CN102335165B - Application of flavonoids compounds in breast cancer resistance - Google Patents
Application of flavonoids compounds in breast cancer resistance Download PDFInfo
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- CN102335165B CN102335165B CN 201110197692 CN201110197692A CN102335165B CN 102335165 B CN102335165 B CN 102335165B CN 201110197692 CN201110197692 CN 201110197692 CN 201110197692 A CN201110197692 A CN 201110197692A CN 102335165 B CN102335165 B CN 102335165B
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Abstract
The invention discloses application of four kinds of known flavonoids compounds to treatment of breast cancers. The four kinds of known flavonoids are known compoundes obtained by separating fruit of sinopodophyllum emodi and have structures shown as structural formulas 1-4 in the specification. Experiments on the effect of the kinds of compounds on inhibiting human breast cancer cells show that the series of compounds have a favorable effect on inhibiting the proliferation of the breast cancer cells.
Description
Technical field
The present invention relates to the application of flavone compound in treatment breast carcinoma.
Background technology
Breast carcinoma is one of the highest malignant tumor of present women's sickness rate, is seriously threatening women's health and lives.According to statistics, the whole world approximately has 1,200,000 women to suffer from breast cancer every year, has 500,000 patients to die from this disease.Breast carcinoma does not have satisfied medicine except the surgery operation so far.Existing anticarcinogen (chemical medicine) toxic and side effects is large, and can not solve the easy drug resistance of tumor stem cell and the easy problem such as relapse and metastasis; Therefore, searching low toxicity, effective Novel breast adenocarcinoma medicine are research and development focuses in recent years.
Fructus Sinopodophylli (Sinopodophylli Fructus) is Tibetan medicine commonly used, and Chinese Pharmacopoeia version in 2010 is recorded its source and is the dry mature fruit of Berberidaceae plant Chinese podophyllum root Sinopodophyllum hexandrum (Royle) Ying.Have the promoting blood flow to regulate menstruation function, be usually used in treating various gynecological diseases.
At present, separating the main compound obtain from Fructus Sinopodophylli has: lignanoids (lignans) chemical compound: podophyllotoxin (podophyllotoxin), deoxypodophyllotoxin (deoxypodophyllotoxin), 4 '-demethyldeoxypodophyllotoxin (4 '-demethyldesoxypodophyllotoxin); Flavonoid (flavones) chemical compound: Quercetin (quercetin), nimbecetin (kaempferol), 8-prenylkaempferol (8-prenylkaemferol), Fructus Citri Limoniae phenol (citrusinol), 8,2 '-diisoamyl thiazolinyl Quercetin 3-methyl ether (8,2 '-diprenylquercetin 3-methyl ether); Other compounds: cupreol (β-sitosterol) and daucosterol (daucosterol).
Summary of the invention
The object of the invention is to propose from Fructus Sinopodophylli, to separate the application of a series of flavone compounds in preparation treatment breast cancer medicines that obtains.
The present invention is by with the Fructus Sinopodophylli drying and crushing, with 80%～95% alcohol reflux 2～4 times, and each 0.5～2 hour, Recycled ethanol, relative density is 1.05～1.30 extractum when being concentrated into 60～80 ℃.Its Uniform Dispersion to water, with ethyl acetate and water-saturated n-butanol extraction, is reclaimed the extract that solvent obtains opposed polarity respectively.Ethyl acetate extraction part is through repeatedly silica gel column chromatography (petroleum ether-acetone or chloroform-methanol eluting), centrifugal thin layer chromatography (chloroform-methanol), Sephadex-LH20 gel column chromatography (chloroform-methanol, methanol), mesolow liquid chromatograph chromatograph (water-acetonitrile, water-methanol), half preparative high-performance liquid chromatographic (acetonitrile-water) separation and purification, obtain 5 known compounds, be respectively Fructus Citri Limoniae phenol (1), 6-isopentene group Quercetin 3-methyl ether (2), 1,3,7,8-tetrahydroxy
Ketone (3), 6-isopentene group nimbecetin 3-methyl ether (4).
The chemical structural formula of chemical compound 1-4 of the present invention is as follows:
Physicochemical property and the structural confirmation of chemical compound are as follows shown in the said structure formula 1 to 4:
Fructus Citri Limoniae phenol is yellow acicular crystal (water-acetonitrile), and the reaction of hydrochloric acid magnesium powder is positive.The spectroscopic data of this chemical compound and document (Shang Mingying, Li Ping, Li Jun etc. the chemical constitution study of the Fruit of Sinopodophyllum emodi. Chinese herbal medicine .2000; 31 (08): 569-571.) report is consistent, therefore determine that it is Fructus Citri Limoniae phenol.
6-isopentene group Quercetin 3-methyl ether is yellow powder, and the reaction of hydrochloric acid magnesium powder is positive.The spectroscopic data of this chemical compound and document (Tao Shuhong, Wu Fenge. the chemical constitution study II of Herba hyperici elodeoidis. research and development of natural products .2004; 16 (1): 26-27.) report is consistent, therefore determine that it is 6-isopentene group nimbecetin 3-methyl ether.
1,3,7,8-tetrahydroxy
Ketone is yellow floccule (water-acetonitrile), and the reaction of hydrochloric acid magnesium powder is positive.
1H-NMR and
13The C-NMR data through with document (Pan Li, Zhang Xiaofeng, Wang Mingkui etc. the Swertia przewalskii Pissjauk. chemical constitution study. Chinese herbal medicine .2002; 33 (7): 583-586) contrast, determine that this chemical compound is 1,3,7,8-tetrahydroxy
Ketone.
6-isopentene group nimbecetin 3-methyl ether is yellow powder, and the reaction of hydrochloric acid magnesium powder is positive.The spectroscopic data of this chemical compound and document (Tahara, Satoshi; Hashidoko, Yasuyuki; Mizutani, Junya.New 3-methoxyflavones in the roots of yellow lupine (Lupinus luteus L.cv.Topaz) .Agricultural and Biological Chemistry.1987; 51 (4): 1039-1044.) report is consistent, therefore determine that it is 6-isopentene group nimbecetin 3-methyl ether.
As from the foregoing, described compound structure is correct, is chemical compound shown in the structural formula 1 to 4.
The application in the preparation cancer therapy drug of cancer therapy drug take above-mentioned chemical compound provided by the invention as active component and this chemical compound belongs to protection scope of the present invention.Wherein, described anticancer be anti-breast cancer.Described breast cancer cell is human breast carcinoma T47D cell or human breast carcinoma MDA-MB-231 cell.
Flavone compound shown in the structural formula 1 to 4 provided by the invention is to separate the known compound that obtains from Fructus Sinopodophylli.This compounds is tested the inhibitory action of human breast cancer cell and is shown, it has the effect of good inhibition Cells Proliferation of Human Breast Cancer.
The specific embodiment
The present invention is further elaborated below in conjunction with specific embodiment, but the present invention is not limited to following examples.Described method is conventional method if no special instructions.Described material all can get from open commercial sources if no special instructions.
Embodiment 1
Dry Fructus Sinopodophylli medical material, about 18.0kg after pulverizing, with 8 times of amount 95% alcohol reflux 2 times, extraction time was respectively 2 hours and 1 hour, decompression recycling ethanol, relative density is approximately 4.2kg of 1.10 extractum when being concentrated into 70 ℃.Get approximately 4.0kg, add the 12L distilled water be stirred well to fully suspend after, extract 6 times with isopyknic ethyl acetate extraction 7 times, water-saturated n-butanol successively.The extract decompression and solvent recovery gets and respectively extracts the position.Get ethyl acetate part 1100g, separate through silicagel column (200～300 order) chromatograph, petroleum ether-acetone (20: 1～0: 20), methanol gradient elution, every 1000ml collects a flow point, collects altogether and obtains 576 flow points.(Qingdao Haiyang silica gel is from bed board according to the TLC testing result; Developer: 1% vanillin-concentrated sulphuric acid; Colour temp: 110 ℃), merging obtains 26 flow points, and wherein, the 8th, 13 flow points are called after Ei and En respectively.
Ei (16.1g) separates (200-300 order through silica gel column chromatography; Sample: silica gel=1: 30), chloroform-methanol (90: 0～0: 15) gradient elution, every 100ml collects a flow point, and (Qingdao Haiyang silica gel is from bed board according to the TLC testing result; Developer: 1% vanillin-concentrated sulphuric acid; Colour temp: 110 ℃), merging obtains 13 flow points.Wherein, the 3rd, 6 flow points difference called after Ei3, Ei6.Ei3 (1.8g) separates (GF254 thin layer silica gel through centrifugal thin layer chromatography, falope ring bandwidth: 8cm), chloroform-methanol (50: 1～0: 50) gradient elution (flow velocity: 5ml/min), collect by the phosphor strip band, (Qingdao Haiyang silica gel is from bed board according to TLC inspection knowledge result; Developer: 1% vanillin-concentrated sulphuric acid; Colour temp: 110 ℃), merging obtains 12 flow points.The 3rd flow point (Ei3-3) is pressed chromatographic isolation (filler: ODS reverse phase silica gel in Ez Purifier; The post specification: 40g), water-acetonitrile (35～80%) gradient elution (flow velocity: 15ml/min), press the peak and collect, collect altogether and obtain 18 sub-flow points.This 7th subflow divides (Ei3-3-7) again through PHPLC preparative hplc (C18 filler; Solvent: 68% acetonitrile solution) separate, obtain Fructus Citri Limoniae phenol (16.5mg).
Ei6 (2.4g) separates (granularity: 200～300 orders through silica gel column chromatography; Sample: silica gel=1: 33), chloroform-methanol (90: 0～0: 15) gradient elution, every 10ml collects a flow point, and (Qingdao Haiyang silica gel is from bed board according to TLC inspection knowledge result; Developer: 1% vanillin-concentrated sulphuric acid; Colour temp: 110 ℃), merging obtains 7 flow points.Wherein, the 3rd flow point called after Ei6-3.Ei6-3 presses chromatographic isolation (filler: thin layer polyamide in Ez Purifier; Post specification: 40g; Granularity: 200 orders), (flow velocity: 15ml/min), every 15ml collects a flow point to chloroform-methanol (100: 0～0: 2) gradient elution, and the result is known in inspection according to TLC, merges to obtain 6 flow points.The 4th flow point (Ei6-4) separates (amount of filler: 110g through the Sephadex-LH20 gel column chromatography; Column length: 150cm; Column internal diameter: 25mm), methanol-eluted fractions, every 10ml collects a flow point, collects altogether and obtains 43 flow points.According to HPLC (instrument: Agilent 1200; Agilent Zorbax SB C-18 post; Mobile phase: water-acetonitrile) analysis result, merging obtains 6 flow points.Its 5th flow point (Ei6-4-5) is pressed chromatographic isolation (filler: ODS reverse phase silica gel in Ez Purifier; Post specification: 40g; ), 57% acetonitrile solution isocratic elution (flow velocity: 15ml/min), obtain 6-isopentene group nimbecetin 3-methyl ether (9.2mg).
En (20.0g) presses chromatographic isolation (filler: thin layer Silon in Ez Purifier; 200g; Granularity: 200 orders; Column length: 300mm; Column internal diameter: 45mm), chloroform-methanol (80: 0～0: 1) gradient elution (flow velocity: 50ml/min), according to HPLC (instrument: Agilent 1200; Agilent Zorbax SB C-18 post; Mobile phase: water-acetonitrile) analysis result, merging obtains 9 flow points.Wherein, the 6th flow point called after En6.En6 presses chromatographic isolation (filler: ODS reverse phase silica gel in Ez Purifier; The post specification: 40g), water-acetonitrile (46～57%) gradient elution (15ml/min) is pressed the peak and is collected, and collects altogether and obtains 22 flow points.The 6th flow point that collection obtains is separated out through being placed with yellow floccule, obtains after filtration 1,3,7,8-tetrahydroxy
Ketone (9.7mg).The 13rd flow point that collection obtains is separated out through being placed with yellow acicular crystal, obtains after filtration 6-isopentene group Quercetin 3-methyl ether (42.0mg).
Embodiment 2
Adopt Acid Phosphatase Method to detect Fructus Citri Limoniae phenol (1), 6-isopentene group Quercetin 3-methyl ether (2), 1,3,7,8-tetrahydroxy
Ketone (3), 6-isopentene group nimbecetin 3-methyl ether (4), paclitaxel (curing three institutes by north provides) is to the inhibitory action of human breast cancer cell.
Human breast carcinoma MDA-MB-231 cell strain (being provided by knubble biological center, Department Of Medicine, Peking University) and Human breast cancer T47D particle (being provided by Department Of Medicine, Peking University's Experimental Animal Center) are all with containing DMEM culture medium (the U.S. Gibco company) cultivation that volume fraction is 10% new-born calf serum (U.S. Gibco company), 100U/mL penicillin, 100U/mL streptomycin, 37 ℃, 95% humidity, 5%CO
2Incubator condition (U.S. Napco company); Conventional 2.5g/L trypsinization goes down to posterity.
Take the logarithm behind the trophophase cell dissociation, make cell suspension by 1.5 * 10
3The density in/hole is inoculated in 96 well culture plates, and after cultivation 24h cell was fully adherent, experimental group added respectively the chemical compound of variable concentrations; The blank group adds the DMEM culture fluid.In the experiment, each concentration is established 6 parallel holes, behind effect 24h, 48h, the 72h, discard the culture medium in 96 orifice plates, each hole is washed 2 times with PBS 100 μ L, abandons PBS, nitrophenyl phosphate solution (Fluka) 100 μ L (the 0.1mol/L acetate buffer solution preparation that adds 10mmol/L, contain 0.1%Triton X-100), place 37 ℃ to hatch 2h after, every hole adds 1mol/L sodium hydroxide 10 μ L cessation reactions.Detect absorbance (A value) record result, repeated experiments 3 times at the 405nm place with enzyme-linked immunosorbent assay instrument (Bio Rad Laboratories).Drug application inhibition concentration software for calculation (Loggt method) calculates IC
50Value.
The result shows, as shown in Table 1 and Table 2, each chemical compound has the effect of stronger inhibition Cells Proliferation of Human Breast Cancer in the table.
Each chemical compound of table 1 and positive control paclitaxel are to the inhibitory action of T47D cell strain propagation
Each chemical compound of table 2 and positive control paclitaxel are to the inhibitory action of MDA-MB-231 cell strain propagation
Claims (2)
1. the application of any one in structural formula 2 to the 4 described chemical compounds in the preparation cancer therapy drug, the cancerous cell in the described cancer therapy drug is breast cancer cell:
2. application according to claim 1 is characterized in that: the cancerous cell in the described cancer therapy drug is human breast carcinoma T47D cell or human breast carcinoma MDA-MB-231 cell.
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