CN103214495A - Anti-cancer 4'-demethylation-4'-oxy-cyclobutyl formyl-deoxidation podophyllotoxin and preparation method thereof - Google Patents
Anti-cancer 4'-demethylation-4'-oxy-cyclobutyl formyl-deoxidation podophyllotoxin and preparation method thereof Download PDFInfo
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Abstract
The invention discloses anti-cancer 4'-demethylation-4'-oxy-cyclobutyl formyl-deoxidation podophyllotoxin and a preparation method thereof, and belongs to the field of medicines. The preparation method of the 4'-demethylation-4'-oxy-cyclobutyl formyl-deoxidation podophyllotoxin comprises the following steps of: dissolving podophyllotoxin material in acetic acid in a high-pressure kettle; adding a palladium-carbon catalyst for enabling the podophyllotoxin to react with hydrogen gas to obtain anthricin under the hydrogen gas pressure of 1.1-2 atmospheres as well as the temperature condition of 90 DEG C to 100 DEG C; enabling the anthricin and hydrogen bromide to react in an acetic acid solution for removing the methyl to obtain 4'-demethylation anthricin; and condensing the 4'-demethylation anthricin with cyclobutyl formic acid to obtain 4'-demethylation-4'-oxy-cyclobutyl formyl-deoxidation podophyllotoxin. According to the research, the 4'-demethylation-4'-oxy-cyclobutyl formyl-deoxidation podophyllotoxin has obvious inhibition and apoptosis-inducing effects to a cervical cancer cell Hela and a mouse melanoma cell B16. Moreover, the preparation method is simple, easy to control, low in cost and high in yield.
Description
Technical field
The invention belongs to field of medicaments, relate to and a kind of cervical cancer cell Hela and mouse melanin tumor cell B16 are had significantly inhibiting 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin and preparation method thereof.
Background technology
In recent years, malignant tumour has become the focus that paid close attention to by the whole world, there are some researches show, malignant tumour, cardiovascular and cerebrovascular diseases and mishap are the world today's three big major causes of death, and the total incidence of annual cancer is trend of rising.What female genital tract malignant tumour sickness rate was the highest is cervical cancer, it is reported the new cases 500,000 of annual whole world cervical cancer nearly, the number that cervical cancer is died from the annual whole world is 290,000 people nearly, and annual new cases 130,000 people of China cervical cancer patient wherein have 30,000 people to die from cervical cancer approximately.In addition, various countries scholar's research report shows that all the morbidity of cervical cancer has the trend of rejuvenation, and the ratio that 35 years old following women suffers from cervical cancer raises gradually.
Cutaneous melanoma is the malignant tumour that originates from neural epiblast, results from melanocyte or its parent cell.Be primary in skin, all there is generation at other each positions, as eyes, gi tract, paranasal sinus etc.Mainly contain surgical intervention, radiotherapy, chemotherapy, immunotherapy and gene therapy for melanomatous treatment measure, domesticly mainly concentrate on preceding four kinds, back two kinds of methods commonly used abroad.But because of melanoma cell heteromorphism is obvious, differentiation is active, and propagation shifts rapidly easily, particularly early stage hematogenous metastasis.Simultaneously, melanoma is insensitive to radiotherapy, chemotherapy and immunotherapy, causes melanomatous poor prognosis, and survival rate is low.Therefore, people pay close attention to and seek prevention and treat melanomatous new way from natural phant.
Wild chervil nthrisc μ s sylvestris(L.) Hoffm., umbelliferae Anthriscus plant is birth canal ground, river medicinal material, the traditional Chinese medical science thinks that wild chervil has invigorating the spleen and replenishing QI, removing blood stasis to reduce swelling, the effect that tonifying lung is relievingd asthma.Pharmacological research prompting wild chervil has enhancing body immunity, anticancer, antiviral, anti-inflammatory, antianaphylaxis and invigorating the spleen and benefiting QI, effect such as promoting blood circulation and removing blood stasis.This seminar is at literature review and from found that of wild chervil extract part screening active ingredients in early stage, and anthricin (Silicicolin) has the effect that suppresses multiple cancer cell multiplication, but toxicity is bigger, and exploitation has certain limitation.The present invention mainly obtains anthricin derivative 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin by the chemosynthesis approach, studies its antitumour activity, does not still have bibliographical information at present.
Summary of the invention
The invention provides a kind of anticancer anthricin derivative of using; promptly 4 '-remove first anthricin and preparation method thereof; discover that described 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin has obvious suppression and apoptosis-induced effect to cervical cancer cell Hela and mouse melanin tumor cell B16, its preparation method is simple, easily control, with low cost, yield is high.
Technical solution of the present invention is as follows:
Anticancer usefulness 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin, its molecular formula is C
26H
26O
8, chemical being called " 5R-5,8,8a, 9-tetrahydrochysene-5-(4-ring fourth methanoyl-3,5-dimethoxy phenyl) furans (3 ', 4 ': 6,7) naphtho--[2,3-d]-1, dioxane alkene-6 (5aH)-ketone between 3-", structural formula is:
Anticancer usefulness 4 '-the go preparation method of first anthricin, it is characterized in that with the podophyllotoxin being raw material, at first in autoclave, the podophyllotoxin raw material is dissolved in acetate, add palladium-carbon catalyst, under the temperature condition of 1.1～2 atmospheric hydrogen pressures and 90～100 ℃, make podophyllotoxin and hydrogen reaction make anthricin; Utilizing anthricin and hydrogen bromide to react demethylating then in acetic acid solution obtains 4 '-removes the first anthricin; Utilize 4 ' at last-go first anthricin and the condensation of ring fourth formic acid to obtain 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin.
In the preparation process of anthricin, described palladium-carbon catalyst quality consumption be the podophyllotoxin raw materials quality 5%～10% between, just can obtain the anthricin of yield about 75%, the catalyst levels greater than 10% does not have influence to the anthricin turnout; Hydrogen pressure should be greater than 1.1 normal atmosphere, and the anthricin that the continuation of hydrogen pressure improves reaction times and reaction generation does not have influence; After reaction times surpassed 5 hours, reaction promptly stopped, and prolonging the reaction times this moment does not more all have influence to the yield and the purity of anthricin.The anthricin crude product of anthricin before demethyl is handled can adopt the mixed solvent of ethyl acetate: sherwood oil=1:3 to carry out recrystallization and purify, and can obtain liquid phase purity after the recrystallization purification greater than 98% white powder anthricin.
In anthricin demethyl preparation 4 '-go in the first anthricin process, can adopt hydrogen bromide or sodium iodide and methylsulfonic acid to prepare, sodium iodide and methylsulfonic acid preparation 4 '-go first anthricin yield lower, (mol ratio of anthricin and hydrogen bromide is 1:3～1:5) preferentially to select hydrogen bromide preparation for use, reaction solvent can be methylene dichloride, chloroform or acetate, preferentially selects for use acetate to do reaction solvent (solvent quality is 5～10 times of anthricin quality); Behind the demethyl 4 '-remove first anthricin crude product can adopt methyl alcohol to carry out recrystallization and purify, can obtain after recrystallization is purified liquid phase purity greater than 98% 4 '-remove the first anthricin.
Utilizing 4 '-go first anthricin and the condensation of ring fourth formic acid to obtain in 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin process, solvent can adopt methylene dichloride, chloroform, N, dinethylformamide or acetonitrile; Condensing agent can adopt DIC, N, N-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide.
Screening and optimizing of the present invention 4 '-go the synthetic route and the technology of first anthricin, high yield prepared 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin.
The present invention uses the MTT colorimetry and detects 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin cervical cancer cell Hela, mouse melanin tumor cell B16 are had significant inhibitory effect; and inhibiting rate and concentration are tangible effect relation; along with the increase of drug level, cell survival rate constantly descends.Observe with inverted microscope, two kinds of growth of tumour cell obviously are suppressed, and cell volume dwindles, and connect to disappear, and with cell detachment on every side, cell becomes round cell by fusiformis and comes off, floating being suspended from the nutrient solution.4 ' of different concns-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin acts on Hela and B16 cell, and with DAPI dyeing, obvious shrinkage and fracture take place visible cell nuclear under the fluorescence behind the 48h.
To sum up, the invention discloses a kind of anthricin derivative, promptly 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin is to the purposes of preventing and treating the aspect of cancer.The preparation technology that the present invention prepares 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin is simple, easily control, with low cost, yield is high.Prepared 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin has obvious restraining effect to the growth of cervical cancer cell Hela, mouse melanin tumor cell B16, and finds that it has obvious inducing action to above two kinds of cancer cell-apoptosis.
Description of drawings
Fig. 1 is the chemical structural formula of 4 '-demethyl-4 ' provided by the invention-oxygen-ring fourth formyl radical-Silicicolin.
Fig. 2 is the restraining effect design sketch of different concns 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin to cervical cancer cell Hela, mouse melanin tumor cell B16.
Fig. 3 is that different concns 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin is handled back cellular form (* 400) figure.
Embodiment
One, the preparation of 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin:
(1) preparation of intermediate anthricin: get podophyllotoxin 100g, be dissolved in the 500ml Glacial acetic acid, add palladium carbon 5～10g, pour into above-mentioned raw materials in the autoclave together, behind the nitrogen replacement 5 times, hydrogen exchange 3 times, 95 ° of C of temperature in being heated to, hydrogen pressure is increased to 1.1atm, reacts after 5 hours, cooling, after the release, filter out catalyzer, behind the concentrated dried solvent, obtain the anthricin crude product, the mixed solvent 200ml recrystallization of crude product ethyl acetate: sherwood oil=1:3 obtains high performance liquid phase purity greater than 98% white powder anthricin 75g.
In the preparation process of anthricin, catalyst levels just can obtain the anthricin of yield about 75% between 5%～10%, and the catalyzer greater than 10% does not have influence to the anthricin turnout.Hydrogen pressure gets final product greater than 1.1atm, and the anthricin that pressure continues to improve reaction times and reaction generation does not have influence.5 hours reaction times afterreaction just stops, and the prolongation reaction times does not all have influence to anthricin yield and purity.
(2) 4 '-go the preparation of first anthricin can adopt the hydrogen bromide preparation, perhaps adopt sodium iodide and methylsulfonic acid to prepare, sodium iodide and methylsulfonic acid preparation 4 '-go first anthricin yield lower, (mol ratio of anthricin and hydrogen bromide is 1:3～1:5) preferentially to select hydrogen bromide for use, reaction solvent can be methylene dichloride, chloroform or acetate, preferentially selects for use acetate to do reaction solvent (solvent quality is 5～10 times of anthricin quality).Concrete operations are, the 10g anthricin adds the acetic acid solution that the 50ml mass concentration is 30% hydrogen bromide, and stirring at room added 200ml water and stirred 10 minutes after 0.5 hour, filter out solid and obtain 4 '-remove first anthricin crude product 8.5g.4 '-go first anthricin crude product to add to obtain after the 25ml recrystallizing methanol 7.2g high performance liquid phase purity greater than 98% 4 '-remove the first anthricin.
The preparation solvent of (three) 4 '-demethyls-4 '-oxygen-ring fourth formyl radical-Silicicolin can be methylene dichloride, chloroform, N, dinethylformamide, acetonitrile etc.Condensing agent can be DIC, N, N-dicyclohexylcarbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide etc.Concrete operations take by weighing 4-Dimethylamino pyridine 20mg subsequently for taking by weighing 4 ' earlier-removing first anthricin 3.84g, take by weighing ring fourth formic acid 1g again, above raw material have been taken by weighing all add in the three-necked bottle, add the 20ml methylene dichloride afterwards.Take by weighing N at last, N-dicyclohexylcarbodiimide 2.5g, immediately with N, the N-dicyclohexylcarbodiimide is dissolved in the 10ml methylene dichloride, and this solution under agitation is added dropwise in the reaction system after having claimed.After dripping 3 hours; after the sampling monitoring 4 '-go the first anthricin to react; add 20ml water in the system, and with 40ml dichloromethane extraction 2 times, merging organic layer; water successively; saturated common salt water washing, organic phase 2g anhydrous sodium sulfate drying is after steaming desolventizes; column chromatography obtains 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin 4.1g, yield 88%.
Two, medical observation
1 materials and methods
1.1 cell: cervical cancer cell Hela, mouse melanin tumor cell B16 are available from West China National Key Laboratory of Sichuan University.
1.2 medicine and reagent: RPMI-1640 and trypsinase all adopt Gibco import packing, MTT believes biological company limited available from treasured.4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin obtains by this laboratory is synthetic.
1.3 key instrument: CO2 constant temperature incubator (3110 types, U.S. Thermo company), Tissue Culture Plate, culturing bottle (U.S. Coster company), microplate reader (Elx-800 type, U.S. Bio-Tek company), whizzer (L420 type, Hunan, Changsha instrument whizzer company limited), inverted fluorescence microscope (Japanese Olympus company), Bechtop (BSW-880, Sujing Group Co., Ltd., Jiangsu Prov).
1.4 experimental technique
1.4.1 cell cultures
From liquid nitrogen, take out two kinds of frozen pipes of tumour cell of Hela, B16 respectively, behind 75% alcohol disinfecting, place 37 ℃ of constant water bath box rapidly, shake gently up and down and make its thawing.Under aseptic condition, carefully open frozen pipe, cell suspension is changed in the centrifuge tube that adds 5mL10%PRMI1640 calf substratum in advance, it is centrifugal to mix back 1000rpm * 5min, remove supernatant liquor with the sputum aspirator suction, add contain 10% calf serum PRMI1640 substratum and blow and beat for several times cell up and down after, be seeded to that the 50ml culturing bottle places 37 ℃, contains 5%CO2, cultivate in the saturated humidity incubator, change nutrient solution next day one time.
When cell density reaches 80%-90%, remove nutrient solution with the sputum aspirator suction, add 2mL and contain the EDTA0.25% pancreatin in 37 ℃ of incubators behind the peptic cell strain 2min, take out, patting the Tissue Culture Dish edge gently splits away off fully until cell, add the RPMI1640 nutrient solution that 3mL contains 10% newborn calf serum again and stop digestion, go nutrient solution to blow and beat attached cell repeatedly with the transfer pipet suction, make its dispersion, move into centrifuge tube, the centrifugal back of 1000rpm * 5min is inhaled with sputum aspirator and is removed supernatant liquor, adds the PRMI1640 nutrient solution that contains 10% calf serum and blows and beats up and down for several times and to be seeded to culturing bottle behind the cell and to place 37 ℃, contain 5%CO2, the cultivation of going down to posterity in the saturated humidity incubator.
1.4.2 cell counting
Cell is taken out from the CO2 incubator, after adding 2mL contains the EDTA0.25% trysinization, make single cell suspension, with the 20 μ L liquid-transfering guns cell suspension that takes a morsel, add cell counting count board, under inverted microscope, with the cell count in four jiao of 16 grid of 40 * object lens observation tally, calculate summation.The following formula of substitution gets cell density: cell count (individual/mL)=(summation/4) * 10
4
1.4.3MTT method is measured the inhibiting rate of medicine to tumour
1. the vegetative period cell of taking the logarithm is made single cell suspension by the passage cultured method, gets the 20ul cell suspension with liquid-transfering gun, adds cell counting count board, counting and to adjust each cell strain concentration be 1 * 10 under inverted phase contrast microscope
4Individual/mL.
2. two kinds of cell inoculations of the Hela that takes the logarithm respectively vegetative period, B16 are in 24 well culture plates that add substratum, every hole 1 * 10
4/ mL cell; 3 multiple holes; CO2 constant temperature is supported case and is cultivated 24h; the substratum that renews; add 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin; establish 7 drug levels altogether; be respectively 0.1%DMSO; 2.5; 5; 10; 20; 40; 80 μ g/mL; every pore volume 500 μ L, behind the cultivation 48h, every hole adds 2mg/mLMTT working fluid 200 μ L; place 4h for 37 ℃; abandon supernatant, every hole adds 200ul DMSO, and 10min is dissolving crystallized for the concussion of 200r/min shaking table; draw 200 μ L to 96 hole enzyme plates detect 490nm wavelength place in full-automatic microplate reader each hole absorbancy (OD value); 0.1%DMSO is as negative control, and according to 0.1%DMSO value curve plotting, relatively the different concns medicine is respectively to Hela; the effect of B16 cell inhibiting.Calculation formula: proliferation inhibition rate (%)=(1-dosing hole A value/control group A value) * 100%.
1.4.4DAPI dyeing: the cleaning sterile cover glass is placed in 6 orifice plates, and planting cell cultures to cell density is 60%～80%.If control group, 10 μ g/ml, 40 μ g/ml anthricin derivative groups (Hela) and control group, 10 μ g/ml, 40 μ g/ml anthricin derivative groups (B16), continue to cultivate 48h respectively, waste liquid is abandoned in suction, uses 4% Paraformaldehyde 96 fixed cell creep plate 35min then, 1xPBS flushing 3 times, each 2min, add 2ml DAPI staining fluid, dyeing 15min, twice of 1xPBS flushing, take out creep plate mounting fluid-tight sheet, fluorescent microscope can detect the nucleus that is blue.Excitation wavelength is about 350nm, and emission wavelength is about 460nm.
1.4.5 statistical analysis
Adopt SPSS17.0 software to carry out data analysis, each is organized data and represents that with x ± s experimental group and control group are relatively used one-way analysis of variance.
2 results
2.14 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin is to the restraining effect of Hela and the growth of B16 cell
Adopt the MTT colorimetry to detect the restraining effect of 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin to cervical cancer cell Hela and mouse melanin tumor cell B16 growth; the result shows; use concentration respectively after 4 ' of 2.5-80ug/ml-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin acts on Hela, B16 cell 48h respectively; along with the rising of drug level, cell survival rate constantly descends.Learning computed in software by statistics draws medicine the IC50 value of Hela and B16 cell is respectively 29.30ug/ml and 23.07ug/ml; illustrate that 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin is obvious to the restraining effect comparison Hela cyto-inhibition of B16, the results are shown in shown in Figure 2.
2.24 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin is to the influence of Hela, B16 apoptosis
Inverted microscope is observed, and after 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin was handled 48h, the growth of two kinds of cells obviously was suppressed; cell volume dwindles, and connects to disappear, with cell detachment on every side; cell becomes round cell by fusiformis and comes off, floating being suspended from the nutrient solution.After the DAPI dyeing, fluorescence microscope arrives, after 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin is handled 48h; the growth of two kinds of cells obviously is suppressed, and tangible nucleus fracture and shrinkage are arranged, and increases with dosage; phenomena of apoptosis is obvious more, the results are shown in shown in Figure 3.
This experimental applications MTT colorimetry detects the restraining effect of 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin to cervical cancer cell Hela, mouse melanin tumor cell B16; draw its IC50 value as calculated and be respectively 29.30ug/ml and 23.07ug/ml; and inhibiting rate and concentration are tangible effect relation; along with the increase of drug level, cell survival rate constantly descends.Observe with inverted microscope, two kinds of growth of tumour cell obviously are suppressed, and cell volume dwindles, and connect to disappear, and with cell detachment on every side, cell becomes round cell by fusiformis and comes off, floating being suspended from the nutrient solution.4 ' of different concns-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin acts on Hela and B16 cell, and with DAPI dyeing, obvious shrinkage and fracture take place visible cell nuclear under the fluorescence behind the 48h.
To sum up, the invention discloses a kind of anthricin derivative, promptly 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin is to the purposes of preventing and treating the aspect of cancer.The preparation technology that the present invention prepares 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin is simple, easily control, with low cost, yield is high.Prepared 4 '-as to go the first anthricin that the growth of cervical cancer cell Hela, mouse melanin tumor cell B16 is had obvious restraining effect, and find that it has obvious inducing action to above two kinds of cancer cell-apoptosis.
Claims (8)
1. anticancer usefulness 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin, its molecular formula is C
26H
26O
8, chemical being called " 5R-5,8,8a, 9-tetrahydrochysene-5-(4-ring fourth methanoyl-3,5-dimethoxy phenyl) furans (3 ', 4 ': 6,7) naphtho--[2,3-d]-1, dioxane alkene-6 (5aH)-ketone between 3-", structural formula is:
2. the preparation method of anticancer usefulness 4 ' according to claim 1-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin, it is characterized in that: be raw material with the podophyllotoxin, at first in autoclave, the podophyllotoxin raw material is dissolved in acetate, add palladium-carbon catalyst, under the temperature condition of 1.1～2 atmospheric hydrogen pressures and 90～100 ℃, make podophyllotoxin and hydrogen reaction make anthricin; Utilizing anthricin and hydrogen bromide to react demethylating then in acetic acid solution obtains 4 '-removes the first anthricin; Utilize 4 ' at last-go first anthricin and the condensation of ring fourth formic acid to obtain 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin.
3. the preparation method of anticancer usefulness 4 ' according to claim 2-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin; it is characterized in that: in the preparation process of anthricin, described palladium-carbon catalyst quality consumption be the podophyllotoxin raw materials quality 5%～10% between.
4. the preparation method of anticancer usefulness 4 ' according to claim 2-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin, it is characterized in that: the time of podophyllotoxin and hydrogen reaction was greater than 5 hours.
5. the preparation method of anticancer usefulness 4 ' according to claim 2-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin; it is characterized in that: the anthricin crude product of anthricin before demethyl is handled; can adopt the mixed solvent of ethyl acetate: sherwood oil=1:3 to carry out recrystallization and purify, can obtain liquid phase purity after recrystallization is purified greater than 98% white powder anthricin.
6. the preparation method of anticancer usefulness 4 ' according to claim 2-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin, it is characterized in that: in anthricin demethyl preparation 4 '-go in the first anthricin process, the mol ratio of anthricin and hydrogen bromide is 1:3～1:5; The acetic acid solvent quality is 5～10 times of anthricin quality.
7. the preparation method of anticancer usefulness 4 ' according to claim 2-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin; it is characterized in that: 4 ' behind the demethyl-go first anthricin crude product; can adopt methyl alcohol to carry out recrystallization and purify, can obtain after recrystallization is purified liquid phase purity greater than 98% 4 '-remove the first anthricin.
8. the preparation method of anticancer usefulness 4 ' according to claim 2-demethyl-4 '-oxygen-ring fourth formyl radical-deoxidation podophyllotoxin, it is characterized in that: utilizing 4 '-go first anthricin and the condensation of ring fourth formic acid to obtain in 4 '-demethyl-4 '-oxygen-ring fourth formyl radical-Silicicolin process, solvent adopts methylene dichloride, chloroform, N, dinethylformamide or acetonitrile; Condensing agent adopts DIC, N, N-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4130008A4 (en) * | 2020-05-11 | 2024-04-24 | J&C Sciences | Novel derivative of beta-apopicropodophyllin and preparation method therefor |
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| CN1474822A (en) * | 2000-11-20 | 2004-02-11 | Novel 4'-demethyl-4'-0-substituted-1-deoxypodophyllotoxin derivative and geometric isomer thereof, process for preparation thereof and anti-cancer composition comprising same | |
| CN101497618A (en) * | 2009-03-11 | 2009-08-05 | 西北农林科技大学 | 4'-podophyllotoxin demethyl deoxidated aromatic ester, substituted benzene sulfonate, ether derivative and use in plant source pesticide preparation |
| CN101647842A (en) * | 2009-09-24 | 2010-02-17 | 北京大学 | Fructus Podophylli extract and application thereof |
| CN102633808A (en) * | 2012-05-03 | 2012-08-15 | 浙江尖峰药业有限公司 | Manufacturing method for deoxypodophyllotoxin |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1474822A (en) * | 2000-11-20 | 2004-02-11 | Novel 4'-demethyl-4'-0-substituted-1-deoxypodophyllotoxin derivative and geometric isomer thereof, process for preparation thereof and anti-cancer composition comprising same | |
| CN101497618A (en) * | 2009-03-11 | 2009-08-05 | 西北农林科技大学 | 4'-podophyllotoxin demethyl deoxidated aromatic ester, substituted benzene sulfonate, ether derivative and use in plant source pesticide preparation |
| CN101647842A (en) * | 2009-09-24 | 2010-02-17 | 北京大学 | Fructus Podophylli extract and application thereof |
| CN102633808A (en) * | 2012-05-03 | 2012-08-15 | 浙江尖峰药业有限公司 | Manufacturing method for deoxypodophyllotoxin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4130008A4 (en) * | 2020-05-11 | 2024-04-24 | J&C Sciences | Novel derivative of beta-apopicropodophyllin and preparation method therefor |
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Application publication date: 20130724 |