CN1165509C - Gronwell naphthaquinone derivative and its application in preparing anticancer medicine - Google Patents

Gronwell naphthaquinone derivative and its application in preparing anticancer medicine Download PDF

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CN1165509C
CN1165509C CNB021149739A CN02114973A CN1165509C CN 1165509 C CN1165509 C CN 1165509C CN B021149739 A CNB021149739 A CN B021149739A CN 02114973 A CN02114973 A CN 02114973A CN 1165509 C CN1165509 C CN 1165509C
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cophnh
phnh
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CN1374288A (en
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古练权
刘宗潮
黄志纾
段志芳
马林
谢冰芬
朱孝峰
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Sun Yat Sen University
National Sun Yat Sen University
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Abstract

The present invention relates to a derivative in the alkanna tinctoria and naphthaquinone class and an application for preparing a medicine for treating cancers. An experiment proves that the derivative in the alkanna tinctoria naphthaquinone class has an obvious inhibiting function for the tumor cell strains of CNE2, Glc-82, S180A, EAC, HepA, etc. A research of a transplantation tumor model of cancer cells of people to a naked mouse also proves the anti-cancer function of the derivative in the alkanna tinctoria and naphthaquinone class. A chemical structural formula of the derivative in the alkanna tinctoria and naphthaquinone class is shown as a formula I, and R1, R2, R2 in the formula I are defined as a specification.

Description

Gronwell naphthaquinone derivative and the application in the preparation cancer therapy drug thereof
Technical field
The present invention relates to a class Gronwell naphthaquinone derivative and be used for the treatment of purposes in the medicine of cancer in preparation.
Technical background
Cancer is current to one of maximum disease of human health and quality of life harm.The exploitation of cancer therapy drug is the hot subject of scientists study always.Because the complicacy and the singularity of cancer mechanism are sought highly selective, are efficiently reached low toxicity, the little cancer therapy drug of side effect, do not obtain ideal results.
The contained naphthoquinone compound of plurality of Chinese has been found has certain anti-tumor activity, but as from the isolating beta-hydroxyisovalerylshiderivative inducing leukemia of gromwell root root HL-60 apoptosis; β, beta-dimethyl-acry-lalkannin to Human Prostate Cancer Cells (DU145, LNCaD, PC-3) inhibited; The lithospermum euchromum Royle element has restraining effect to colorectal cancer cells, and makes apoptosis etc.Just, still fail at present in clinical use [institute of Materia Medica,Chinese Academy of Medical Sciences, herbal medicine modern study (second volume), p274,, Beijing Medical University-combined publication society of China Concord Medical Science University in 1996] because their anti-tumor activity is not high enough.
Summary of the invention
The purpose of this invention is to provide the Gronwell naphthaquinone derivative shown in the formula I and be used for the treatment of application in the medicine of cancer in preparation.The present invention experiment showed, that Gronwell naphthaquinone derivative has significant inhibitory effect for various tumor cell strains, and the model research of human cancer cell transplanted tumor in nude mice has also proved the antitumous effect of Gronwell naphthaquinone derivative.
We find that they can react with different nucleophilic reagents, generate the derivative of different replacement degree, different the position of substitution when research Gronwell naphthaquinone compound chemistry reaction property.These derivatives are carried out the cancer cell in vitro inhibition test show, they to the cytotoxicity of multiple cancer cells than natural Gronwell naphthaquinone compound much better than (50～250 times).Carrying out in vivo test with human cancer cell transplanted tumor in nude mice model has proved the derivative of natural Gronwell naphthaquinone compound through obtaining after the chemically modified, has good antitumour activity.
Gronwell naphthaquinone derivative of the present invention is as with shown in the following formula I:
Figure C0211497300031
Formula I
R among the formula I 1, R 2, R 3The group of representative can be one of and the following:
(1), R 1Be OH, (CH 3) 2C=CHCOO, CH 2COO or CH 3COOC (CH 3) 2CH 2COO; R 2Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S; R 3Be H;
(2), R 1Be OH, (CH 3) 2C=CHCOO, CH 3COO or CH 3COOC (CH 3) 2CH 2COO; R 2Be H; R 3Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S;
(3), R 1Be OH, (CH 3) 2C=CHCOO, CH 3COO or CH 3COOC (CH 3) 2CH 2COO; R 2Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S; R 3Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S, HOC 2H 4S or C 2H 5S;
(4), R 1Be PhNH, p-CH 3COPhNH, PhS, HOC 2H 4S or C 2H 5S; R 2Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S; R 3Be H;
(5), R 1Be PhNH, p-CH 3COPhNH, PhS, HOC 2H 4S or C 2H 5S; R 2Be H; R 3Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S;
(6), R 1Be PhNH, p-CH 3COPhNH, PhS, HOC 2H 4S or C 2H 5S; R 2Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S; R 3Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S;
(7), R 1Be OH, CH 3) 2C=CHCOO, CH 3COO or CH 3COOC (CH 3) 2CH 2COO; R 2=R 3=H.
Gronwell naphthaquinone derivative shown in the formula I of the present invention can generate the Gronwell naphthaquinone derivative of different replacement degree, different the position of substitution by natural Gronwell naphthaquinone compound and different nucleophilic reagent reactions.
The said natural Gronwell naphthaquinone compound of the present invention, for example Shikonin (shikonin), acetylshikonin (acetyshikonin), β, (β, β-dimethyacrylalkannin) wait and can extract from Asian puccoon makes through separation and purifying beta-dimethyl-acry-lalkannin.
The present invention shows that by the cancer cell in vitro inhibition test Gronwell naphthaquinone derivative has very strong cytotoxicity to multiple cancer cells.
The present invention has proved that by the in vivo test of human cancer cell transplanted tumor in nude mice model Gronwell naphthaquinone derivative has good antitumour activity.
The present invention tests by animal pharmacology, determines that the using dosage scope of Gronwell naphthaquinone derivative or its pharmacy combination is 10～100mg/kg/day.
The present invention tests by animal toxicology, determines that Gronwell naphthaquinone derivative is the medicine that class toxic side effect in the dose therapeutically effective scope is little, can take for a long time.
According to the present invention, compound shown in the above-mentioned formula I or the combination of its pharmacy can be made the form of injection, tablet, pill, capsule, suspension agent, emulsion and be used; That its route of administration can be is oral, through skin, vein or muscle.
Embodiment
The present invention will be further described by the following examples.
Embodiment one: the extraction of Shikonin compounds, separation and purifying
Shikonin compounds [R 1=OH, (CH 3) 2C=CHCOO, CH 3COO or CH 3COOC (CH 3) 2CH 2COO, R 2=R 3=H] be configured as the R-type, content is higher in Yunnan Asian puccoon (Onosma confertum W.W.Smith).
Take by weighing close colored Yunnan, the Sichuan Asian puccoon of 5kg, ground 20 mesh sieves, carry out normal temperature percolation with 95% ethanol and extract, till closely colourless.United extraction liquid, concentrating under reduced pressure adds the 2%NaOH that is equivalent to 1/3～1/2 concentrated solution volume in concentrated solution, and solution becomes blueness by red-purple.Add dense HCl acidifying after removing by filter insolubles, this moment, solution became red-purple by blueness, had a large amount of throw outs to generate standing over night simultaneously.Leach throw out, be washed till nearly neutrality with distilled water.With drying precipitate, get the about 60g of pulverulent solids crude product.Crude product is dissolved with methylene dichloride, add an amount of stirring of silica gel and spare, volatilize the back upper prop naturally.The filler of chromatographic column is 120～160 order silica gel, eluent sherwood oil (60～90 ℃)-acetone and sherwood oil-acetone-trichloromethane, wash-out and collection successively.Concentrate after recrystallization obtains following four Shikonin compounds respectively: Shikonin (Shikonin, 1) 0.60g, acetylshikonin (acetylshikonin, 2) 0.85g, β, beta-dimethyl-acryloyl Shikonin (β, β-dimethylacrylshikonin, 3) 2.30g, β-acetoxyl group isovaleryl Shikonin (β-acetoxyisovalerylshikonin, 4) 0.93g.Product structure MNR, MSUV and ultimate analysis data is determined.
Compound 1 compound 2
Compound 3 compounds 4
Embodiment two: the extraction of acarnine naphthoquinone compound, separation and purifying
Alkannin compound [R 1=OH, (CH 3) 2C=CHCOO, CH 3COO or CH 3COOC (CH 3) 2CH 2COO, R 2=R 3=H] the S-type that is configured as of naphthoquinone derivatives, content is higher in Xinjiang Radix Arnebiae [Arnebia euchroma (Royle) Johust].
After Radix Arnebiae dried root 5kg in Xinjiang pulverizes,, extract twice in soaking at room temperature with sherwood oil (30～60 ℃) 12 liters.After leaching liquid filters,, get the about 80g of dark red paste through normal pressure and decompression desolventizing.Should extract enriched material silica gel column chromatography rough segmentation,, obtain four red component of opposed polarity solvent elution with sherwood oil (69-90 ℃)-ethyl acetate gradient elution.Further carry out separation and purification, use the petroleum ether-ethyl acetate gradient elution with quick silica gel column chromatography.Isolate four redness or red-purple material at last: A Kaning (alkannin, 5) 1.20g, acetyl A Kaning (acetylalkannin, 6) 1.65g, β, beta-dimethyl-acry-lalkannin (β, β-dimethylacrylalkannin, 7) 2.85g, β-acetoxyl group isovaleryl A Kaning (β-acetoxyisovalerylalkannin, 8) 1.42g.Product structure UV, IR, NMR is analyzed definite.
Figure C0211497300061
Compound 5 compounds 6
Figure C0211497300062
Compound 7 compounds 8
Embodiment three: R 2Or R 3Synthetic for the Asian puccoon naphthoquinone derivatives of substituted benzene amino
With 0.2mmol β, the methanol solution (8mL) of beta-dimethyl-acry-lalkannin and 1mmol aniline is stirring reaction 6 days at room temperature, follows the tracks of reaction with TLC.After reaction is finished, the decompression desolventizing, crude product separates (is eluent with the petroleum ether-ethyl acetate solvent) with rapid column chromatography, obtains the product (9,10) that C-7 or C-8 position hydrogen are replaced by aryl amine, overall yield about 80%.
Use identical method, use β, beta-dimethyl-acry-lalkannin is a raw material, can synthetic compound 11 and 12.
Figure C0211497300064
Compound 11 compounds 12
(OR＝(CH 3) 2C＝CHCOO)
Embodiment four: R 1Be substituted benzene amino, R 2Or R 3Synthetic for the Asian puccoon naphthoquinone derivatives of substituted benzene amino
At ice bath with under stirring, once with NaBH 4Solid (0.45mmol) is added to 0.2mmol β, in the methanol solution of beta-dimethyl-acry-lalkannin and 1mmol aniline (8mL), red solution becomes faint yellow immediately, at room temperature continues to stir 12 hours, yellow solution gradually becomes red-purple again, and the TLC detection reaction is complete.The decompression desolventizing, crude product separates (is eluent with the petroleum ether-ethyl acetate solvent) with rapid column chromatography, obtains C-11 position ester group and is replaced by aryl amine, the red-purple product (13,14) that while C-7 or C-8 position hydrogen are replaced by aryl amine, overall yield about 75%.
Figure C0211497300071
Embodiment five: R 1Be thiophenyl, R 2Or R 3Synthetic for the Asian puccoon naphthoquinone derivatives of thiophenyl
With 0.2mmol β, the methanol solution (8mL) of beta-dimethyl-acry-lalkannin and 0.45mmol thiophenol is stirring reaction 8 hours at room temperature, follows the tracks of reaction with TLC.The decompression desolventizing, crude product separates (is eluent with the petroleum ether-ethyl acetate solvent) with rapid column chromatography, obtains C-11 position ester group and is substituted, the red-purple product (15,16) that while C-7 or C-8 position hydrogen are replaced by aromatic thiohydroxy, overall yield about 85%.
Figure C0211497300072
Use identical method, use β, beta-dimethyl-acry-lalkannin is a raw material, can synthetic compound 17 and 18.
Figure C0211497300081
Compound 17 compounds 18
Embodiment six: R 1Be thiophenyl, R 2Or R 3Synthetic for the Asian puccoon naphthoquinone derivatives of anilino
With compound 9 or 10 and the long-time stirring and refluxing of methanol solution of thiophenol, follow the tracks of reaction with TLC.The decompression desolventizing, crude product separates (is eluent with the petroleum ether-ethyl acetate solvent) with rapid column chromatography, obtains C-11 position ester group and is replaced by thiophenyl, the red-purple product (19,20) that while C-7 or C-8 position hydrogen are replaced by aryl amine, overall yield about 75%.
Figure C0211497300082
Embodiment seven: R 1, R 2And R 3Be Asian puccoon naphthoquinone derivatives synthetic of sulfydryl
With 0.2mmol β, the methanol solution of the 2 mercapto ethanol of beta-dimethyl-acry-lalkannin and 1mmol (10mL) is stirring reaction 3d at room temperature, the decompression desolventizing, crude product separates (is eluent with the petroleum ether-ethyl acetate solvent) with rapid column chromatography, can obtain R 1, R 2And R 3Be the red-purple compound (21) of sulfydryl, productive rate about 88%.
Embodiment eight: β, beta-dimethyl-acry-lalkannin (7) * and derivative thereof be to S180, EAC, the cytotoxicity method of HepA: mtt assay.S180, FAC and the HepA cell of taking the logarithm and growing are diluted to 2 * 10 respectively 4Individual/mL, be sub-packed in 96 orifice plates (0.2mL/ hole).If there is not the medicine control group, the tested compounds of DMSO control group and 5 different concns, every hole 10 μ L.Each group is established 4 parallel holes, puts 37 ℃, 5% CO 2Cultivate 72h in the incubator.4h added MTT liquid (5mg/mL) 10 μ L/ holes before experiment stopped, and cultivated 4h again.Discard nutrient solution, add DMSO 100 μ L/ holes, the mixing vibration is dissolved the brilliant first Za of knot fully, under the 570nm wavelength, measures the OD value with BioRad produced in USA 550 type microplate reader, goes out inhibitory rate of cell growth (half-inhibition concentration, IC by following formula 50).
Growth inhibition ratio=(the average OD value of the average OD value/control group of 1-medication group) * 100%
IC 50Be worth more for a short time, the cytotoxicity of this compound is big more.
* in the natural Asian puccoon naphthoquinone compound, β, beta-dimethyl-acry-lalkannin (7) activity is the highest, and we select this compound as standard, the activity of more various synthetic Asian puccoon naphthoquinone derivatives.
Table 1. β, beta-dimethyl-acry-lalkannin (7) and derivative thereof be to S180, EAC, the cytotoxicity (IC of HepA 50)
Cell strain Compound number/IC 50(μg/mL)
7 9 10 13 14 16
S180 300 80 76 50 40 1.92
EAC 250 80 70 30 35 1.17
HepA 280 85 81 50 50 1.54
The result shows that compound 7 (β, beta-dimethyl-acry-lalkannin) is less to the cytotoxicity of S180, EAC and HepA; The cytotoxicity of compound 9,10,13,14 strengthens 3-8 doubly than 7, demonstrates the moderate cytotoxicity; The cytotoxicity of compound 16 is very strong, strengthens 156-213 doubly than the cytotoxicity of compound 7, demonstrates strong cytotoxicity.
Embodiment nine: β, beta-dimethyl-acry-lalkannin (7) and derivative thereof are to the restraining effect of 5 kinds of human cancer cells
Method: mtt assay.Experimental technique is with embodiment eight.
Table 2. β, beta-dimethyl-acryloyl Ah Ka (7) and other 5 derivatives are to the restraining effect of 5 kinds of human cancer cells
Group Drug level Inhibiting rate (%)
(μg/ml) Nasopharyngeal carcinoma CNE2 Mammary cancer MCF-7 Liver cancer Bel-7402 Lung cancer GLC-82 Large bowel cancer HT-29
Compound 7 100 27.8 31.2 29.3 38.5 21.8
200 48.3 41.3 39.8 43.8 39.6
400 755 69.7 70.2 84.5 62.3
Compound 9 40 30.4 41.1 38.5 30.3 29.4
70 57.3 61.8 47.6 50.8 48.5
100 93.1 84.3 89.8 87.5 79.8
Compound 10 50 40.3 41.5 32.2 28.7 39.6
80 57.6 63.3 56.4 64.3 60.4
110 88.3 90.2 87.3 95.5 95.0
Compound 13 20 27.3 40.2 42.8 39.5 35.6
50 67.3 54.3 64.3 48.3 56.9
80 98.8 84.8 93.2 87.6 89.0
Compound 14 20 27.3 38.4 40.3 47.5 32.3
50 59.6 49.2 63.8 53.8 44.6
80 88.7 73.5 87.5 89.4 87.8
Compound 16 0.8 29.9 32.8 41.0 38.3 39.3
1.4 67.4 53.4 63.8 49.2 47.7
2.0 97.3 84.3 92.7 87.2 90.5
Compound 18 0.8 35.3 40.5 39.8 41.8 42.1
1.4 64.7 70.3 69.3 72.9 68.7
2.0 91.3 94.4 89.4 98.6 97.6
The result shows, compound 16 and 18 pairs of nasopharyngeal carcinoma, mammary cancer, liver cancer, lung cancer and large bowel cancers have a significant inhibitory effect.
Embodiment ten: the restraining effect of the compound 16 and the 18 pairs of nasopharyngeal carcinoma and liver cancer transplanted tumor in nude mice
The KB cell CNE2 or the liver cancer cell Bel-7402 that take the logarithm and grow are with being made into 1 * 10 after the trysinization 7Individual/the mL single cell suspension, under aseptic condition, be inoculated in the BALB/C nude mouse and keep right that O.2mL/ armpit is subcutaneous only (is equivalent to 2 * 10 6Individual cell).Inoculate back 7 days, when treating that tumour is grown to diameter 3-5mm, size by volume is divided into the basic, normal, high dosage group of control group, 5-Fu group (positive drug control group), compound 16 and 18, every group of 8 mouse at random.Began administration the same day after the grouping, abdominal injection, and be administered once every day, and 6 times weekly, 3 weeks of logotype.Drug withdrawal is weighed next day, puts to death nude mice, strips out the record of weighing behind the knurl piece, calculates average tumor weight, calculates tumour inhibiting rate by following formula, and does the t test.
Tumour inhibiting rate=(the average tumor weight of the average tumor weight/control group of 1-experimental group) * 100%
The restraining effect of 16,18 pairs of human nasopharyngeal carcinomas of table 3. compound and liver cancer cell Bel-7402 transplanted tumor in nude mice
Grouping Dosage Knurl strain and inhibiting rate (%)
(mg/kg) Nasopharyngeal carcinoma cell CNE Liver cancer cell Bel-7402
Control group N.S 0 0
5-Fu (positive control) group 25 62.5 57.4
Compound 16 20 37.2 41.5
50 59.3 56.3
80 77.9 71.6
Compound 18 20 60.0 54.3
50 72.2 69.0
80 87.5 82.1
The result shows that compound 16 and 18 has the good restraining effect to nasopharyngeal carcinoma and liver cancer cell transplanted tumor in nude mice model under the animal tolerance dose, and inhibiting rate and dosage are proportionate.
Practicality pharmaceutically
The above embodiment of the present invention shows:
(1) by Gronwell naphthaquinone derivative to cancer cells inhibition test and cancer cells transplanted tumor in nude mice model trial, proved that natural Gronwell naphthaquinone compound has good antitumour activity through the derivative that obtains after the chemically modified.
(2) use Gronwell naphthaquinone derivative shown in the formula 1 of the present invention, the using dosage scope is 10～100mg/kg/day.
(4) use Gronwell naphthaquinone derivative shown in the formula 1 of the present invention, under normal dose, it is safe as medicinal application.
(5) use the combination of compound shown in the formula 1 of the present invention or its pharmacy, have that anticancer effect is good, side effect is little and the characteristics of applied range.

Claims (5)

1. the Gronwell naphthaquinone derivative shown in the formula I:
Figure C021149730002C1
Formula I
R among the formula I 1, R 2, R 3The group of representative is one of and the following:
(1), R 1Be OH, (CH 3) 2C=CHCOO, CH 3COO or CH 3COOC (CH 3) 2CH 2COO; R 2Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S; R 3Be H;
(2), R 1Be OH, (CH 3) 2C=CHCOO, CH 3COO or CH 3COOC (CH 3) 2CH 2COO; R 2Be H; R 3Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S;
(3), R 1Be OH, (CH 3) 2C=CHCOO, CH 3COO or CH 3COOC (CH 3) 2CH 2COO; R 2Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S; R 3Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S, HOC 2H 4S or C 2H 5S;
(4), R 1Be PhNH, p-CH 3COPhNH, PhS, HOC 2H 4S or C 2H 5S; R 2Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S; R 3Be H;
(5), R 1Be PhNH, p-CH 3COPhNH, PhS, HOC 2H 4S or C 2H 5S; R 2Be H; R 3Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S;
(6), R 1Be PhNH, p-CH 3COPhNH, PhS, HOC 2H 4S or C 2H 5S; R 2Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S; R 3Be (CH 3) 2N, PhNH, p-CH 3COPhNH, Ph-N-CH 3, PhS, HOC 2H 4S or C 2H 5S.
2. Gronwell naphthaquinone derivative according to claim 1 is characterized in that this Gronwell naphthaquinone derivative is the product of compound through obtaining after the chemically modified that separation and purification obtains in the natural Asian puccoon.
3. the Gronwell naphthaquinone derivative of the described formula I of claim 1 is used for the treatment of application in the medicine of cancer in preparation.
4. medicine that is used for the treatment of cancer wherein contains the Gronwell naphthaquinone derivative shown in the formula I of claim 1, and pharmaceutically acceptable auxiliary.
5. medicine according to claim 4 is characterized in that described medicine is to make injection, tablet, pill, capsule, suspension agent or emulsion.
CNB021149739A 2002-03-19 2002-03-19 Gronwell naphthaquinone derivative and its application in preparing anticancer medicine Expired - Fee Related CN1165509C (en)

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CN100455283C (en) * 2003-05-08 2009-01-28 北京金本草中药科技发展有限公司 Medicine containing acarnine compound as active component
EP2004174A4 (en) 2006-04-07 2010-07-28 Sunten Phytotech Co Ltd Naphthalenedione compounds
CN101265212B (en) * 2008-03-27 2010-07-28 上海交通大学 Antineoplastic alkanna tinctoria ketoximes derivatives
CN101683331B (en) * 2008-09-27 2013-01-30 厦门大学 Application of alkannin derivant
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CN102198124B (en) * 2010-03-26 2014-10-29 山东靶点药物研究有限公司 Gromwell extract for treating rheumatoid arthritis, and soft capsules thereof
CN102020598A (en) * 2010-11-11 2011-04-20 中山大学 Gronwell naphthaquinone derivative, preparation method of gronwell naphthaquinone derivative and application of gronwell naphthaquinone derivative serving as anticarcinoma drug
CN103054976B (en) * 2011-10-21 2014-09-24 上海中医药大学 Chinese medicinal composition for treating thrombopenia as well as preparation method and application of composition
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CN108409570A (en) * 2018-03-06 2018-08-17 泰山医学院 Acetylshikonin rapidly and efficiently purification process in Asian puccoon

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