CN109045017A - A kind of Polymethoxylated flavanones is preparing the application in anti-oxidation stress medicine - Google Patents
A kind of Polymethoxylated flavanones is preparing the application in anti-oxidation stress medicine Download PDFInfo
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Abstract
The invention discloses (2S) -5,6,7,3', 4'- pentamethoxyl flavanones in the application for preparing oxidative stress and inducing an illness in drug.(2S) -5 shown in formula I, 6,7,3', 4'- pentamethoxyl flavanones is a kind of Nrf2 agonist, it can be used for preventing and treating Cells Induced by Reactive Oxygen Species disease, including Chronic Obstructive Pulmonary Disease, respiratory inflammation, cardiovascular disease, neurodegenerative disease and diabetic nephropathy, preferably Chronic Obstructive Pulmonary Disease and respiratory inflammation.(2S) -5,6,7,3', 4'- pentamethoxyl flavanones of the invention can activate Nrf2 signal path, and Scavenger of ROS inhibits response to oxidative stress, shows good preventive and therapeutic action to Chronic Obstructive Pulmonary Disease, respiratory inflammation.Therefore, it can be prepared into corresponding drug and health care product, and be used for above-mentioned disease prevention and treatment.
Description
Technical field
The invention belongs to field of medicaments, are related to the application of (2S) -5,6,7,3', 4'- pentamethoxyl flavanones, and in particular to
(2S) -5,6,7,3', 4'- pentamethoxyl flavanones is induced an illness in preparation prevention or therapeutic activity oxygen in drug or health care product
Using.
Background technique
In recent years due to the increase of the exacerbation of environmental pollution and number of smokers, body be directly exposed to some noxious materials or
In oxidant, such as carbon sulphur nitrogen oxides (CO, SO2、NO2Deng), heavy metal (lead, chromium, arsenic etc.), vehicle exhaust and building mineral
The haze etc. that dirt is formed.These substances will lead to the raising of (ROS) horizontal abnormality of active oxygen in body, and redox is unbalance, causes
Oxidative stress then damages cell component (such as lipid, protein and nucleic acid), and causes including Chronic Obstructive Pulmonary Disease, exhales
Inhale many diseases including road inflammation, cardiovascular disease, neurodegenerative disease and tumour.
Nuclear factor Nrf2 (Nuclear factor-erythroid 2-related factor 2) signal path is
Signal of interest access in body antioxidant system.When body is in oxidative stress status, Nrf2 enters nucleus, with antioxygen
After changing enzyme and II phase detoxication enzyme promoter region Antioxidation reaction original part (ARE) combination, starting downstream gene transcription.Nrf2 regulation
Downstream target proteins include the II phase detoxication enzyme such as GST, NQO1；The antioxidases such as HO-1, SOD and γ-GCS.Activate Nrf2 signal
Access can induce the expression of a variety of II phase detoxication enzymes and antioxidase that regulate and control downstream, and active oxygen in scavenger-cell remains thin
Redox equilibrium state intracellular, to play endogenous protection effect.
In the more than ten years in past, cellular redox balance is adjusted by activation Nrf2 access, Scavenger of ROS is intervened
Cells Induced by Reactive Oxygen Species disease has been achieved for significant achievement.More and more research and probes simultaneously confirm under different pathological conditions
The protective effect of Nrf2, and Nrf2 participate in the protective effect in damage and oxidative stress caused by confrontation pollutant.It is aoxidizing
It is found in stress induction disease model, activation Nrf2 access can raise II phase detoxication enzyme and antioxidant enzyme levels, remove pollution
Carcinogenic substance in object reduces its toxicity；The expression of up-regulation Nrf2 can also increase glutathione levels, enhance antioxygen
Change enzymatic activity, active oxygen in scavenger-cell.Therefore, Nrf2 signal path is activated using exogenous Nrf2 agonist, enhances body
Oxidation resistance becomes the available strategy of the treatment of many Cells Induced by Reactive Oxygen Species diseases.
Natural products is the important sources of lead compound, is made that significant contribution to human medicine development history.From
The lead compound with preventive and therapeutic action is found in natural products, is the important channel of medicament research and development.Currently, many
Nrf2 agonist is all derived from natural products or extracts from natural products and obtains, such as in brassicaceous vegetable
Sulforaphen, the curcumin in turmeric, cinnamic acid in cortex cinnamomi etc..Flavones is important as Nrf2 agonist
Source, having, which becomes prevention and treatment oxidative stress, induces an illness the potentiality of drug.Although the Nrf2 largely about flavones has been carried out
Agonism and Antioxidation Mechanism research, but mostly these flavones it is ingredient that is commercially available or being easy to get, such as Quercetin,
Kaempferol, genistein etc..Still there is the flavonoids Nrf2 agonist of large result novelty, superior activity urgently to study at present,
And there are the potentiality as lead compound.
Summary of the invention
In order to solve the above technical problems, the present invention puts technical solution:
It is an object of the present invention to provide (2S) -5,6,7,3', 4'- pentamethoxyl flavanones in preparation therapeutic activity oxygen
Induce the application in disease medicament and health care product.The chemical formula of the compound is as follows:
Found in research process of the present invention, (2S) -5,6,7,3', 4'- pentamethoxyl flavanones can promote Nrf2,
The expression of NQO1, γ-GCS protein level and NQO1, GCLM mRNA level in-site, activation mechanism are turned by induction Nrf2 albumen
Position enters core, inhibits Nrf2 protein degradation, increases what Nrf2 protein stability was realized；On human bronchial using smoke from cigarette induction
The skin Beas-2B cellular damage model evaluation cytoprotection of (2S) -5,6,7,3', 4'- pentamethoxyl flavanones, as a result
Show that the compound is able to suppress the ROS generation of smoke from cigarette induction, increases endogenous cellular antioxidant agent GSH level, inhibit
The Beas-2B cellular damage of smoke from cigarette induction；It is thin to glomerulus membrane system cell SV40MES13 cell, rat stellate glioma
Born of the same parents' C6 cells show goes out similar cytoprotection.It is above-mentioned the experimental results showed that, it is (2S) -5,6,7,3' of the present invention,
4'- pentamethoxyl flavanones has prevention and treatment Chronic Obstructive Pulmonary Disease, respiratory inflammation, cardiovascular disease, nervus retrogression disease
The effect of disease and diabetic nephropathy.
Preferably, active oxygen induction disease includes Chronic Obstructive Pulmonary Disease, respiratory inflammation, angiocarpy in above-mentioned application
The diseases such as disease, neurodegenerative disease and tumour.
Preferably, in above-mentioned application, compound (2S) -5,6,7,3', 4'- pentamethoxyl flavanones concentration be 3.12~
25 μM, it is further preferred that being 6.25 μM.
The second purpose of the present invention is to provide the separation method of above compound, steps of the method are: take cat's whisker meadow
Upper part crushes, and ethanol solution refluxing extraction is added, extracting solution is concentrated under reduced pressure to give extraction medicinal extract.It is extracted in medicinal extract to gained
Add water to be suspended, successively use petroleum ether, ethyl acetate and extracting n-butyl alcohol, obtain ethyl acetate portion, take ethyl acetate portion,
Gradient elution is carried out by eluant, eluent of petroleum ether-acetone, merges elution ingredient to obtain 14 under the directive function of thin-layer chromatography
A part goes out column sequence by chromatography eluant and is denoted as Frs.1-14.Wherein MCI post separation will be used by Fr.6, and be elution with methanol-water
Agent carries out gradient elution, obtains six parts, goes out column sequence by chromatography eluant and is denoted as Fr.6.1-Fr.6.6.There is knot in Fr.6.5
Crystalline substance recrystallizes to obtain yellow needles as (2S) -5,6,7,3', 4'- pentamethoxyl Huang using methylene chloride-methanol system
Alkanone.
Preferably, the ethanol solution that the ethanol solution in above-mentioned separation method is 95%.
Preferably, above-mentioned Mao Xu Cao is added ethanol solution refluxing extraction four times, merging filtrate；Wherein Mao Xu Cao and ethyl alcohol are molten
The ratio of liquid is 1:5 to 1:8.
Preferably, above-mentioned petroleum ether-acetone gradient elution, petroleum ether: acetone isocratic elution from 20:1 to 1:1.
Preferably, above-mentioned methanol-water gradient elution, methanol: water is from 30:70 isocratic elution.
Preferably, in above-mentioned methylene chloride-methanol system, methylene chloride: methanol=1:1.
The three of the object of the invention are to provide a kind of pharmaceutical composition, and the pharmaceutical composition is by (2S) -5,6,7,3', 4'-
Pentamethoxyl flavanones or (2S) -5,6,7,3', 4'- pentamethoxyl flavanones and other flavanone compounds composition.
Preferably, in aforementioned pharmaceutical compositions, compound (2S) -5,6,7,3', 4'- pentamethoxyl flavanones concentration is
3.12~25 μM, it is further preferred that being 6.25 μM.
The four of the object of the invention are to provide a kind of pharmaceutical preparation for therapeutic activity oxygen induction disease, the pharmaceutical preparation
Ingredient be aforementioned pharmaceutical compositions and customary adjuvant.
Preferably, said medicine preparation be capsule, tablet, powder, granule, injection, oral solution, vina, pill,
Mixture or tincture.
The five of the object of the invention are to provide a kind of preparation method for therapeutic activity oxygen induction disease tablet, incite somebody to action
It is sieved after (2S) -5,6,7,3', 4'- pentamethoxyl flavanones, starch and dextrin mixing, adds sodium carboxymethylcellulose system
Grain, tabletting is after magnesium stearate mixing is then added up to tablet.
Preferably, in above-mentioned preparation method, (2S) -5,6,7,3', 4'- pentamethoxyl flavanones, starch and dextrin quality
Than for 1~2:1~2:2~4.
The six of the object of the invention are to provide one kind (2S) -5,6,7,3', 4'- pentamethoxyl flavanones as Nrf2 excitement
The application of agent, or enter as Nrf2 the application of core inducer, or the application as GSH inducer.
Beneficial effects of the present invention
1. causing oxidation to be answered in recent years, the levels of toxic substances in air increases with the exacerbation of environmental
The disease incidence for swashing disease increases, and exploitation is of great significance for the drug of anti-oxidation stress disease.(2S) -5 in the present invention,
6,7,3', 4'- pentamethoxyl flavanones have good reparation to the bronchiolar epithelium Beas-2B cellular damage model that cigarette induces
Effect shows that the compound is able to suppress the active oxygen generation of smoke from cigarette induction.
2. in the prior art about compound (2S) -5,6,7,3', 4'- pentamethoxyl flavanones separation method and active
Study less, the present invention is by having researched and proposed the side that one kind efficiently separates (2S) -5,6,7,3', 4'- pentamethoxyl flavanones
Method, and confirmed its antioxidant activity.Under the premise of inventor's correlative study in the prior art more blank, completion mentions it
Separation and active research, the research achievement is taken to have unobviousness.
3.Kumar, H et al. are in document " Natural product-derived pharmacological
modulators of Nrf2/ARE pathway for chronic diseases."Natural Product Reports
31.1 (2013): change in many natural extracts such as apiolin, Luteolin and the present invention although being disclosed in 109-139.
Closing object has similar mother nucleus structure, but the inhibitor as Nrf2/ARE access, shows complete with the compounds of this invention
Opposite pharmacological activity.The present invention confirmed that compound (2S) -5,6,7,3', 4'- pentamethoxyl flavanones can by research
Promote the expression of Nrf2, NQO1, γ-GCS protein level and NQO1, GCLM mRNA level in-site, activation mechanism is to pass through induction
Nrf2 protein translocation enters core, inhibits Nrf2 proteins ubiquitin, increases what Nrf2 protein stability was realized.The public affairs of this mechanism of action
It opens, those skilled in the art can be helped to research and develop related drugs for related target, there is important medical significance.
(4. 2S) -5,6,7,3', 4'- pentamethoxyl flavanones induced activity evaluation experimental the result shows that, the present invention in change
Object is closed to the inducing action of NQO1 better than other compounds in the prior art, it is stronger that induction Nrf2 enters core effect, under 6.25 μM
It can reach the effect of good protection cell, protection efficiency height, cost economy.
Detailed description of the invention
The accompanying drawings constituting a part of this application is used to provide further understanding of the present application, and the application's shows
Meaning property embodiment and its explanation are not constituted an undue limitation on the present application for explaining the application.
The histogram of Fig. 1 NQO1 induced activity test；
Fig. 1 shows (2S) -5,6,7,3', 4'- pentamethoxyl flavanones to hepa 1c1c7 cell II phase can be induced to solve
The expression of toxenzyme NQO1 simultaneously enhances its activity, and (2S) -5,6,7,3', 4'- pentamethoxyl flavanones concentration unit in figure is μM,
2.0 μM of sulforaphen are positive control.
The western blot figure of Fig. 2 various concentration (2S) -5,6,7,3', 4'- pentamethoxyl flavanones；
Fig. 2 shows that (2S) -5,6,7,3', 4'- pentamethoxyl flavanones can raise Nrf2 and downstream II phase detoxication enzyme
NQO1 antioxidase and γ-GCS protein level, wherein (2S) -5,6,7,3', 4'- pentamethoxyl flavanones concentration unit is μ
M。
The real-time fluorescence PCR figure of Fig. 3 various concentration (2S) -5,6,7,3', 4'- pentamethoxyl flavanones；
Fig. 3 shows that (2S) -5,6,7,3', 4'- pentamethoxyl flavanones can raise NQO1 and GCLM mRNA level in-site, figure
2.0 μM of middle sulforaphen are control.
The fluorescence micrograph figure of Fig. 4 cellular immunity；
Fig. 4 shows that (2S) -5,6,7,3', 4'- pentamethoxyl flavanones can promote Nrf2 indexing to enter core, radish sulphur in figure
2.0 μM of element are control, and (2S) -5,6,7,3', 4'- pentamethoxyl flavanones concentration is 25 μM.
The ubiquitination figure of Fig. 5 (2S) -5,6,7,3', 4'- pentamethoxyl flavanones；
Fig. 5 shows that (2S) -5,6,7,3', 4'- pentamethoxyl flavanones is able to suppress Nrf2 proteins ubiquitin, wherein
(2S) -5,6,7,3', 4'- pentamethoxyl flavanones concentration is 25 μM.
The western blot figure of Fig. 6 different time (2S) -5,6,7,3', 4'- pentamethoxyl flavanones；
Fig. 6 shows that (2S) -5,6,7,3', 4'- pentamethoxyl flavanones is able to extend Nrf2 protein half-life, wherein
(2S) -5,6,7,3', 4'- pentamethoxyl flavanones concentration is 25 μM.
The intracellular ROS fluorescence micrograph figure of Fig. 7；
Fig. 7 shows that (2S) -5,6,7,3', 4'- pentamethoxyl flavanones is able to suppress the ROS generation of smoke from cigarette induction,
Wherein, (2S) -5,6,7,3', 4'- pentamethoxyl flavanones concentration is 6.25 μM, and the concentration of smoke from cigarette is 180 μ g/mL.
The histogram that Fig. 8 (2S) -5,6,7,3', 4'- pentamethoxyl flavanones influences glutathione；
Fig. 8 shows that (2S) -5,6,7,3', 4'- pentamethoxyl flavanones can increase human bronchial epithelial Beas-2B cell
Endogenous antioxidant glutathione level, wherein 5 μM of sulforaphen are positive control, five methoxy of (2S) -5,6,7,3', 4'-
Base flavanones concentration unit is μM.
The histogram of the cell survival amount of Fig. 9 cell toxicity test；
Fig. 9 A is that various concentration (2S) -5,6,7,3', 4'- pentamethoxyl flavanones induces carefully 180 μ g/mL smoke from cigarette
The protective effect of cellular toxicity, Fig. 9 B show that (2S) -5,6,7,3', 4'- pentamethoxyl flavanones lures various concentration smoke from cigarette
The protective effect of guided cell toxicity, Fig. 9 C show (2S) -5,6,7,3', 4'- pentamethoxyl flavanones to transfection Nrf2-siRNA
Cell unprotect effect.
Specific embodiment
It is noted that following detailed description is all illustrative, it is intended to provide further instruction to the application.Unless another
It indicates, all technical and scientific terms used herein has usual with the application person of an ordinary skill in the technical field
The identical meanings of understanding.
It should be noted that term used herein above is merely to describe specific embodiment, and be not intended to restricted root
According to the illustrative embodiments of the application.As used herein, unless the context clearly indicates otherwise, otherwise singular
Also it is intended to include plural form, additionally, it should be understood that, when in the present specification using term "comprising" and/or " packet
Include " when, indicate existing characteristics, step, operation, device, component and/or their combination.
As background technique is introduced, exist in the prior art that have studied flavones mostly commercially available or be easy to get
The deficiency of ingredient, in order to solve technical problem as above, present applicant proposes (2S) -5,6,7,3', 4'- pentamethoxyl flavanones
Preparing the application in Cells Induced by Reactive Oxygen Species disease medicament and health care product.
In a kind of exemplary embodiment of the invention, (2S) -5,6,7,3', 4'- pentamethoxyl flavanones is provided and is being prepared
Therapeutic activity oxygen induces the application in disease medicament and health care product.The chemical formula of the compound is as follows:
In preferred embodiment, active oxygen induction disease includes Chronic Obstructive Pulmonary Disease, respiratory tract in above-mentioned application
The diseases such as inflammation, cardiovascular disease, neurodegenerative disease and tumour.
In preferred embodiment, in above-mentioned application, compound (2S) -5,6,7,3', 4'- pentamethoxyl flavanones is dense
Degree is 3.12~25 μM, it is further preferred that being 6.25 μM.
In another exemplary embodiment of the invention, the separation method of above compound is provided, steps of the method are:
It takes Mao Xu Cao aerial part to crush, ethanol solution refluxing extraction is added, extracting solution is concentrated under reduced pressure to give extraction medicinal extract.To gained
It extracts in medicinal extract plus water is suspended, successively use petroleum ether, ethyl acetate and extracting n-butyl alcohol, obtain ethyl acetate portion, take second
Acetoacetic ester part carries out gradient elution by eluant, eluent of petroleum ether-acetone, ingredient will be eluted under the directive function of thin-layer chromatography
Merging obtains 14 parts, goes out column sequence by chromatography eluant and is denoted as Frs.1-14.Wherein MCI post separation will be used by Fr.6, with first
Alcohol water is that eluant, eluent carries out gradient elution, obtains six parts, goes out column sequence by chromatography eluant and is denoted as Fr.6.1-Fr.6.6.
Have crystallization in Fr.6.5, using methylene chloride-methanol system, recrystallize yellow needles be (2S) -5,6,7,3',
4'- pentamethoxyl flavanones.
In preferred embodiment, ethanol solution that ethanol solution in above-mentioned separation method is 95%.
In preferred embodiment, Mao Xu Cao is added after ethanol solution refluxing extraction four times, merging filtrate；Wherein, every time
When refluxing extraction, the ratio of Mao Xu Cao and ethanol solution is 1:5 to 1:8.
In preferred embodiment, petroleum ether-acetone gradient elution, petroleum ether: acetone isocratic elution from 20:1 to 1:1.
In preferred embodiment, methanol-water gradient elution, methanol: water is from 30:70 isocratic elution.
In preferred embodiment, in methylene chloride-methanol system, methylene chloride: methanol=1:1.
In another exemplary embodiment of the invention, provide a kind of pharmaceutical composition, the pharmaceutical composition by (2S) -5,
6,7,3', 4'- pentamethoxyl flavanones or (2S) -5,6,7,3', 4'- pentamethoxyl flavanones and other flavanone compounds
Composition.
In preferred embodiment, in aforementioned pharmaceutical compositions, compound (2S) -5,6,7,3', 4'- pentamethoxyl flavane
The concentration of ketone is 3.12~25 μM, in specific embodiment, is 6.25 μM.
In another exemplary embodiment of the invention, a kind of drug system for therapeutic activity oxygen induction disease is provided
Agent, the ingredient of the pharmaceutical preparation are aforementioned pharmaceutical compositions and customary adjuvant.
In preferred embodiment, said medicine preparation be capsule, tablet, powder, granule, injection, oral solution,
Vina, pill, mixture or tincture.
In another exemplary embodiment of the invention, a kind of preparation for therapeutic activity oxygen induction disease tablet is provided
(2S) -5,6,7,3' is sieved after 4'- pentamethoxyl flavanones, starch and dextrin mixing, adds carboxymethyl cellulose by method
Plain sodium granulation, tabletting is after magnesium stearate mixing is then added up to tablet.
In preferred embodiment, in above-mentioned preparation method, (2S) -5,6,7,3', 4'- pentamethoxyl flavanones, starch
And dextrin mass ratio is 1~2:1~2:2~4.
In another exemplary embodiment of the invention, one kind (2S) -5,6,7,3', 4'- pentamethoxyl flavanones is provided
As the application of Nrf2 agonist, or enter as Nrf2 the application of core inducer, or the application as GSH inducer.
In order to enable those skilled in the art can clearly understand the technical solution of the application, below with reference to tool
The technical solution of the application is described in detail in the embodiment of body.
Embodiment 1:(2S) -5,6,7,3', the separation and identification of 4'- pentamethoxyl flavanones
After taking 6 kilograms of Mao Xu Cao aerial part to crush, it is heated to reflux with 95% ethyl alcohol or cold soaking extracts 4 Mao Xu Caos and second
The ratio of alcoholic solution is 1:5 to 1:8, and combined extract extracts 600 grams of medicinal extract by being concentrated under reduced pressure to give.Into gained medicinal extract
1 liter of water is added to be suspended, successively uses petroleum ether, ethyl acetate and extracting n-butyl alcohol, obtains 100 grams of ethyl acetate portion.Take acetic acid
Ethyl ester position, using petroleum ether-acetone as eluant, eluent, eluant, eluent ratio is petroleum ether-acetone (20:1 to 1:1), with thin-layer chromatography
Method guidance merges, and obtains 14 parts, goes out column sequence by chromatography eluant and is denoted as Frs.1-14.Fr.6 uses MCI post separation, with methanol
Water is eluant, eluent, and eluant, eluent ratio is that (30:70 to 100:0) obtains 6 parts to methanol-water, goes out column sequence by chromatography eluant and is denoted as
Fr.6.1-Fr.6.6.There is crystallization in Fr.6.5, further uses methylene chloride-methanol (1:1) system, recrystallize to obtain yellow needle
Shape crystallization.Its structure is confirmed by nuclear magnetic resoance spectrum, spectral data is as follows:
1H NMR (600MHz, DMSO-d6): δ H 5.46 (dd, J=16.0,3.0Hz, H-2), 3.15 (dd, J=16.0,
12.5Hz, H-3a), 2.63 (dd, J=12.5,3.1Hz, H-2b), 6.53 (s, H-8), 7.14 (d, J=1.8Hz, H-2 '),
7.04 (dd, J=8.7,1.8Hz, H-5 '), 3.77 (s, MeO-5,6), 3.84,3.78,3.67 (each 3H, s, MeO-3 ',
4',7).To its structure elucidation, confirming the yellow needles is (2S) -5,6,7,3', 4'- pentamethoxyl flavanones.
Embodiment 2:(2S) -5,6,7,3', the NQO1 induced activity evaluation of 4'- pentamethoxyl flavanones
(1) culture of murine hepatocarcinoma cell hepa 1c1c cell line
Murine hepatocarcinoma cell hepa 1c1c cell line is purchased from American Type Culture collection warehousing (ATCC), using containing 10%
The MEM culture medium of fetal calf serum (FBS), is placed in 37 DEG C, 5%CO2It is cultivated in incubator.
(2) NQO1 induced activity is tested
By hepa 1c1c7 cell (1.0 × 104A cells/well) it is inoculated in 96 orifice plates, and with (2S)-of various concentration
5,6,7,3', 4'- pentamethoxyl flavanones are handled 24 hours.Culture medium is absorbed, 27 μ L cell pyrolysis liquids are added and [contain 0.8% mao
Glutinous rehmannia saponin(e and 2mM EDTA solution (pH=7.8)], 37 DEG C are incubated for 15 minutes.The 170 complete reaction mixtures of μ L are added (to contain
Bovine serum albumin(BSA), MTT, 1.5% polysorbas20,0.5M Tris-HCl, 7.5mM FAD, 150mM G-6-P, grape
Sugar -6- phosphate dehydrogenase, 50mM NADP and 50mM menadione).It is placed at room temperature for about 3-5 minutes, is examined under microplate reader 630nm wavelength
Survey absorbance.(2.0 μM) of SF are used as positive control.
As a result: as shown in Figure 1, (2S) -5,6,7,3', 4'- pentamethoxyl flavanones can activate hepa 1c1c7 cell
Middle NQO1 activity, maximum induced activity are 2.35 times (50 μM), and positive control medicine sulforaphen (2.0 μM) is blank control
2.92 times of group.The above results show that (2S) -5,6,7,3', 4'- pentamethoxyl flavanones can activate II phase detoxication enzyme, right
Human body cell has protective effect.
Embodiment 2:(2S) -5,6,7,3', 4'- pentamethoxyl flavanones can raise Nrf2, γ-GCS and NQO1 albumen
It is horizontal
(1) culture of human bronchial epithelial Beas-2B cell
Human bronchial epithelial Beas-2B cell is purchased from American Type Culture collection warehousing (ATCC), using 1640 culture mediums,
And 10% fetal calf serum (FBS) is added thereto, 5% glutamine is placed in 37 DEG C, 5%CO2It is cultivated in incubator.
(2) immunoblotting assay (Western blot) detects the variation of protein level in cell
By Beas-2B cell inoculation in diameter 35mm culture dish, after culture reaches 70%-80% to density, it is added not
(2S) -5,6,7,3', 4'- pentamethoxyl flavanones with concentration handles 18h, and PBS is washed 2 times, and cell pyrolysis liquid (50 μ are added
G/ml Aprotinin, 0.5mM phenylmethylsulfonyl fluoride, 1mM sodium vanadate, 10mM sodium fluoride, 10mM β-phosphoglycerol), collect albumen
And protein concentration is measured using Bradford method.Sample protein (100 μ g) loading is respectively taken, SDS-PAGE protein isolate component is simultaneously adopted
Protein band is transferred on cellulose nitrate film by electricity consumption transfer method.Film prepares 5% skimmed milk power solution room temperature through PBS
After closing 1h, it is incubated overnight respectively with 4 DEG C of each testing protein antibody.Horseradish peroxidase idol is separately added into after PBS is washed
After the secondary antibody of connection is incubated for 1h, analysis of protein is carried out with enhanced ECL chemiluminescence.
As a result: as shown in Fig. 2, cell through (2S) -5,6,7,3', 4'- pentamethoxyl flavanones processing 18h after, Nrf2 and
II phase detoxication enzyme NQO1 and anti-oxidant γ-GCS protein level are presented dose dependent and increase downstream, it was demonstrated that the compound can
Nrf2 signal path is activated on protein level.
Embodiment 3:(2S) -5,6,7,3', 4'- pentamethoxyl flavanones up-regulation NQO1 and GCLM mRNA level in-site
Method: the variation of mRNA level in-site in real-time fluorescence PCR detection cell
By Beas-2B cell (4 × 105A cells/well) it is inoculated into diameter 35mm culture dish, with difference after being incubated overnight
(2S) -5,6,7,3', 4'- pentamethoxyl flavanones of concentration handles 18h.Albumen is collected, RNA is extracted, measures RNA in each sample
Concentration is prepared following PCR reaction solution on ice and is added in eight platoons after reverse transcription reaction: 0.2 μ L primer mixed liquor (10 μ
M), 0.2 μ L DNA profiling, 4.6 μ L DEPC water, 5 μ LSYBR Premix Ex Taq (Tli RNaseH Plus) (2 ×), from
It is detected after the heart with fluorescence quantitative PCR instrument, (one cycle: 95 DEG C, 2min is carried out amplification reaction using three-step approach；45 circulations: 95
DEG C, 5s, 55 DEG C, 30s, 72 DEG C, 30s).
As a result: as the result is shown (Fig. 3), cell is through at (2S) -5,6,7,3', 4'- pentamethoxyl flavanones for real-time fluorescence PCR
After managing 18h, NQO1 and GCLM mRNA level in-site is presented dose dependent and increases, it was demonstrated that the compound can activate on rna level
Nrf2 signal path.
Embodiment 4:(2S) -5,6,7,3', 4'- pentamethoxyl flavanones promote Nrf2 protein translocation enter core
Method: immuno-fluorescence assay Nrf2 intracellular locations
Cell climbing sheet is placed in 24 orifice plates, Beas-2B cell is inoculated with, (2S) -5 is added after cell is adherent, 6,7,
3', 4'- pentamethoxyl flavanones are handled 8 hours, and the PBS being pre-chilled with 4 DEG C is washed 2 times, and the methanol that 500 μ L-20 DEG C of addition are pre-chilled/
Acetone (1:1) fixes 10min, then the PBS being pre-chilled with 4 DEG C is washed 3 times, is added 4 DEG C of Nrf2 antibody and is incubated overnight；PBS washing 3
Secondary, secondary antibody is incubated at room temperature 1h；PBS is washed 3 times, and every hole is added 500 μ L DAPI and dyes 10min；The PBS-TX being pre-chilled with 4 DEG C is washed
It washs 3 times, creep plate is tipped upside down on the anti-quencher of fluorescence, with fluorescence microscope and take pictures in darkroom.
As a result: immunofluorescence results are shown (Fig. 4), and under normal condition, Nrf2 is located in cytoplasm, are added (2S) -5,6,
After 7,3', 4'- pentamethoxyl flavanones and positive control sulforaphen are handled 8 hours, Nrf2 indexing enters nucleus.
Embodiment 5:(2S) -5,6,7,3', the inhibition Nrf2 proteins ubiquitinization degradation of 4'- pentamethoxyl flavanones
Method: immunoprecipitation and immunoblotting assay combine detection Nrf2 ubiquitination level
By Beas-2B cell inoculation in 60 culture dish of diameter, cell density transfects Nrf2, Keap1 when reaching 80%,
HA-Ub and Vector plasmid.After transfecting 36h, 10 μM of MG132 and drug-treated cell 4h are added, collects albumen and is exempted from respectively
Epidemic disease trace and immunoprecipitation analysis, the specific steps are as follows:
(1) PBS is washed 1 time, and the 2%SDS/TBS that 200 μ L DTT containing 1mM are added collects albumen, and 95 DEG C of denaturation 10min surpass
It is centrifuged after sound 20s, takes 30 μ L supernatants into new centrifuge tube, 2 μ L cell pyrolysis liquids are added and carry out immunoblotting assay；
(2) 1%Triton-X-100/TBS is added according to 1:4 ratio in remaining liq, and 10 μ Lprotein Abeads are added,
4 DEG C of shaking tables shake 30min, are centrifuged Aspirate supernatant after 30min, and 1.5 μ LNrf2 or IgG antibody is added, and 4 DEG C of shaking tables shake 2h,
50 μ L protein A beads are added, 4 DEG C overnight, discard supernatant liquid, with the 0.5M LiCl/TBS of the DTT containing 1mM after centrifugation
It washed once, then washed 2 times with the 1%Triton-X-100/TBS containing 1mMDTT, 15 μ 2 × PLB of L (passive are added
Lysis buffer), isometric cell pyrolysis liquid is added and boils 10min, carries out immunoblotting assay.
As a result: as shown in figure 5, after being handled through (2S) -5,6,7,3', 4'- pentamethoxyl flavanones, Nrf2 ubiquitination level
It is substantially reduced, shows that (2S) -5,6,7,3', 4'- pentamethoxyl flavanones is able to suppress the degradation of Nrf2 proteins ubiquitinization.
Embodiment 6:(2S) -5,6,7,3', 4'- pentamethoxyl flavanones extension Nrf2 protein half-life
Method: immunoblotting assay detects Nrf2 protein half-life
By Beas-2B cell inoculation in diameter 35mm culture dish, after culture reaches 70%-80% to density, it is added
(2S) -5,6,7,3', 4'- pentamethoxyl flavanones 8h, is then added cycloheximide, receives respectively at 0,10,20,30,40 minute
Albumen is taken, immunoblotting assay detection is carried out, is quantified using Image J software.
As a result: as shown in fig. 6, blank group Beas-2B cell Nrf2 protein half-life is 12.9 minutes, through (2S) -5,6,
After 7,3', 4'- pentamethoxyl flavanones handle 8h, Nrf2 protein half-life extends to 23.4 minutes, shows (2S) -5,6,7,
3', 4'- pentamethoxyl flavanones are able to extend Nrf2 protein half-life.
Embodiment 7:(2S) -5,6,7,3', 4'- pentamethoxyl flavanones be able to suppress smoke from cigarette induction ROS generate
Method: ROS kit detects intracellular reactive oxygen content
By Beas-2B cell (4 × 105A cells/well) it is inoculated into 35 culture dish of diameter, it is first used after overnight incubation
(2S) -5,6,7,3', 4'- pentamethoxyl flavanones protects 8h in advance, adds stimulant processing for 24 hours.According to ROS detection kit
Specification performs the following operation: active oxygen positive control Rosup is diluted by the culture medium of 1:1000 serum-free, is being added
10~20min is added before DCFH-DA；Original cell culture fluid is removed, DCFH-DA (the 1:1000 serum-free that 1mL has diluted is added
Culture medium dilution), place 20min in incubator；It is washed 2 times with PBS, in 400 × fluorescence microscope of darkroom and is clapped
According to.
As a result: being lured as shown in fig. 7, (2S) -5,6,7,3', 4'- pentamethoxyl flavanones can significantly inhibit smoke from cigarette
The ROS led is generated, and protects cells from damage caused by ROS.
Embodiment 8:(2S) -5,6,7,3', 4'- pentamethoxyl flavanones can increase endogenous cellular antioxidant agent paddy Guang
Sweet peptide level
Method: the measurement of glutathion inside cell content
It seeds cells into 60 culture dish of diameter, five first of various concentration (2S) -5,6,7,3', 4'- is used after being incubated overnight
For 24 hours, cell is collected in digestion to the processing of oxygroup flavanones, and PBS is washed 2-3 times, and low-speed centrifugal collects cell, and 220 μ L 1mM are added
Cell is resuspended in EDTA/PBS solution, and sonicated cells take 100 μ L cell suspensions, according to glutathione assay kit explanation
Book operates, and absorbance is detected under 405nm wavelength and calculates glutathione content.
As a result: as shown in figure 8, (2S) -5,6,7,3', 4'- pentamethoxyl flavanones can dramatically increase intracellular paddy Guang
Sweet peptide level enhances intracellular reducing power.
Embodiment 9:(2S) -5,6,7,3', the human bronchial epithelial that 4'- pentamethoxyl flavanones induces smoke from cigarette
The protective effect of Beas-2B cellular damage
Method: mtt assay measures (2S) -5,6,7,3', 4'- pentamethoxyl flavanones to smoke from cigarette inducing cytotoxic
Protective effect
By Beas-2B cell inoculation on 96 orifice plates, after cell is adherent, prescribed concentration (2S) -5,6,7,3', 4'- is added
Pentamethoxyl flavanones pretreatment cell 8 hours, the stimulant for adding prescribed concentration are handled 24 hours, and 20 μ L are added in every hole
2mg/mL MTT solution, is placed in incubator and is incubated for 3-4h, removes supernatant, and 100 μ L DMSO are added in every hole, shakes dissolving crystallized
Purple detects absorbance under microplate reader 570nm wavelength.
As a result: as shown in Figure 9 A, using (2S) -5,6,7,3', 4'- pentamethoxyl flavanones pretreatment cell 8 hours, energy
The cytotoxicity of 180 μ g/mL smoke from cigarette induction is enough significantly inhibited, cells survival rate is increased, wherein 6.25 μM of concentration (2S) -5,
6,7,3', 4'- pentamethoxyl flavanones are best.As shown in Figure 9 B, using 6.25 μM of concentration (2S) -5,6,7,3', 4'-, five methoxy
Base flavanones can significantly inhibit the cytotoxicity that the smoke from cigarette of 100,150,180 μ g/mL induces, increase as protection drug
Refinement born of the same parents' survival rate.As shown in Figure 9 C, 6.25 μM of concentration (2S) -5,6,7,3', 4'- pentamethoxyl flavanones are to transfection Nrf2-
The cell unprotect of siRNA acts on.The results show that (2S) -5,6,7,3', 4'- pentamethoxyl flavanones is able to suppress cigarette cigarette
The toxicity of mist induction, and be that protective effect is generated by activation Nrf2 access.
Embodiment 10: the preparation of tablet
Starch 1g, dextrin 2g, mistake is added in (2S) -5,6,7,3', 4'- pentamethoxyl flavanones (confirmation of embodiment 1) 1g
Sieve, addition sodium carboxymethylcellulose is appropriate, granulation.Be added Magnesium Stearate proper quantity, mix, tabletting to get.
The foregoing is merely preferred embodiment of the present application, are not intended to limit this application, for the skill of this field
For art personnel, various changes and changes are possible in this application.Within the spirit and principles of this application, made any to repair
Change, equivalent replacement, improvement etc., should be included within the scope of protection of this application.
Claims (10)
1. (2S) -5,6,7,3', 4'- pentamethoxyl flavanones is in preparation therapeutic activity oxygen induction disease medicament and health care product
Using.
2. application as described in claim 1, the active oxygen induction disease be Chronic Obstructive Pulmonary Disease, respiratory inflammation,
Cardiovascular disease, neurodegenerative disease and tumour.
3. application as described in claim 1, the concentration of (2S) -5,6,7,3', 4'- pentamethoxyl flavanones is 3.12~
25 μM, it is preferred that be 6.25 μM.
4. the separation method of (2S) -5,6,7,3', 4'- pentamethoxyl flavanones described in claim 1, steps of the method are:
It takes Mao Xu Cao aerial part to crush, ethanol solution refluxing extraction is added, extracting solution is concentrated under reduced pressure to give extraction medicinal extract；To described
It extracts in medicinal extract plus water is suspended, successively use petroleum ether, ethyl acetate and extracting n-butyl alcohol, obtain ethyl acetate portion, take institute
Ethyl acetate portion is stated, carries out gradient elution by eluant, eluent of petroleum ether-acetone, it will elution under the directive function of thin-layer chromatography
Ingredient merges to obtain 14 parts, goes out column sequence by chromatography eluant and is denoted as Frs.1-14；Wherein MCI post separation will be used by Fr.6,
Gradient elution is carried out by eluant, eluent of methanol-water, obtains six parts, goes out column sequence by chromatography eluant and is denoted as Fr.6.1-
Fr.6.6；Wherein have crystallization in Fr.6.5, using methylene chloride-methanol system, recrystallize yellow needles be (2S)-
5,6,7,3', 4'- pentamethoxyl flavanones；Preferably, the ethanol solution is the ethanol solution of volume fraction 95%；It is preferred that
, the petroleum ether-acetone gradient elution, petroleum ether: acetone isocratic elution from 20:1 to 1:1；Preferably, the methanol-water
Gradient elution, methanol: water is from 30:70 isocratic elution；Preferably, in the methylene chloride-methanol system, methylene chloride and methanol
Volume ratio be 1:1.
5. separation method as claimed in claim 4, which is characterized in that refluxing extraction four after ethanol solution is added in the Mao Xu Cao
Secondary, merging filtrate, the ratio for extracting the Mao Xu Cao and ethanol solution every time is 1:5 to 1:8.
6. a kind of pharmaceutical composition, ingredient is (2S) -5,6,7,3', 4'- pentamethoxyl flavanones or (2S) -5,6,7,3', 4'-
Pentamethoxyl flavanones and other flavanone compounds.
7. pharmaceutical composition as claimed in claim 4, which is characterized in that (2S) -5,6,7,3', 4'- pentamethoxyl is yellow
The concentration of alkanone is 3.12~25 μM, it is preferred that is 6.25 μM.
8. a kind of pharmaceutical preparation for active oxygen induction disease, the ingredient of the pharmaceutical preparation are medicine described in claim 4-5
Compositions and customary adjuvant, it is preferred that the pharmaceutical preparation is capsule, tablet, powder, granule, injection, takes orally
Liquid, vina, pill, mixture or tincture.
9. a kind of preparation method for therapeutic activity oxygen induction disease tablet, by (2S) -5,6,7,3', 4'- pentamethoxyl is yellow
It is sieved after alkanone, starch and dextrin mixing, adds sodium carboxymethylcellulose granulation, tabletting after magnesium stearate mixing is then added
To obtain the final product；Preferably, described (2S) -5,6,7,3', 4'- pentamethoxyl flavanones, starch and dextrin mass ratio are 1~2:1~2:2
~4.
10. (2S) -5,6,7,3', 4'- pentamethoxyl flavanones enters core inducer or GSH induction as Nrf2 agonist or Nrf2
The application of agent.
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