoid Glycosides glycoside and its pharmaceutically acceptable derivates in preparing IDO inhibitor；
The IDO inhibitor is for treating cancer, Alzheimer disease, ankylosing spondylitis, autoimmune disease, thin
Bacterium infection, cataract, mood disorder, depressive and anxiety neurosis；The pharmaceutically acceptable derivates are selected from salt, ester, prodrug
Or solvate；
The Phenylpropanoid Glycosides glycoside has structure as follows：
Wherein, R1、R2、R5、R6It is independently from each other-H or-CH3, R3And R4It is independently from each otherAt least one of be formed by glycosyl residue.
The present invention also provides Phenylpropanoid Glycosides glycosides and its pharmaceutically acceptable derivates in the color ammonia for preparing treatment IDO mediations
Purposes in the drug of the disease of the pathological characteristics of acid metabolic approach；
The disease be cancer, Alzheimer disease, ankylosing spondylitis, autoimmune disease, bacterium infection, it is white in
Barrier, mood disorder, depressive and anxiety neurosis；The pharmaceutically acceptable derivates are selected from salt, ester, prodrug or solvate；
The Phenylpropanoid Glycosides glycoside has structure as follows：
Wherein, R1、R2、R5、R6It is independently from each other-H or-CH3, R3And R4It is independently from each otherAt least one of be formed by glycosyl residue.
Preferably, in such use, R1、R2、R5、R6It is independently from each other-H or-CH3, R3And R4Independently of one another
It is selected fromIn one kind being formed by glycosyl residue.
It is further preferred that in such use, the Phenylpropanoid Glycosides glycoside is selected from：
Preferably, do not include following technical scheme in such use：
The purposes of echinacoside and its pharmaceutically acceptable derivates in preparing IDO inhibitor, the IDO inhibitor
For treating cancer, autoimmune disease or Alzheimer disease；
The purposes of resupinate woodbetony leaf or root glycosides A and its pharmaceutically acceptable derivates in preparing IDO inhibitor, the IDO inhibit
Agent is used for treating cancer.
Preferably, do not include following technical scheme in such use：
Echinacoside and its pharmaceutically acceptable derivates are in the disease for preparing the tryptophan metabolic pathway that treatment IDO is mediated
Purposes in the drug of the disease of feature of science, the disease are cancer, autoimmune disease or Alzheimer disease；
Resupinate woodbetony leaf or root glycosides A and its pharmaceutically acceptable derivates are preparing the tryptophan metabolic pathway for the treatment of IDO mediations
Purposes in the drug of the disease of pathological characteristics, the disease are cancer.
Preferably, in such use, the Phenylpropanoid Glycosides glycoside and its pharmaceutically acceptable derivates according to common process,
Customary adjuvant is added, clinically acceptable tablet, capsule, powder, mixture, pill, granule, syrup, emplastrum is made
Agent, suppository, aerosol, ointment or injection.
The customary adjuvant is：Filler, disintegrant, lubricant, suspending agent, adhesive, sweetener, corrigent, anti-corrosion
Agent, matrix etc..Filler includes：Starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose etc.；It collapses
Solving agent includes：Starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low substitution hydroxyl
Third cellulose, cross-linked carboxymethyl cellulose are received；Lubricant includes：Magnesium stearate, lauryl sodium sulfate, talcum powder, dioxy
SiClx etc.；Suspending agent includes：Polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methyl cellulose etc.；Bonding
Agent includes starch slurry, polyvinylpyrrolidone, hydroxypropyl methyl cellulose etc.；Sweetener includes：Saccharin sodium, aspartame, sugarcane
Sugar, honey element, enoxolone etc.；Corrigent includes：Sweetener and various essence；Preservative includes：Parabens, benzoic acid,
Sodium benzoate, sorbic acid and its esters, benzalkonium bromide, the fixed, eucalyptus oil of acetic acid chloroethene etc.；Matrix includes：PEG6000,
PEG4000, insect wax etc..
Technical scheme of the present invention has the following advantages that：
The present invention passes through the study found that echinacoside, resupinate woodbetony leaf or root glycosides A and resupinate woodbetony leaf or root glycosides H live to the inhibition of intracellular IDO
Property be superior to inhibitory activity of the positive control drug 1- methyl tryptophans (1-MT) to intracellular IDO, with significant IDO suppression
System activity can be used for treating cancer, Alzheimer disease, ankylosing spondylitis, autoimmune disease, bacterium infection, white
Cataract or glaucoma, mood disorder, depressive and anxiety neurosis.
Specific implementation mode
In following embodiment of the present invention and experimental example, echinacoside can be obtained by buying, can also be according to the present invention
The method of embodiment 1 is prepared, and can also be prepared according to existing literature；Resupinate woodbetony leaf or root glycosides A and resupinate woodbetony leaf or root glycosides H can be with
It is prepared, can also be prepared according to existing literature according to the method for the embodiment of the present invention 2.
Embodiment 1The preparation of echinacoside
The dry meat stem of Herba Cistanches (Cistanche deserticola Ma) is taken, the volumetric concentration of 10 times of weight is added
For 75% ethanol water heating and refluxing extraction 2 times, 2 hours are extracted for the 1st time, extracted 1 hour for the 2nd time, merge extracting solution, subtract
Pressure is concentrated into no alcohol taste, obtains Herba Cistanches medicinal extract；
The Herba Cistanches medicinal extract is suspended in the water of 1 times of weight, then carries out extraction 2 times by extractant of n-butanol,
The organic phase for collecting extract liquor, is then concentrated under reduced pressure, obtains Herba Cistanches extracting n-butyl alcohol position medicinal extract；
By Herba Cistanches extracting n-butyl alcohol position medicinal extract through AB-8 macroporous resin column chromatographies purifying (macroporous resin column it is a diameter of
8cm, column volume 3.5L), using water as mobile phase A, using ethyl alcohol as Mobile phase B, gradient elution (gradient is carried out according to following procedure
The flow velocity of elution is 3BV/h)：First use A：B volume ratios are 100%：0% mobile phase elutes 3BV, then uses A：B volume ratios are
80%：20% mobile phase elutes 4BV, then uses A：B volume ratios are 60%：40% mobile phase elutes 4BV, then uses A：B volumes
Than being 40%：60% mobile phase elutes 4BV, then uses A：B volume ratios are 5%：95% mobile phase elution makes macroreticular resin again
Raw, collection mobile phase is A：B volume ratios are 80%：20% eluent, is then concentrated under reduced pressure, and Herba Cistanches ethanol elution is obtained
Position medicinal extract；
C18 reverse phase of the Herba Cistanches alcohol elution medicinal extract through Agilent SD-1 is prepared into liquid phase separation purifying, with water
For mobile phase C, using methanol as mobile phase D, according to following procedure carry out gradient elution：First use C：D volume ratios are 90%：10%
Mobile phase elutes, then uses C：D volume ratios are 80%：20% mobile phase elution, then use C：D volume ratios are 70%：30% stream
It is dynamic mutually to elute, then use C：D volume ratios are 60%：40% mobile phase elution, then use C：D volume ratios are 50%：50% flowing
It mutually elutes, is detected by TLC detections or HPLC-MS, collection mobile phase is C：D volume ratios are 60%：40% eluent, then
It is concentrated under reduced pressure, dried, obtain echinacoside (HPLC purity >=95%).
The above-mentioned compound being prepared is passed through1H-NMR、13C-NMR and HPLC-MS carry out structural confirmation, by with it is existing
Have document (Herba Cistanches chemical constitution study,《Chinese Pharmaceutical Journal》, 2011,46 (14), 1053-1058.) in1H-NMR、13C-NMR and HPLC-MS are compared, it is known that preparation-obtained compound is echinacoside.
Embodiment 2The preparation of resupinate woodbetony leaf or root glycosides A and resupinate woodbetony leaf or root glycosides H
Pedicularis resupinata (Pedicularis spicata) is taken, the ethanol water that the volumetric concentration of 9 times of weight is 95% is added
Solution heating and refluxing extraction 2 times, the 1st extraction 2 hours, the 2nd extraction 1 hour merge extracting solution, are concentrated under reduced pressure into no alcohol
Taste obtains Pedicularis resupinata medicinal extract；
Pedicularis resupinata medicinal extract is suspended in the water of 1 times of weight, then carries out extraction 2 times by extractant of n-butanol,
The organic phase for collecting extract liquor, is then concentrated under reduced pressure, obtains Pedicularis resupinata extracting n-butyl alcohol position medicinal extract；
By Pedicularis resupinata extracting n-butyl alcohol position medicinal extract through AB-8 macroporous resin column chromatographies purifying (macroporous resin column it is straight
Diameter is 8cm, column volume 3.5L), using water as mobile phase A, using ethyl alcohol as Mobile phase B, gradient elution is carried out according to following procedure
(flow velocity of gradient elution is 3BV/h)：First use A：B volume ratios are 100%：0% mobile phase elutes 3BV, then uses A：B volume ratios
It is 70%：30% mobile phase elutes 4BV, then uses A：B volume ratios are 50%：50% mobile phase elutes 4BV, then uses A：B bodies
Product is than being 30%：70% mobile phase elutes 4BV, then uses A：B volume ratios are 5%：95% mobile phase elution makes macroreticular resin
Regeneration, collection mobile phase are A：B volume ratios are 50%：50% eluent, is then concentrated under reduced pressure, and Pedicularis resupinata second is obtained
Alcohol elutes position medicinal extract；
C18 reverse phase of the Pedicularis resupinata alcohol elution medicinal extract through Agilent SD-1 is prepared into liquid phase separation purifying,
Using water as mobile phase C, using methanol as mobile phase D, according to following procedure carry out gradient elution：First use C：D volume ratios are 85%：
15% mobile phase elution, then use C：D volume ratios are 75%：25% mobile phase elution, then use C：D volume ratios are 65%：
35% mobile phase elution, then use C：D volume ratios are 55%：45% mobile phase elution, then use C：D volume ratios are 35%：
65% mobile phase elution, is detected by TLC detections or HPLC-MS, and it is C to collect mobile phase respectively：D volume ratios are 65%：
35%, C：D volume ratios are 55%：Then 45% eluent is concentrated under reduced pressure, is dried respectively, respectively resupinate woodbetony leaf or root glycosides A and
Resupinate woodbetony leaf or root glycosides H (HPLC purity >=95%).
The above-mentioned compound being prepared is passed through respectively1H-NMR、13C-NMR and HPLC-MS carries out structural confirmation, respectively
By with existing literature (document 1：Muscicolous woodbetony root chemical constitution study,《Lanzhou University's journal：Natural science edition》, 1997,1,
69-74；Document 2：Lousewort plant Phenylpropanoid Glycosides glucoside composition Study (I),《Chemical Journal of Chinese Universities》, 1992,4,481-
482.) in1H-NMR、13C-NMR and HPLC-MS are compared, it is known that preparation-obtained compound is respectively resupinate woodbetony leaf or root glycosides A
With resupinate woodbetony leaf or root glycosides H.
Experimental example 1The research of echinacoside, resupinate woodbetony leaf or root glycosides A and resupinate woodbetony leaf or root glycosides H to the inhibitory activity of IDO
1, experiment purpose
Using plasmid pcDNA3.1-IDO transfected HEK 293s, makes its height expression IDO, then measure Echinacea purpurea respectively
Glycosides, resupinate woodbetony leaf or root glycosides A and resupinate woodbetony leaf or root glycosides H are in cellular level to the inhibitory activity of IDO.
2, experimental method
293 cells of HEK are inoculated in the density of 2.5X104 cells/wells in 96 orifice plates, DMEM medium cultures (contain
10% fetal calf serum, 50U/mL penicillin and 50mg/mL streptomysins), be placed in 37 DEG C, humidity 95%, 5%CO2Incubator in
Culture.After culture for 24 hours, pcDNA3.1-hIDO plasmid transfections are mediated using liposome Lipofectamin 2000, are divided into the positive
Control group and experimental group 1-3 groups.Positive controls with 1- methyl tryptophans (1-MT) be test sample, experimental group 1-3 groups respectively with
The resupinate woodbetony leaf or root glycosides A and resupinate woodbetony leaf or root glycosides H of echinacoside, the preparation of embodiment 2 prepared by embodiment 1 are test sample.
After transfection for 24 hours, each group is separately added into corresponding test sample and is incubated.After being incubated 5h, take 140 μ L supernatants to another
In 96 orifice plates, 10 μ L 30% (w/v) trichloroacetic acids are added, 15min is heated at 65 DEG C, then 12000rpm centrifuges 10min, takes
The acetic acid solution mixing colour developing of isometric 2% (w/v) p- dimethylaminobenzaldehyde, finally uses microplate reader to be detected in 492nm and inhales
Light value, determination of activity result IC50Value indicates.
3, experimental result
The results are shown in Table 1 for specific experiment of each group to the inhibitory activity of IDO.
Specific experiment result of 1 each group of table to the inhibitory activity of cellular level IDO
As shown in Table 1：(1) experimental group 1-3 groups are superior to positive controls to cell to the inhibitory activity of intracellular IDO
The inhibitory activity of interior IDO, the inhibitory activity with significant IDO；
(2) experimental group 1-3 groups are suitable to the inhibitory activity of intracellular IDO, this shows the R of Phenylpropanoid Glycosides glycoside1、R2、R3、
R4、R5And R6The difference of substituent group has no significant effect inhibitory activity.
4, experiment conclusion
Echinacoside, resupinate woodbetony leaf or root glycosides A and resupinate woodbetony leaf or root glycosides H are superior to positive control drug to the inhibitory activity of intracellular IDO
1- methyl tryptophans (1-MT) are to the inhibitory activity of intracellular IDO, the inhibitory activity with significant IDO.
Experimental example 2Therapeutic effect of the Phenylpropanoid Glycosides glycoside to ankylosing spondylitis
1, experiment purpose
Mouse ankylosing spondylitis model is established using proteoglycans immunization method, then gavage echinacoside, resupinate woodbetony leaf or root
Glycosides A and resupinate woodbetony leaf or root glycosides H, ELISA method detection Inflammatory Mediators Serum TNF-α and NF- к B receptor activations factor ligand (RANKL) water
It is flat, and detect the effect of serum I DO is active (Kyn/Trp), and verification Phenylpropanoid Glycosides glycoside is for ankylosing spondylitis.
2, experimental method
2.1 experimental animal
Healthy male BALB/c mouse 32, weight (18 ± 2) g, age of mouse 4~5 weeks are purchased from Shanghai Si Laike.
2.2 for reagent object
Resupinate woodbetony leaf or root glycosides H prepared by the echinacoside and embodiment 2 prepared with embodiment 1 is for reagent object.
2.3 experiment packets and modeling
After mouse adaptable fed 1 week, wherein 8 are taken to be only used as blank control group.Remaining 24 are taken to gather only with albumen
Sugared immunization method establishes ankylosing spondylitis model, and proteoglycans emulsion 0.15mL (75 μ g+ Freund's adjuvants) is injected intraperitoneally in mouse, first
It is secondary it is immune after 7 days can booster immunization, 0.15mL emulsions, modeling totally 21 days is injected intraperitoneally；After modeling success, it is divided into 3 groups：Experimental group
1-2 groups and model control group.The horse that experimental group 1-2 groups give the echinacoside of the preparation of embodiment 1 respectively and prepared by embodiment 2 is first
Wormwood artemisia glycosides H gastric infusions, one time a day, each 0.2g/10g.Model control group and blank control group give normal saline filling
Stomach.Each group is administered 60 days, and blood is taken in the 61st day eye socket.
2.4 inflammatory factors measure
Serum TNF-α and RANKL levels in animal peripheral blood are detected using ELISA, operated according to kit specification.
2.5IDO Activity determination
Detect Trp concentration and Kyn concentration in mice serum simultaneously using high-efficient liquid phase chromatogram technology.Because IDO can be catalyzed
Substrate Trp metabolism generates product Kyn, therefore Kyn/Trp ratios can reflect IDO activity.
Serum is stood overnight at 4 DEG C, and 3000rpm centrifuges 15min.Supernatant serum is taken, 5% isometric perchloric acid is added
Solution, in mixing 0.5-1min on whirlpool misfortune vortex mixer.It is stored at room temperature 10-15min, fully to precipitate the albumen in serum, then
10min is centrifuged with 12000rpm, takes supernatant that 1/2 volumes methanol (chromatographically pure) is added, vibrates 5min on whirlpool misfortune instrument, then
12000rpm centrifuges 10min, and last supernatant carries out loading after 0.45 μm of filter filters, detect kynurenin in serum/
Tryptophan (Kyn/Trp) ratio, to reflect the active variations of IDO.Chromatographic condition：C18 columns (250mm × 4.6mm, 5 μm)；Stream
Dynamic phase：15mmol/L sodium acetate-acetic acids solution (acetonitrile for being 7% containing volume fraction, pH 3.5)；Flow velocity：1mL/min；Detection
Wavelength：225nm；Sample size：20μL；25 DEG C of column temperature.
2.6 statistical procedures
It is analyzed using SPSS22.0 statistics softwares, continuous data mean ± standard deviation It indicates, row
T is examined；Enumeration data is expressed as a percentage, row chi-square criterion；P < 0.05 indicate that difference is statistically significant.
3, experimental result
The results are shown in Table 2 for the specific experiment of each group mouse.
2 each group mice serum TNF-α of table and RANKL are horizontal and to the active inhibiting effect of IDO
#The P < 0.05 compared with blank control group,*The P < 0.05 compared with model control group
As shown in Table 2, the Serum TNF-α of (1) model control group mouse and RANKL are horizontal significantly raised, this shows tetanic
Property rachitis model modeling success；(2) Serum TNF-α and RANKL levels of experimental group 1-2 groups mouse significantly reduce (P <
0.05), and IDO activity (P < 0.05) is significantly reduced；This shows prepared by echinacoside prepared by embodiment 1 and embodiment 2
Resupinate woodbetony leaf or root glycosides H is by inhibiting IDO activity to play the therapeutic effect to ankylosing spondylitis.
4, experiment conclusion
Echinacoside and resupinate woodbetony leaf or root glycosides H can significantly reduce the Serum TNF-α and RANKL water of ankylosing spondylitis model
It is flat, and there is significant inhibiting effect to IDO activity；Echinacoside and resupinate woodbetony leaf or root glycosides H have ankylosing spondylitis significant
Therapeutic effect.
Experimental example 3Therapeutic effect of the Phenylpropanoid Glycosides glycoside for streptococcal infection
1, experiment purpose
By to streptococcal infection intragastric administration on mice echinacoside and resupinate woodbetony leaf or root glycosides H, detecting it for streptococcal infection mouse
Dead inhibiting rate, verify its therapeutic effect to streptococcal infection.
2, experimental method
2.1 experimental animal
Healthy male mouse of kunming 40, weight (18 ± 2) g, age of mouse 4~5 weeks are purchased from Shanghai Si Laike.
2.2 for reagent object
Resupinate woodbetony leaf or root glycosides H prepared by the echinacoside and embodiment 2 prepared with embodiment 1 is for reagent object.
2.3 experiment packets and modeling
32171 reference cultures of hemolytic streptococcus CMCC (B) are inoculated with rabbit blood agar plate, cultivate and have been obtained obviously after scribing line
The single bacterium colony of zone of hemolysis.Single bacterium colony is taken to be inoculated in THY culture mediums (containing 5% calf serum) amplification overnight, OD600nm=0.6 is (about
109When CFU/ml), 4 DEG C save backup.(every liter contains 20 grams of tryptone, 3 grams of yeast extract, beef extract 5 to THY culture mediums
Gram, 2 grams of sodium chloride, 4 grams of glucose, 2.5 grams of sodium carbonate, 0.4 gram of disodium hydrogen phosphate, tune pH to 7.4.Solid medium：Again plus
Enter 1.5% agar powder, autoclaving 30min is placed in 4 DEG C of preservations).
10 mouse are taken, as blank control group.Remaining 30 mouse is divided into 3 groups：Experimental group 1-2 groups and model pair
According to group, every group of 10 mouse.The horse that experimental group 1-2 groups give the echinacoside of the preparation of embodiment 1 respectively and prepared by embodiment 2 is first
Wormwood artemisia glycosides H gastric infusions, each 80mg/kg.Model control group and blank control group give normal saline gavage.Experimental group
After 1-2 groups and model control group gavage 1h, equal tail vein injection OD600nm=0.6 micrococcus scarlatinaes 322171PBS solution,
Injection dosage：0.4ml bacterium solutions/10g mouse, are administered once every for 24 hours, every 6h observe 1 time, respectively record time 6h, 12h,
For 24 hours, the death condition of the mouse of 48h.
3, experimental result
Influence of each group different time to streptococcal infection dead mouse is as shown in table 3.
Influence (n=10) of the 3 each group different time of table to streptococcal infection dead mouse
As shown in Table 3, after (1) is administered 48 hours, the mouse survival rates of experimental group 1-2 groups is respectively 70% and 70%, and
The survival rate of model control group mouse is only 20%；This shows echinacoside prepared by embodiment 1 and horse prepared by embodiment 2
First wormwood artemisia glycosides H can significantly improve the survival rate of streptococcal infection mouse, have significant therapeutic effect to streptococcal infection.
4, experiment conclusion
Echinacoside and resupinate woodbetony leaf or root glycosides H have significant therapeutic effect to streptococcal infection.
Obviously, the above embodiments are merely examples for clarifying the description, and does not limit the embodiments.It is right
For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of variation or
It changes.There is no necessity and possibility to exhaust all the enbodiments.And it is extended from this it is obvious variation or
It changes still within the protection scope of the invention.
Claims (7)
1. the purposes of Phenylpropanoid Glycosides glycoside and its pharmaceutically acceptable derivates in preparing IDO inhibitor；
The IDO inhibitor is for treating cancer, Alzheimer disease, ankylosing spondylitis, autoimmune disease, bacterium sense
Dye, cataract, mood disorder, depressive and anxiety neurosis；The pharmaceutically acceptable derivates are selected from salt, ester, prodrug or molten
Object is closed in agent；
The Phenylpropanoid Glycosides glycoside has structure as follows：
Wherein, R1、R2、R5、R6It is independently from each other-H or-CH3, R3And R4It is independently from each otherAt least one of be formed by glycosyl residue.
2. Phenylpropanoid Glycosides glycoside and its pharmaceutically acceptable derivates are in the disease for preparing the tryptophan metabolic pathway that treatment IDO is mediated
Purposes in the drug of the disease of feature of science；
The disease be cancer, Alzheimer disease, ankylosing spondylitis, autoimmune disease, bacterium infection, cataract,
Mood disorder, depressive and anxiety neurosis；The pharmaceutically acceptable derivates are selected from salt, ester, prodrug or solvate；
The Phenylpropanoid Glycosides glycoside has structure as follows：
Wherein, R1、R2、R5、R6It is independently from each other-H or-CH3, R3And R4It is independently from each otherAt least one of be formed by glycosyl residue.
3. purposes according to claim 1 or 2, which is characterized in that
R1、R2、R5、R6It is independently from each other-H or-CH3, R3And R4It is independently from each otherIn one kind being formed by glycosyl residue.
4. purposes according to claim 3, which is characterized in that the Phenylpropanoid Glycosides glycoside is selected from：
5. according to claim 1-4 any one of them purposes, which is characterized in that do not include following technical scheme：
The purposes of echinacoside and its pharmaceutically acceptable derivates in preparing IDO inhibitor, the IDO inhibitor are used for
Treating cancer, autoimmune disease or Alzheimer disease；
The purposes of resupinate woodbetony leaf or root glycosides A and its pharmaceutically acceptable derivates in preparing IDO inhibitor, the IDO inhibitor are used
In treating cancer.
6. according to claim 1-4 any one of them purposes, which is characterized in that do not include following technical scheme：
Echinacoside and its pharmaceutically acceptable derivates are in the pathology for preparing the tryptophan metabolic pathway that treatment IDO is mediated
Purposes in the drug of the disease of feature, the disease are cancer, autoimmune disease or Alzheimer disease；
Resupinate woodbetony leaf or root glycosides A and its pharmaceutically acceptable derivates are in the pathology for preparing the tryptophan metabolic pathway that treatment IDO is mediated
The purposes in the drug of the disease of feature is learned, the disease is cancer.
7. according to claim 1-6 any one of them purposes, which is characterized in that the Phenylpropanoid Glycosides glycoside and its can pharmaceutically connect
The derivative received is added customary adjuvant and clinically acceptable tablet, capsule, powder, mixture, ball is made according to common process
Agent, granule, syrup, emplastrum, suppository, aerosol, ointment or injection.
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| CN201710292570.6A CN108785319B (en) | 2017-04-28 | 2017-04-28 | Application of phenylpropanoid glycosides in preparation of IDO inhibitor |
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| CN201710292570.6A CN108785319B (en) | 2017-04-28 | 2017-04-28 | Application of phenylpropanoid glycosides in preparation of IDO inhibitor |
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| CN108785319B CN108785319B (en) | 2021-04-30 |
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Cited By (1)
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| CN115105518A (en) * | 2022-06-30 | 2022-09-27 | 广东省农业科学院作物研究所 | Application of pedicularioside A in preparing chicken feed or medicine for resisting chicken coccidiosis |
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| CN103483400A (en) * | 2013-09-17 | 2014-01-01 | 南京通泽农业科技有限公司 | Purifying process of pedicularioside A |
| CN105920061A (en) * | 2016-04-19 | 2016-09-07 | 王胜 | Alkali plant salt with bacteriostasis and preparation method thereof |
| CN106236762A (en) * | 2016-08-12 | 2016-12-21 | 成都中医药大学 | Echinacoside and the new application of acteoside |
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| CN103483400A (en) * | 2013-09-17 | 2014-01-01 | 南京通泽农业科技有限公司 | Purifying process of pedicularioside A |
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| CN115105518A (en) * | 2022-06-30 | 2022-09-27 | 广东省农业科学院作物研究所 | Application of pedicularioside A in preparing chicken feed or medicine for resisting chicken coccidiosis |
| CN115105518B (en) * | 2022-06-30 | 2023-08-18 | 广东省农业科学院作物研究所 | Application of pedicellus et pericarpium citri reticulatae glycoside A in preparation of chicken feed or medicine for resisting chicken coccidiosis |
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| CN108785319B (en) | 2021-04-30 |
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