CN106349032B - Bibenzyl compound and preparation method thereof and purposes in the preparation of antitumor drugs - Google Patents
Bibenzyl compound and preparation method thereof and purposes in the preparation of antitumor drugs Download PDFInfo
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- CN106349032B CN106349032B CN201610722938.3A CN201610722938A CN106349032B CN 106349032 B CN106349032 B CN 106349032B CN 201610722938 A CN201610722938 A CN 201610722938A CN 106349032 B CN106349032 B CN 106349032B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/34—Separation; Purification; Stabilisation; Use of additives
- C07C41/36—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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Abstract
The invention discloses II compound represented of formula or its pharmaceutically acceptable salt, crystal form, solvates: where R1、R2Separately it is selected from hydroxyl or sulfydryl；R3、R4Separately it is selected from C1~C4The C that alkyl or halogen replace1~C4Alkyl.
Description
Technical field
Purposes the present invention relates to Bibenzyl compound and preparation method thereof and in the preparation of antitumor drugs.
Background technique
Existing literature reports Bibenzyl compound as follows, has and inhibits passive cutaneous anaphylaxis (passive
Cutaneous anaphylaxis) and RBL-2H3 cell (basophilic leukemia cell) is inhibited to discharge β-hexosaminidase
Drug effect and purposes (see Matsuda H et al.Antiallergic Phenanthrenes and ... Planta Med
2004；70:847-855):
Currently, there are no the research report of compound shown in formula II, chemical combination shown in formula II more there are no
Object is used to prepare the research report of anti-tumor drug.
Summary of the invention
The purpose of the present invention is to provide all different new Bibenzyl compounds of a kind of structure and medical value: II institute of formula
The compound shown.
II compound represented of formula provided by the invention or its pharmaceutically acceptable salt, crystal form, solvate:
Wherein,
R1、R2Separately it is selected from hydroxyl or sulfydryl；
R3、R4Separately it is selected from C1~C4The C that alkyl or halogen replace1~C4Alkyl.
Further, R1、R2It is simultaneously selected from hydroxyl.
Further, R3、R4Separately it is selected from methyl, ethyl, propyl or isopropyl.
Further, the compound is
The present invention also provides the method for prepare compound C a kind of, it the following steps are included:
I, bletilla is taken, is extracted with ethyl alcohol, ethanol extract is obtained；
Ii, ethanol extract is taken, is concentrated, obtains liquid extract；
It is iii, liquid extract is water-dispersible, successively use ethyl acetate, extracting n-butyl alcohol, combined ethyl acetate part, recycling
Solvent obtains ethyl acetate extract；
Iv, ethyl acetate extract is taken, using silica gel column chromatography, is successively with petroleum ether-acetone=100:1,50:1,30:1
Eluant, eluent carries out gradient elution, obtains eluent Fr.16 when petroleum ether-acetone=30:1；
V, reverse phase polystyrene type resin column on Fr.16, successively with alcohol-water=10:90,30:70,50:50,70:30,
90:10,100:0 are that eluant, eluent carries out gradient elution, obtain Fr.16-j when alcohol-water=100:0；
The upper sephadex chromatography column of vi, Fr.16-j successively elutes 0.8 using methylene chloride-methanol=1:1 as eluant, eluent
Times column volume, 2.2 times of column volumes, respectively obtain Fr.16-j-1, Fr.16-j-2；
Vii, Fr.16-j-2 elute 3 cylinders using methylene chloride-methanol=1:0 as eluant, eluent by silica gel column chromatography
Product, recycling design obtain Fr.16-j-2a；Fr.16-j-2a, which passes through, prepares thin-layer chromatography, is with dichloromethane-acetone=20:1
Solvent, Rf=0.65, separation obtains compound C.
Further,
In step iv, the amount of the ethyl acetate extract is 155~165g, and the condition of gradient elution is as follows:
In step v, the amount of the Fr.16 is 15~20g, and the condition of gradient elution is as follows:
The present invention also provides above-mentioned compounds or its pharmaceutically acceptable salt, crystal form, solvate to control in preparation
Purposes in the drug for the treatment of and/or pre- preventing tumor.
Further, the tumour is cancer.
Further, the cancer is lung cancer.
The present invention also provides it is a kind for the treatment of and/or pre- preventing tumor pharmaceutical composition, it be with above compound or its
Pharmaceutically acceptable salt, crystal form, solvate are active constituent, in addition the preparation that pharmaceutically common auxiliary material is prepared.
Noval chemical compound shown in formula II provided by the invention has good inhibiting effect to tumour cell, in particular, right
Lung carcinoma cell has good inhibiting effect, IC50Reach 6.37 μ g/mL；Meanwhile the preparation method letter of the compounds of this invention
Just, reaction condition is mild, and convenient for operation and control, energy consumption is small, and yield is high, at low cost, is very suitable to industrialization production.
Compound and derivative provided in the present invention can according to IUPAC (International Union of Pure and Applied Chemistry) or
The name of CAS (chemical abstracts service, Columbus, OH) naming system.
About the definition of the invention using term: unless otherwise indicated, group or term herein provide initial
Definition is suitable for group or term of entire description；For the term being not specifically defined herein, it should according to open
Content and context, their meaning can be given by providing those skilled in the art.
" substitution " refers to that the hydrogen atom in molecule is replaced by other different atoms or molecule.
The minimum value and maximum value of carbon content are indicated by prefix in hydrocarbon group, for example, prefix Ca~CbAlkyl table
Bright any alkyl comprising " a " to " b " a carbon atom.Thus, for example, C1~C4Alkyl refers to the alkane comprising 1~4 carbon atom
Base, in other words, C1~C4Alkyl includes methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or to be formed by salt usual
In chemistry or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and physiologically mutually compatible with receptor.
Term " salt " and " pharmaceutical salt " refer to above compound or its stereoisomer, with inorganic and/or organic acid
The acid and/or basic salt formed with alkali also includes amphoteric ion salt (inner salt), further includes quaternary ammonium salt, such as alkylammonium salt.This
A little salt can be to be directly obtained in being finally separating and purify of compound.It is also possible to by by above compound or it is vertical
Body isomers is obtained by mixing with a certain number of acid or alkali appropriate (such as equivalent).These salt may be in the solution
It forms precipitating and is collected with filter method, or recycle obtain after the solvent evaporates, or be freeze-dried after reacting in an aqueous medium
It is made.Heretofore described salt can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, the hydrogen of compound
Fluorate, phosphate, acetate, propionate, succinate, oxalates, malate, succinate, fumarate, maleic acid
Salt, tartrate or trifluoroacetate.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes
(but being not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions mixing: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example
Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin
Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include
Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and
Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition
Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material
And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant.
Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need
Propellant be mixed together.
Pharmaceutically acceptable auxiliary material of the present invention refers in addition to the active ingredient (s include substance in dosage form.
Pharmaceutically acceptable complementary ingredient of the present invention, it has certain physiological activity, but the addition of the ingredient
The leading position of aforementioned pharmaceutical compositions in the course of disease treatment will not be changed, and only play auxiliary effect, these auxiliary
Effect is only the utilization to the ingredient known activity, is the usual adjuvant treatment modality of field of medicaments.If by above-mentioned complementary
Ingredient is used cooperatively with pharmaceutical composition of the present invention, still falls within the scope of protection of the invention.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Detailed description of the invention
The HR-ESI-MS that Fig. 1 is the compounds of this invention C is composed.
Fig. 2 is the compounds of this invention C's1H H NMR spectroscopy.
Fig. 3 is the compounds of this invention C's13C H NMR spectroscopy.
Specific embodiment
Raw material, equipment used in the specific embodiment of the invention are known product, are obtained by purchase commercial product.
1. medicinal material
Bletilla striata medicinal materials are purchased from Neijiang City in Sichuan Province in August, 2012, are accredited as through Chengdu University of Traditional Chinese Medicine professor Li Min white
And the dry tuber of Bletilla striata (Thunb.) Rchb.f..
2. reagent and filler
Column chromatography silica gel, 200~300 mesh (SILVER REAGENT) are purchased from Qingdao Haiyang silica-gel desiccant factory；
Tlc silica gel G, GF254 and H (chemistry is pure), are purchased from Qingdao Haiyang silica-gel desiccant factory；
MCI gel CHP 20P, is reverse phase polystyrene type resin, is purchased from Mitsubishi chemical company by 75~150 μm；
Sephadex LH-20 sephadex is purchased from Amersham company, Sweden；
GF254 silica gel prepares thin layer, is purchased from Yantai Jiang You silica gel development corporation, Ltd.；
Chromatography methanol, is purchased from Fisher company, the U.S. by 4L/ bottles；
The analytical reagents such as petroleum ether, ethyl acetate, n-butanol, acetone, methanol are purchased from Chengdu Ke Long chemical reagent factory.
3. laboratory apparatus
6000 high performance liquid chromatograph (U.S. Cometro) of Cometro；
Waters Synapt G2HDMS high-resolution flight time mass spectrum (U.S. Waters)；
Nuclear Magnetic Resonance: Bruker-600 Nuclear Magnetic Resonance；Measuring temperature: 297K；Using solvent peak-to-peak signal as reference；
Vector 22FT-IR infrared spectrometer (Switzerland Bruker)；
Shimadzu UV-260 spectrophotometry instrument (Japanese Shimadzu)；
Ten a ten thousandth electronic balance (Switzerland Sartorius) of BP211D；
R-210 rotary evaporator (Switzerland BUCHI)；
DZG-6050 type vacuum oven (the gloomy letter in Shanghai).
Embodiment 1, the extraction of compound C and Structural Identification
(1) extraction of medicinal material:
Dry Bletilla striata medicinal materials coarse powder (3kg) extracts 3 times (30L × 3), each 2h with 95% alcohol reflux；
(2) ingredient isolates and purifies:
1., ethanol extract (90L) is through being concentrated under reduced pressure dry semisolid flow medicinal extract 510g；
2., by semisolid flow medicinal extract (500g) with water (5L) disperse, successively with ethyl acetate (20L), n-butanol (20L) extract
It takes, solvent is recovered under reduced pressure in combined ethyl acetate part, obtains ethyl acetate extract 160g；
3., using silica gel column chromatography ethyl acetate extract (160g) is separated, petroleum ether: acetone carries out gradient and washes
De-, eluent is detected through thin-layered chromatography, obtains petroleum ether: eluent Fr.16 when acetone=30:1；
The condition of gradient elution is as follows:
4., Fr.16 component (18g) handles by MCI and carries out gradient elution with the ethanol water of 10%-100%v/v, and tie
It closes thin-layer chromatography to be detected, respectively obtains 10 component Fr.16-a~Fr.16-j；
The condition of gradient elution is as follows:
5., Fr.16-j component (3.0g) pass through gel LH-20 chromatographic column, using methylene chloride-methanol=1:1 as eluant, eluent,
It is eluted, Fr.16-j-1, Fr.16-j-2, Fr.16-j-3 are respectively to elute 0.8 times of column volume, 2.2 times of column volumes, 3 times of columns
The component successively collected when volume, wherein Fr.16-j-2 group is divided into the concentration position of bibenzyl derivative；
6., Fr.16-j-2 component (1.8g) pass through silica gel column chromatography, respectively with methylene chloride-methanol 1:0,200:1,
100:1,50:1 are eluted, 3 column volumes of each ratio eluent, and solvent is recovered under reduced pressure, and are collected 1:0 and are eluted position
Fr.16-j-2a, to prepare thin-layer chromatography, (solvent is dichloromethane-acetone=20:1, Rf=0.65) isolated compound
C；
When Bibenzyl compound thin-layer chromatography develops the color in bletilla, sprays with 10% sulfuric acid ethyl alcohol test solution, develop the color at 105 DEG C
The more displaing yellows of 3min, Chinese red to blush spot, can be used for the trace detection of bibenzyl；
Compound C molecular formula C23H24O4, high resolution mass spectrum data: HR-ESI-MS m/z 363.1605 [M-H]-
(C23H23O4Calculated value be 363.1596), degree of unsaturation 12；
Compound C nuclear magnetic resonance spectroscopy (1H-NMR) and carbon-13 nmr spectra (13C-NMR) by Bruker-AV-600 core
Magnetic resonance device measurement, specific data are shown in Table 1；
Table 1, compound C1H NMR (600MHz) and13C NMR(150MHz)in CD3COCD3Data
It is determined by above-mentioned data, compound C is 3 '-hydroxyl -4- to hydroxyl benzyl -3,5- dimethoxy bibenzyl, and structure is such as
Under:
Below by way of test example, beneficial effects of the present invention are illustrated.
The antitumor test of test example 1
(1) experimental material:
1. cell
Lung cell A549 derives from U.S. ATCC company.
2. laboratory apparatus
HWCL-1 temperature constant magnetic stirring bathes (Zhengzhou Greatwall Scientific Industrial & Trading Co., Ltd.)；
Ten a ten thousandth electronic balance (Switzerland Sartorius) of BP211D；
DZG-6050 type vacuum oven (the gloomy letter in Shanghai)；
Microplate reader (Thermo 3001, Thermo Fisher Scientific company)；
Electronic balance (ESJ120-4 type, Longteng Electronic Weighing Instrument Co., Ltd., Shenyang)；
Super-clean bench (MCV-B161F (T), Japanese SANYO company)；
Microscope (Primo Vert, AxioCam ERc 5s, ZEISS company)；
CO2Incubator (HH.CP-T, Shanghai Qi Xin scientific instrument Co., Ltd).
(2) experimental method:
1. cell inoculation
With the cell of 0.25% pancreatin digestion logarithmic growth phase.It is made into the cell culture medium culture containing 10%FBS slender
Born of the same parents' suspension.It is counted using cell counting board, by A549 tumor cell inoculation in good condition in 96 orifice plates, makes cell density 4
×103A/mL, every hole are added 100 μ L of cell suspension, are placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator.
2. drug-treated
Each sample is since 20 μ g/mL, and with culture medium gradient dilution sample, 5 drug concentrations are arranged, often in 2 times of dilutions
A concentration does multiple holes test.With concentration for the every 100 μ L of hole dosing of 20,10,5,2.5,1.25 μ g/mL, each concentration sets 3 again
Hole is repeated 3 times.Negative control group is the culture medium solution containing appropriate DMSO, and blank control group is not celliferous culture medium
And solvent.96 orifice plates are put back into incubator, 37 DEG C of effect 72h.
3. colour developing and IC50Calculating
After 72h is acted on, MTT solution (5g/L) 20 μ L is added in every hole under the conditions of being protected from light, and is continued after incubating culture 4h, is abandoned
Fall supernatant, every hole is added 150 μ L DMSO, is placed on shaking table and shakes 10min at a slow speed, make first a ceremonial jade-ladle, used in libation after completely dissolution, use microplate reader
Measure the OD value at 570nm wavelength.
Using improvement karber's method IC50=log-1[Xm-i (∑ P-0.5)] is calculated, wherein Xm: the maximum concentration of design
Logarithm；I: the logarithm of each concentration multiple proportions concentration；Σ P: the sum of each group growth inhibition ratio；0.5: empirical.Pass through weight
It is multiple to test three times, 3 IC are calculated50Value (retains two-decimal), averages；Test result is shown in Table 2.
Table 2, Bibenzyl compound C of the present invention are to the cytotoxic activity IC of A549 tumour cell50
| NO. | IC50(μg/mL) |
| Compound C | 6.37 |
The above results show that Bibenzyl compound of the present invention has good inhibiting effect to tumour cell, can be used in
Prepare anti-tumor drug.
In conclusion noval chemical compound shown in formula II provided by the invention, has good inhibiting effect to tumour cell,
In particular, there is good inhibiting effect, IC to lung carcinoma cell50Reach 6.37 μ g/mL；Meanwhile the system of the compounds of this invention
Preparation Method is easy, and reaction condition is mild, and convenient for operation and control, energy consumption is small, and yield is high, at low cost, is very suitable to industry metaplasia
It produces.
Claims (7)
1. compound C or its pharmaceutically acceptable salt:
2. a kind of method of prepare compound C, it is characterised in that: it the following steps are included:
I, bletilla is taken, is extracted with ethyl alcohol, ethanol extract is obtained；
Ii, ethanol extract is taken, is concentrated, obtains liquid extract；
It is iii, liquid extract is water-dispersible, successively use ethyl acetate, extracting n-butyl alcohol, combined ethyl acetate part, recycling design,
Obtain ethyl acetate extract；
Iv, ethyl acetate extract is taken, is successively elution with petroleum ether-acetone=100:1,50:1,30:1 using silica gel column chromatography
Agent carries out gradient elution, obtains eluent Fr.16 when petroleum ether-acetone=30:1；
V, reverse phase polystyrene type resin column on Fr.16, successively with alcohol-water=10:90,30:70,50:50,70:30,90:
10,100:0 is that eluant, eluent carries out gradient elution, obtains Fr.16-j when alcohol-water=100:0；
The upper sephadex chromatography column of vi, Fr.16-j successively elutes 0.8 times of column using methylene chloride-methanol=1:1 as eluant, eluent
Volume, 2.2 times of column volumes, respectively obtain Fr.16-j-1, Fr.16-j-2；
Vii, Fr.16-j-2 elute 3 column volumes using methylene chloride-methanol=1:0 as eluant, eluent by silica gel column chromatography, return
Solvent is received, Fr.16-j-2a is obtained；Fr.16-j-2a is expansion with dichloromethane-acetone=20:1 by preparing thin-layer chromatography
Agent, Rf=0.65, separation obtains compound C
3. the method for prepare compound C according to claim 2, it is characterised in that:
In step iv, the amount of the ethyl acetate extract is 155~165g, and the condition of gradient elution is as follows:
In step v, the amount of the Fr.16 is 15~20g, and the condition of gradient elution is as follows:
4. compound described in claim 1 or its pharmaceutically acceptable salt are in preparation treatment and/or the drug of pre- preventing tumor
In purposes.
5. purposes according to claim 4, it is characterised in that: the tumour is cancer.
6. purposes according to claim 5, it is characterised in that: the cancer is lung cancer.
7. the pharmaceutical composition of a kind for the treatment of and/or pre- preventing tumor, it is characterised in that: it is with compound described in claim 1
Or its pharmaceutically acceptable salt is active constituent, in addition the preparation that pharmaceutically common auxiliary material is prepared.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001064A (en) * | 2015-07-10 | 2015-10-28 | 浙江中医药大学 | Bletilla striata fibrous root blestriarene A and preparation method and application thereof |
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2016
- 2016-08-24 CN CN201610722938.3A patent/CN106349032B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001064A (en) * | 2015-07-10 | 2015-10-28 | 浙江中医药大学 | Bletilla striata fibrous root blestriarene A and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 中药白及中一新的联苄化合物;韩广轩 等;《药学学报》;20021231;第37卷(第3期);第194-195页 |
| 白及的化学成分及生物活性研究进展;仰莲 等;《中药与临床》;20141231;第5卷(第6期);第59-64页 |
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