CN104987340B - Fluffy flavone A of alkali and its production and use - Google Patents
Fluffy flavone A of alkali and its production and use Download PDFInfo
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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Abstract
The present invention relates to pharmaceutical technology field, there is provided a kind of flavonoids class noval chemical compound with immunosuppressive activity --- the fluffy flavone A of alkali, chemical name：The hydroxyl coumaronochromone of 5,6,8 trimethoxy 7（5,6,8‑trimethoxy‑7‑hydroxycoumaronochromone）, structural formula is as follows..The invention further relates to the lymphopoietic effect that the preparation method of the compound and its compound are induced LPS and ConA.Result of study finds that the fluffy flavone A of alkali has and suppresses lymphopoietic activity, IC well50Value can be used to prepare the medicine for the treatment of immunity relevant disease up to 0.39 μM.
Description
Technical field
It is a kind of noval chemical compound --- fluffy Huang of alkali with enhancing body's immunity the present invention relates to pharmaceutical technology field
Ketone A, chemical name：5,6,8- trimethoxy -7- hydroxyls coumaronochromone（5,6,8-trimethoxy 7-
ydroxycoumaronoch- romone）Preparation method and in field of medicaments enhancing immunity of organisms purposes.Specifically
It is related to extract a kind of isolated noval chemical compound from the fluffy herb of alkali, the compound has lipopolysaccharide-induced Spleen cell proliferation
Good inhibitory activity, IC50Up to 0.39 μM, can be used to prepare the medicine for the treatment of hypoimmunity disease.
Background technology
Alkali is fluffySuaeda glauca (Bunge) Bunge is Chenopodiaceae Chenopodiaceae SuaedasSuaedaForsk.
The true salt plant of ex Scop. annual herbs.It is distributed widely in Xinjiang of China, Shandong, Hebei, Liaoning, Jilin, the Inner Mongol and
The saline and alkaline desert and Coastal beach on the ground such as Gansu.Known naturally occurring plant flavone shows extensive bioactivity, including
Anti-oxidant, antitumor, antiatherosclerosis, anti-inflammatory etc..Research shows, abundant nutritional ingredient, the fluffy kind of alkali are contained during alkali is fluffy
Sub- fat content is higher, the 36.5% of its dry is accounted for, higher than soybean；The protein content of the fluffy fresh and tender cauline leaf of alkali is 40%；Remove
Outside above nutritional ingredient, also containing vitamin and trace element necessary to the abundant mankind during alkali is fluffy, containing a large amount of during alkali is fluffy
Flavone compound, but it is less to its chemical constitution study.The fluffy medicinal material of alkali first recorded in《Herbal for Relief of Famines》, cloud：" its leaf taste is micro-
It is salty, cold nature ".According to the Qing Dynasty《A Supplement to the Compendium of Materia Medica》Record：Alkali is fluffy " taste saltiness is cool, heat-clearing disperse accumulations ", and modern medicine study finds,
Alkali is fluffy pharmacological activity and to the elderly, hypertensive patient to have certain guarantor with anti-inflammatory, liver protection, reducing blood lipid, anti-ageing waiting for a long time
Strong effect, separately has document report coumaronochromone flavone compounds to have preferable immunosuppressive activity.
The content of the invention
The present invention provides a kind of with the noval chemical compound for significantly increasing body's immunity --- the preparation side of the fluffy flavone A of alkali
Method and the purposes in terms for the treatment of immunity disease in field of medicaments.
The invention discloses the structural formula of the compound（See Figure of abstract）
Molecular formula is：C18H14O7, degree of unsaturation is 12.Molecular weight：342.
It is named as：The fluffy flavone A of alkali, chemical name：5,6,8- trimethoxy -7- hydroxyls coumaronochromone（5,6,8-
trimethoxy-7-hydroxycoumaronochromone）.
The preparation method of above-claimed cpd is as follows in the present invention：
It is characterized in that with August part originate from Shouguang City of Shandong Province alkali it is fluffy as raw material, through iterating through silica gel or spherical silicon
The hands such as one or more column chromatographies and recrystallization in glue, Sephadex LH-20 (Sep.) gel filtration chromatography, reversed material ODS
Section is isolated and purified and obtains the compound.
Novel compound of present invention and its derivative are used to exempt from medically acceptable pharmaceutic adjuvant composition pharmaceutical preparation
The low relevant disease of epidemic disease power.The formulation that can be prepared has：Tablet, capsule, granule and injection.
4th, illustrate：
Can be reported as APPENDIX MATERIALSThe using figure below.
Fig. 1, compound1H-NMR spectrum 2, compound13C-NMR is composed
Fig. 3, the DEPT spectrograms 4, compound of compound1H-1The spectrum of H COSY
Fig. 5, hsqc spectrum Fig. 6 of compound, the HMBC spectrums of compound
The ESI-MS spectrums of Fig. 7, the ROESY spectrograms 8, compound of compound
5th, specific embodiment：
With reference to specific embodiment, the invention will be further described, but present disclosure be not restricted to it is cited
Implementation method.
Embodiment 1. separates and identifies the noval chemical compound from the fluffy herb of alkali
Alkali is fluffy to dry the Kg of herb about 10, crushes, and through 80% ethanol heating and refluxing extraction 3 times, concentration obtains total medicinal extract, according to
It is secondary to obtain the g of ethyl acetate extract medicinal extract 180 through petroleum ether, ethyl acetate, n-butanol equal-volume extraction 3 times, through silica gel column chromatography,
Petroleum ether-ethyl acetate-methanol elution gradient, collects 11 stream parts altogether, and stream part 6 is repeatedly through silicagel column, Sephadex LH-20
Post, reversed phase column chromatography from alkali is fluffy dry herb ethanol extract in obtain the monomeric compound, by physicochemical property, spectral method
The fluffy flavone A of alkali is accredited as, the compound is noval chemical compound by literature search.
The compound structure identifies as follows through nuclear magnetic resoance spectrum：
Colorless needle crystals, are soluble in the organic solvents such as chloroform, methyl alcohol.Nothing is substantially glimmering under showing ultraviolet 365nm with TLC methods
Light, there is blackening under the ultraviolet light of 254nm, sprays the concentrated sulfuric acid-vanillic aldehyde developer and shows glassy yellow after heating, and sprays FeCl3Aobvious dirt
Green, Molish and Liebermann-Burchard reactions are all negative.ESI-MS（m/z）：341（[M+H]-）Draw its point
Son amount is 342.With reference to1H-NMR and13C-NMR spectrum datas infer that the molecular formula of SG-11 is C18H14O7, degree of unsaturation is 12, is pushed away
Seco compound is a typical coumaronochromone framework types flavones.
1H-NMR（500MHz, DMSO-d 6 ）δ H：10.54（1H, brs）The signal peak of phenolic hydroxyl group,δ HOccur compared with low field, cherish
It is probably to form intramolecular hydrogen bond to doubt, and it is moved to low field direction, thus it is speculated that for 7-OH replaces flavones structure fragment；δ H：
8.02（1H,J=7.9,1.9Hz）, 7.74（1H,J=7.9,1.9 Hz）, 7.45（1H,J=7.9,1.9 Hz）, 7.44（1H,J=
7.9,1.9Hz）Speculate that the compound has 4 fragrant hydrogen signals of AA ' BB ' systems；δ H：3.90（3H, s）, 3.84（3H, s）,
3.83（3H, s）It is 3 signal peaks of-OMe.With reference to1H-1During H COSY are composed and ROESY is composedδ H：7.74（1H,J=7.9,1.9
Hz）With 7.45（1H,J=7.9,1.9 Hz）, 8.02（1H,J=7.9,1.9 Hz）Have relevant peaks andδ H：7.45（1H,J=7.9,
1.9 Hz）With 8.02（1H,J=7.9,1.9 Hz）There are relevant peaks, can be inferred that in the presence of 1 ', 2 '-di-substituted aryl perfume B rings.
13C-NMR（135MHz, DMSO-d 6 ）Combined with DEPT spectrums and understand there are 4-CH i.e.δ C：125.1,125.0,120.6,
111.4；3-OMe areδ C：61.9,61.2,61.1；11 quaternary carbons areδ C：172.2,163.5,149.0,148.6,148.5,
144.9,140.2,132.8,122.9,110.3,97.9；- CH is not contained2, whereinδ C：172.2,163.5,97.9 is typicalα,β- unsaturated carbonyl carbon signal.
Hsqc spectrum understandsδ H：8.02（1H,J=7.9,1.9 Hz）Withδ C：120.6 have relevant peaks；δ H：7.44（1H,J=7.9,
1.9 Hz）Withδ C：125.0 have relevant peaks；δ H：7.45（1H,J=7.9,1.9 Hz）, 7.74（1H,J=7.9,1.9 Hz）Respectively withδ C：125.1,111.4 have relevant peaks, it was confirmed that 4 fragrant Hydrogen Protons connect with 4 carbon phases of B rings；δ H：3.83（3H, s）, 3.90
（3H, s）, 3.84（3H, s）Respectively withδ C：61.1,61.2,61.9 have relevant peaks 3 presence of-OMe of proof.
From HMBC spectrumsδ H：3.83（3H, s）Withδ C：140.2 have relevant peaks,δ H：3.84（3H, s）, 3.90（3H, s）Withδ C：148.6,132.8 have relevant peaks, it is known that C-5, C-6, C-8 connection are all-OMe；δ H：8.02（1H,J=7.9,1.9 Hz）
Withδ C：125.1,120.6,111.4,97.9 have relevant peaks andδ H：7.74（1H,J=7.9,1.9 Hz）Withδ C：148.5,
125.1,122.9 have relevant peaks,δ H：7.45（1H,J=7.9,1.9 Hz）Withδ C：125.0,120.6,111.4 have relevant peaks andδ H：7.44（1H,J=7.9,1.9 Hz）Withδ C：148.5., 125.1,122.9,120.6,111.4 have relevant peaks, it is known that C-3 ',
C-4 ', C-5 ', C-6 ' connection are H.
In summary information, infers the structure of compound（See Figure of abstract）.Compound structure is input into
ScienceFinder is retrieved, it is found that this is a noval chemical compound.Chemical name：5,6,8- trimethoxy -7- hydroxyls
coumaronochromone (5,6,8-trimethoxy-7-hydroxycoumaronochromone).By its Chinese name life
It is entitled：The fluffy flavone A of alkali（suaeglaucin A）.
Table 1.1 compounds1H-NMR (500MHz),13The signal full ownership of C-NMR (135MHz) and each other
Dependency relation
Embodiment 2.
Immunosuppressive activity is tested
1st, test method：
（1）Experimental animal
BALB/c mouse inbred lines, female, 18-20 grams, purchased from Chinese Academy of Sciences's Shanghai animal experimental center（IACUC ratifies
Number 2012-02-zjp-13）.
（2）The preparation of mouse spleen lymphocyte：
The de- cervical vertebra of mouse is put to death, aseptic to take its spleen, routinely prepares single lymphocyte suspension, erythrocyte cracked liquid removal
Red blood cell, after washing 3 times containing 2% FBS, after washing 1 time with the RPMI-1640 nutrient solutions containing 10%FBS, is adjusted to cell concentration 4 and multiplies
106/ mL 。
（3）Influence of the mtt assay detection compound to mouse spleen lymphocyte activity：
The μ L of mouse spleen lymphocyte suspension 100（4 multiply 105/ hole）96 orifice plates are inoculated in, while adding various concentrations
Compound, separately sets corresponding Vehicle controls and nutrient solution Background control, and cumulative volume is 200 μ L.37 DEG C, 5% CO2In incubator
Culture supernatant, adds 150 μ L DMSO dissolving cells, and OD values are determined at 570 nm with ELIASA.
（4）3Influence of the H-TdR incorporation methods detection compound to mouse spleen lymphocyte expanding capacity：
The μ L of mouse spleen lymphocyte suspension 100（4 multiply 105/ hole）96 orifice plates are inoculated in, 50 μ L ConA are added（It is dense eventually
Spend 5 μ g/mL）, or the LPS for adding 50 μ L（The μ g/mL of final concentration 10）, the μ L of various concentrations compound 50, cumulative volume is 200 μ
L, each multiple holes of concentration 3, and set corresponding without ConA or without LPS control wells and without drug control hole.7 DEG C, 5% CO2Culture
48 h are cultivated in case, culture terminates preceding 8 h, and 25 μ L are added per hole3H- thymidylic acids（10 μCi/mL）, continue to train
Support to experiment and terminate.Cell cell collector is collected to glass fibre membrane, scintillation solution is added after Beta calculating instruments
（MicroBeta Trilux, PerkinElmer）Read and mix cell DNA3H-TdR is measured, and representing cell with cpm values breeds
Situation.
, experiment sample
Noval chemical compound：The fluffy flavone A of alkali（5,6,8- trimethoxy -7- hydroxyls coumaronochromone）
3rd, experimental result
Influence of the compounds of Table 2.1 to mouse spleen lymphocyte activity
The influence of the B lymphocyte proliferation function that the compounds of Table 2.2 are induced LPS
The influence of the T the proliferative function of lymphocyte that the compounds of Table 2.3 are induced ConA
4th, conclusion
Result of the test shows that the fluffy flavone A of alkali can significantly inhibit the propagation of lymphocytic B cells and T cell, shows that the compound can
For preparing immunodepressant, and to autoimmune disease, there is such as rheumatoid arthritis, lupus erythematosus treatment to make
With while finding the IC of the compound50Value is smaller, and SI values are larger, therefore, its toxic and side effect is smaller, with treatment region wider
Between.
Claims (5)
1. a kind of flavone compound, it is characterised in that the compound --- the fluffy flavone A of alkali, chemical name：5,6,8- trimethoxies-
7- hydroxyls coumaronochromone (5,6,8-trimethoxy-7-hydroxycoumaronochromone), chemistry knot
Structure formula is：
2. the preparation method of compound described in claim 1, it is characterised in that take that alkali is fluffy to dry the Kg of herb 10, crushes, through 80%
Ethanol heating and refluxing extraction 3 times, concentration, obtains total medicinal extract, successively through petroleum ether, ethyl acetate, n-butanol equal-volume extraction 3
It is secondary, the g of ethyl acetate extract medicinal extract 180 is obtained, through silica gel column chromatography, petroleum ether-ethyl acetate-methanol elution gradient collects 11 altogether
Individual stream part, stream part 6 obtains the monomeric compound through silicagel column, Sephadex LH-20 posts, reversed phase column chromatography repeatedly.
3. the pharmaceutical preparation that the compound described in claim 1 is constituted with medically acceptable pharmaceutic adjuvant.
4. the pharmaceutical preparation described in claim 3, it is characterised in that preparation formulation is tablet, capsule, granule or injection.
5. purposes of the compound described in claim 1 in terms of immunosuppressive drug is prepared.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103027962A (en) * | 2011-10-08 | 2013-04-10 | 盐城纺织职业技术学院 | Method for extracting suaeda salsa flavone and measuring content of flavones in suaeda salsa |
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| JP2011519947A (en) * | 2008-05-06 | 2011-07-14 | バイオノボ・インコーポレーテッド | Estrogen-like extract used to treat vaginal and vulvar atrophy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103027962A (en) * | 2011-10-08 | 2013-04-10 | 盐城纺织职业技术学院 | Method for extracting suaeda salsa flavone and measuring content of flavones in suaeda salsa |
Non-Patent Citations (3)
| Title |
|---|
| "A new Coumaronochromone from Sophora japonica";Yu-Ping Tang et al.;《Journal of Asian Natural Products Research》;20100909;第4卷(第1期);第1-5页 * |
| "Structure determination of Aervins A-D, new coumaronochromone analogues from Aerva persica, by 1D and 2D NMR spectroscopy";Muhammad Imran et al.;《Magnetic Resonance in Chemistry》;20090305;第47卷;第532-536页 * |
| "南方碱蓬叶总黄酮提取工艺研究";黄晓冬 等;《海峡药学》;20071231;第19卷(第3期);第30-33页 * |
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