CN102617664A - Plumbagin-5-O-glucose and synthetic method and application thereof - Google Patents

Plumbagin-5-O-glucose and synthetic method and application thereof Download PDF

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CN102617664A
CN102617664A CN2012101087323A CN201210108732A CN102617664A CN 102617664 A CN102617664 A CN 102617664A CN 2012101087323 A CN2012101087323 A CN 2012101087323A CN 201210108732 A CN201210108732 A CN 201210108732A CN 102617664 A CN102617664 A CN 102617664A
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plumbagin
glucose
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volume ratio
acetonitrile
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梁宏
陈振锋
刘延成
张敏敏
彭艳
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Guangxi Normal University
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Abstract

The invention discloses a plumbagin-5-O-glucose and a synthetic method and an application thereof. A plumbagin is used to serve as an active mother nucleus to synthesize the plumbagin-5-O-glucose by an glucosidation reaction, compared with a water solubility of the plumbagin, the water solubility of the plumbagin-5-O-glucose is remarkably improved, and the problem that the plumbagin serving as a potential antitumor drug is not good in water solubility is effectively solved; and an inhibitory activity of the plumbagin-5-O-glucose for proliferations of a plurality of human tumor cell lines is investigated, a result shows that an antitumor activity of the plumbagin-5-O-glucose is still maintained on the condition that the water solubility is remarkably improved, and the plumbagin-5-O-glucose has a good potential medical value and is expected to be used for preparing various antitumor drugs. According to the plumbagin-5-O-glucose and the synthetic method and the application thereof, the structural formula of the plumbagin-5-O-glucose is shown as follows.

Description

Plumbagin-5-O-glucose and compound method and application
Technical field
The present invention relates to medical technical field, be specifically related to plumbagin-5-O-glucose and compound method and application.
Background technology
(Plumbagin, molecular formula is C to plumbagin 11H 8O 3Molecular weight is 188g/mol, and chemical name is a 5-hydroxy-2-methyl-1, the 4-naphthoquinones) be a kind of remarkable pharmacologically active quinones of (as anticancer, antibiotic, anti-oxidant etc.) that has; Mainly from traditional Chinese medicine plant Whiteflower Leadword Root plant (especially its root), separate obtaining, and name therefrom.The chemical structure of plumbagin is shown below:
Figure BDA0000153281800000011
TaiWan, China investigator Lin etc. has carried out anti tumor activity in vitro research to plumbagin, and the result shows that its growth-inhibiting effect to HeLa, Wish, Raii and four kinds of tumor cell lines of Calu-1 is better, IC 50(being half-inhibition concentration) is all below 25.0 μ M.Other discovers; Plumbagin can suppress the growth of P388 leukemic lymphoblastoid cancer cells, can induce the apoptosis of uterus cancer cells ME-180, and possible cause is its generation that has stimulated ME-180 intracellular reactive oxygen; Damaged plastosome; Make membrane potential descend, thereby cause the apoptosis of this cell, and apoptosis rate and the proportional relation of plumbagin concentration.Tilak etc. are model with the mouse, discover that plumbagin can remove hydroxyl radical free radical in the finite concentration scope, can suppress by Fe 2+The mouse mitochondrial swelling that-vitamins C causes shows anti-oxidant activity.Jaber etc. have studied plumbagin to against mycobacterium tuberculosis bacteriostatic action such as M.smegmatis, M.intracellulare, M.ehelonei, M.xenopeiand; Shown the better inhibited effect, and positive cooperativity has been arranged with the antitubercular agent vazadrine.
Though plumbagin has above-mentioned remarkable pharmacologically active, its poorly water-soluble, toxicity are big etc., and characteristics have seriously limited its further research and development as potential drug.Although some researchists have carried out base group modification and modification to plumbagin in recent years, obtained some plumbagin verivates, and failed to significantly improve that it is water-soluble, (like anti-tumor activity) also fails to obtain significant raising aspect pharmacologically active.
Summary of the invention
The technical problem that the present invention will solve provides a kind of water-soluble good than plumbagin, and can keep plumbagin-5-O-glucose and the compound method and the application of plumbagin anti-tumor activity.
The applicant synthesizes plumbagin-5-O-glucose (molecular weight is 350g/mol) with plumbagin and the reaction of 2-bromo glucose ester, and its structural formula is shown below:
Figure BDA0000153281800000021
The preparation method of above-mentioned plumbagin-5-O-glucose gets plumbagin and silver suboxide and places acetonitrile to form suspension, gets then to drip in above-mentioned suspension after 2-bromo glucose ester dissolves with acetonitrile; Lucifuge stirring reaction 12～48h, reacting liquid filtering, recovery solvent, the gained resistates dissolves with methylene dichloride; With the saturated sodium bicarbonate solution extraction, extract surplus washing mutually, anhydrous magnesium sulfate drying; Reclaim solvent then, obtain the dark brown solid product; With silica gel column chromatography on the dark brown solid product, be that 3～10: 1 sherwood oil and ETHYLE ACETATE mixed solution are eluent with volume ratio, obtain intermediate product plumbagin-5-O-glucose ester; The gained intermediate product uses volume ratio, and mixed solvent that to be 1: 1～5 methylene dichloride form with methyl alcohol dissolves; Add sodium methylate stirring reaction 4～12h then; Concentrating under reduced pressure boils off most of solvent; Silica gel column chromatography on the residuum wet method is that 15～50: 1 chloroform and methyl alcohol mixed liquor are eluent with volume ratio, promptly gets title product plumbagin-5-O-glucose.
The preparation method of more concrete plumbagin-5-O-glucose may further comprise the steps:
1) by plumbagin: the proportioning of silver suboxide: acetonitrile=10mmol: 10mmol: 50～200mL takes by weighing each raw material, places acetonitrile to form suspension plumbagin and silver suboxide, gets then to drip in above-mentioned suspension after 8～20mmol 2-bromo glucose ester dissolves with an amount of acetonitrile; Lucifuge stirring reaction 12～48h, reacting liquid filtering, filtrating is reclaimed solvent; The gained resistates dissolves with methylene dichloride; With saturated sodium bicarbonate solution extraction 3～4 times, extract surplus washing mutually, anhydrous magnesium sulfate drying; Reclaim solvent then, obtain the dark brown solid product;
2) with silica gel column chromatography on the dark brown solid product, be that 3～10: 1 sherwood oil and ETHYLE ACETATE mixed solution are eluent with volume ratio, the elutriant solvent evaporated obtains intermediate product plumbagin-5-O-glucose ester;
3) getting the intermediate product plumbagin of 1mmol-5-O-glucose ester to use volume ratio be 1: 1～5 methylene dichloride the mixed solvent of forming with methyl alcohol dissolves; The sodium methylate that adds 1～3 times of intermediate product molar weight then stirs 4～12h; Concentrating under reduced pressure is removed 80～95% solvent, and silica gel column chromatography on the residuum wet method is that 15～50: 1 chloroform and methyl alcohol mixed liquor are eluent with volume ratio; The elutriant solvent evaporated promptly gets title product plumbagin-5-O-glucose.
In the aforesaid method,
In the step 1), the acetonitrile consumption that is used to dissolve 2-bromo glucose ester is preferably 30～100mL.In this step, preferably preparation forms suspension under 30～60 ℃ condition; The consumption of methylene dichloride is generally 20～100mL; During each the extraction, the consumption of saturated sodium bicarbonate solution is advisable with 10～20mL.
In the step 1); Before adding 2-bromo glucose ester;
Figure BDA0000153281800000031
molecular sieve that can add 5～10g earlier; Reducing the moisture content in the reaction solution, thereby more help the carrying out that react.
Step 2) in, the volume ratio of sherwood oil and ETHYLE ACETATE is preferably 5: 1.
In the step 3), the volume ratio of said chloroform and methyl alcohol is preferably 20～30: 1.In this step, the consumption that is used to dissolve the mixed solvent of intermediate product plumbagin-5-O-glucose ester can be selected as required, specifically can be the mixed solvent dissolving of the intermediate product of 1mmol with 15～60mL; When the concentrating under reduced pressure steaming desolventized, temperature was controlled at 25～50 ℃ usually.
The present invention also comprises the application of above-mentioned plumbagin-5-O-glucose in the preparation antitumor drug.
The present invention also comprises with above-mentioned plumbagin-5-O-glucose being the antitumor drug of effective ingredient preparation.
Compared with prior art; The present invention is active parent nucleus with plumbagin, through glycosylation, has synthesized plumbagin-5-O-glucose; It is water-soluble to significantly improve water-soluble not good enough problem when efficiently solving plumbagin as potential antitumor drug than plumbagin; The applicant is through investigating the proliferation inhibition activity of plumbagin-5-O-glucose to multiple human tumor cell line; The result shows that its anti-tumor activity still keeps under the water-soluble condition that significantly improves; Have potential preferably pharmaceutical use, be expected to be used for various preparing anti-tumor medicine.
Description of drawings
The proton nmr spectra spectrogram of the final product that Fig. 1 makes for the embodiment of the invention 1;
The carbon-13 nmr spectra spectrogram of the final product that Fig. 2 makes for the embodiment of the invention 1;
The electrospray ionization mass spectrum spectrogram of the final product that Fig. 3 makes for the embodiment of the invention 1.
Embodiment
With embodiment the present invention is described further below, but the present invention is not limited to these embodiment.
Embodiment 1:
1) takes by weighing plumbagin and silver suboxide (Ag respectively 2O) each 10mmol is measured acetonitrile (MeCN) solvent 80mL, and plumbagin and silver suboxide are added in the acetonitrile solvent, and thorough mixing becomes the suspension form under 50 ℃ of conditions; In suspension, add 5g's then
Figure BDA0000153281800000032
Molecular sieve is got 10mmol 2-bromo glucose ester again and is dissolved in the 100mL acetonitrile solvent, and progressively drops in the above-mentioned suspension lucifuge stirring reaction 24h; Reacting liquid filtering, filtrating is reclaimed acetonitrile solvent, and the gained resistates is with the dissolving of 50mL methylene dichloride, again with saturated NaHCO 3Solution extraction 3 times (each consumption 15mL) extracts surplus phase (being the dichloromethane solution of product) with the washing that is equivalent to its 3 times of volumes, uses anhydrous magnesium sulfate thorough drying 24h again, reclaims methylene dichloride then, obtains the dark brown solid product;
2) with silica gel column chromatography on the dark brown solid product; With volume ratio is that 5: 1 sherwood oil and ETHYLE ACETATE mixed solution is the eluent wash-out; The elutriant solvent evaporated obtains yellow solid product, and this is intermediate product plumbagin-5-O-glucose ester (reaction yield 65%);
3) take by weighing plumbagin-5-O-glucose ester of 1mmol, be dissolved in 40mL exsiccant CH 2Cl 2And CH 3Mixed solvent (the CH that OH forms 2Cl 2And CH 3The volume ratio of OH is 1: 4) in; Add the 1mmol sodium methylate then, at room temperature stir 10h, concentrating under reduced pressure boils off 90% mixed solvent under 40 ℃ of conditions; The residue mother liquor is mixed silica gel column chromatography on the silica gel wet method; With volume ratio is that 25: 1 chloroform and methyl alcohol mixed liquor is the eluent wash-out, and the elutriant solvent evaporated obtains yellow solid product (reaction yield 88%).
The gained yellow solid product is identified:
(1), proton nmr spectra and carbon spectrum, their spectrogram is as illustrated in fig. 1 and 2 respectively. 1H?NMR(500MHz，CD 3OD)：δ7.82(dd，J＝6.5Hz，J＝2.5Hz，1H，H9)，7.74(m，2H，H8and?H7)，6.79(s，1H，H10)，4.99(d，J＝7.5Hz，1H，H1)，3.93(m，1H，H2)，3.74(dd，J＝12.0Hz，J＝6.9Hz，1H，H5)，3.63(m，1H，H3)，3.52(m，2H，H6)，3.44(m，1H，H4)，2.13(s，3H，H11)；
13C NMR (125MHz, CD 3OD): δ 185.2,184.9 (the two carbonylic carbon atoms of naphthoquinones ring); 157.2,146.6,137.1,134.8,133.9,123.7,121.2,102.7 (naphthoquinones ring skeleton carbon atoms); 77.3,76.1,73.4,69.9,61.2 (sugar ring skeleton carbon atoms); (14.4 naphthoquinones cyclohexyl methyl carbon atom).
(2), electrospray ionization mass spectrum, its spectrogram is as shown in Figure 3.
ESI-MS?m/z：349.15[M-H] -.
Therefore, can confirm that the yellow solid product of gained is plumbagin-5-O-glucose, its structural formula is following:
Figure BDA0000153281800000041
Embodiment 2
1) take by weighing each 6mmol of plumbagin and silver suboxide respectively, measure acetonitrile solvent 60mL, plumbagin and silver suboxide are added in the acetonitrile solvent, thorough mixing becomes the suspension form under 30 ℃ of conditions; In suspension, add 4g's then
Figure BDA0000153281800000042
Molecular sieve is got 5mmol 2-bromo glucose ester again and is dissolved in the 50mL acetonitrile solvent, and progressively drops in the above-mentioned suspension lucifuge stirring reaction 48h; Reacting liquid filtering, filtrating is reclaimed acetonitrile solvent, and the gained resistates is with the dissolving of 20mL methylene dichloride, again with saturated NaHCO 3Solution extraction 4 times (each consumption 10mL) extracts surplus phase (being the dichloromethane solution of product) with the washing that is equivalent to its 5 times of volumes, uses anhydrous magnesium sulfate thorough drying 20h again, reclaims methylene dichloride then, obtains the dark brown solid product;
2) with silica gel column chromatography on the dark brown solid product; With volume ratio is that 8: 1 sherwood oil and ETHYLE ACETATE mixed solution is the eluent wash-out; The elutriant solvent evaporated obtains yellow solid product, and this is intermediate product plumbagin-5-O-glucose ester (reaction yield 60%);
3) take by weighing plumbagin-5-O-glucose ester of 2mmol, be dissolved in 120mL exsiccant CH 2Cl 2And CH 3Mixed solvent (the CH that OH forms 2Cl 2And CH 3The volume ratio of OH is 1: 5) in, add the 3mmol sodium methylate then, at room temperature stir 12h; Concentrating under reduced pressure boils off 95% mixed solvent under 50 ℃ of conditions; The residue mother liquor is mixed silica gel column chromatography on the silica gel wet method, is that 15: 1 chloroform and methyl alcohol mixed liquor is the eluent wash-out with volume ratio, the elutriant solvent evaporated; Obtain yellow solid product, this is title product plumbagin-5-O-glucose (reaction yield 72%).
Embodiment 3
1) take by weighing each 10mmol of plumbagin and silver suboxide respectively, measure acetonitrile solvent 200mL, plumbagin and silver suboxide are added in the acetonitrile solvent, thorough mixing becomes the suspension form under 40 ℃ of conditions; Get 10mmol 2-bromo glucose ester again and be dissolved in the 60mL acetonitrile solvent, and progressively drop in the above-mentioned suspension lucifuge stirring reaction 20h; Reacting liquid filtering, filtrating is reclaimed acetonitrile solvent, and the gained resistates is with the dissolving of 100mL methylene dichloride, again with saturated NaHCO 3Solution extraction 3 times (each consumption 15mL) extracts surplus phase (being the dichloromethane solution of product) with the washing that is equivalent to its 1 times of volume, uses anhydrous magnesium sulfate thorough drying 15h again, reclaims methylene dichloride then, obtains the dark brown solid product;
2) with silica gel column chromatography on the dark brown solid product; With volume ratio is that 3: 1 sherwood oil and ETHYLE ACETATE mixed solution is the eluent wash-out; The elutriant solvent evaporated obtains yellow solid product, and this is intermediate product plumbagin-5-O-glucose ester (reaction yield 50%);
3) take by weighing plumbagin-5-O-glucose ester of 1mmol, be dissolved in 15mL exsiccant CH 2Cl 2And CH 3Mixed solvent (the CH that OH forms 2Cl 2And CH 3The volume ratio of OH is 1: 1) in, add the 3mmol sodium methylate then, at room temperature stir 6h; Concentrating under reduced pressure boils off 80% mixed solvent under 25 ℃ of conditions; The residue mother liquor is mixed silica gel column chromatography on the silica gel wet method, is that 30: 1 chloroform and methyl alcohol mixed liquor is the eluent wash-out with volume ratio, the elutriant solvent evaporated; Obtain yellow solid product, this is title product plumbagin-5-O-glucose (reaction yield 66%).
Embodiment 4
1) take by weighing each 8mmol of plumbagin and silver suboxide respectively, measure acetonitrile solvent 40mL, plumbagin and silver suboxide are added in the acetonitrile solvent, thorough mixing becomes the suspension form under 60 ℃ of conditions; Get 16mmol 2-bromo glucose ester again and be dissolved in the 80mL acetonitrile solvent, and progressively drop in the above-mentioned suspension lucifuge stirring reaction 12h; Reacting liquid filtering, filtrating is reclaimed acetonitrile solvent, and the gained resistates is with the dissolving of 70mL methylene dichloride, again with saturated NaHCO 3Solution extraction 4 times (each consumption 10mL) extracts surplus phase (being the dichloromethane solution of product) with the washing that is equivalent to its 2 times of volumes, uses anhydrous magnesium sulfate thorough drying 30h again, reclaims methylene dichloride then, obtains the dark brown solid product;
2) with silica gel column chromatography on the dark brown solid product; With volume ratio is that 10: 1 sherwood oil and ETHYLE ACETATE mixed solution is the eluent wash-out; The elutriant solvent evaporated obtains yellow solid product, and this is intermediate product plumbagin-5-O-glucose ester (reaction yield 62%);
3) take by weighing plumbagin-5-O-glucose ester of 2mmol, be dissolved in 80mL exsiccant CH 2Cl 2And CH 3Mixed solvent (the CH that OH forms 2Cl 2And CH 3The volume ratio of OH is 1: 3) in, add the 2mmol sodium methylate then, at room temperature stir 4h; Concentrating under reduced pressure boils off 85% mixed solvent under 30 ℃ of conditions; The residue mother liquor is mixed silica gel column chromatography on the silica gel wet method, is that 50: 1 chloroform and methyl alcohol mixed liquor is the eluent wash-out with volume ratio, the elutriant solvent evaporated; Obtain yellow solid product, this is title product plumbagin-5-O-glucose (reaction yield 85%).
In order to prove absolutely the plumbagin of the present invention-purposes of 5-O-glucose in pharmacy, the applicant has carried out anti-tumor activity experiment and solubility experiment to plumbagin-5-O-glucose and plumbagin respectively.
One, plumbagin and plumbagin-5-O-glucose is tested the proliferation inhibition activity of multiple human tumor cell line:
1, cell strain and cell cultures
Colon cancer cell HCT-116, liver cancer cell BEL-7404, adenocarcinoma of stomach cell SGC-7901, cervical cancer cell HeLa, lung cell A549 and 7 kinds of human tumor cell lines such as breast cancer cell MCF-7 and mouse leukemia cell L1210 are selected in this experiment for use.
The all cells strain is all cultivated in the RPMI-1640 nutrient solution that contains the little ox blood of 10wt%, 100U/mL penicillium mould, 100U/mL Streptomycin sulphate, puts 37 ℃ and contains volumetric concentration 5%CO 2Cultivate in the incubator.
2, the preparation of testing compound
The purity of used plumbagin-5-O-glucose and plumbagin all>=95%; The DMSO liquid storage of two kinds of compounds all is mixed with the whole solution of 250 μ mol/L after dilution; Solubility promoter DMSO final concentration≤1% is wherein tested under this concentration compound to the inhibition degree of various growth of tumour cell.
3, cell growth inhibition test (mtt assay)
The tumour cell of (1) taking the logarithm vegetative period; Behind tryptic digestion; The nutrient solution that use contains 10% calf serum is mixed with the cell suspension that concentration is 5000/ml; Be inoculated in 96 well culture plates with every hole 190 μ l, make cell density to 1000 to be measured～10000 holes (marginal pore is filled with aseptic PBS);
(2) 5%CO 2, hatch 24h for 37 ℃, be paved with the hole to cell monolayer at the bottom of, every hole adds the medicine 10 μ l of finite concentration gradient, each concentration gradient is established 4 multiple holes;
(3) 5%CO 2, to hatch 48 hours for 37 ℃, inverted microscope is observed down;
(4) every hole adds the MTT solution (5mg/ml PBS, i.e. 0.5%MTT) of 10 μ l, continues to cultivate 4h;
(5) stop to cultivate, the careful suction goes the nutrient solution hole in, every hole to add 150 μ lDMSO fully to dissolve first a ceremonial jade-ladle, used in libation deposition, behind the vibrator mixing, use wavelength to be 570nm at ELIASA, and reference wavelength is the OD value in each hole of 450nm mensuration;
(6) zeroing hole (substratum, MTT, DMSO), control wells (the medicine dissolution medium of cell, same concentrations, nutrient solution, MTT, DMSO) are set simultaneously.
(7) according to the OD value (OD value) that records, judge viable cell quantity, the OD value is big more, and cytoactive is strong more.Utilize formula:
Figure BDA0000153281800000071
Calculate the inhibiting rate of medicine to growth of tumour cell.Its test result is shown in following table 1.
Table 1: plumbagin and plumbagin-5-O-glucose when 250 μ M to the growth inhibition ratio (%) of different tumor cell lines
Figure BDA0000153281800000072
From the primary dcreening operation result, plumbagin-5-O-glucose is compared with plumbagin, and is except that the inhibiting rate to the human lung cancer cell A549 is starkly lower than the plumbagin, active all suitable with plumbagin to the inhibition of other 6 kinds of tumour cells.Wherein, plumbagin-5-O-glucose all has more active than higher inhibition for human liver cancer cell BEL-7404, adenocarcinoma of stomach cell SGC-7901, breast cancer cell MCF-7 and mouse leukemia cell L1210.This shows that under the concentration of 250 μ M, plumbagin-5-O-glucose can be controlled the growth of cell uncontrolled through suppressing tumor cell proliferation well.
Can find out by The above results; Plumbagin of the present invention-5-O-glucose is compared with plumbagin; On the basis that water-soluble significantly improves; Aggregate performance has gone out the anti tumor activity in vitro suitable with plumbagin, has potential preferably pharmaceutical use, is expected to be used for various preparing anti-tumor medicine.
Two, the solubility experiment of plumbagin and plumbagin-5-O-glucose:
Experimental technique: accurately take by weighing plumbagin-5-O-glucose 0.1g that the present invention makes, place the 100mL small beaker; Under 25 ℃ of water-baths and continuous stirring condition; Add zero(ppm) water on a small quantity makes it to dissolve gradually repeatedly; Guaranteeing on the abundant dissolved basis, confirming all required water yields of dissolving of compound, thereby converse the solubility values (unit: g/100g water) of compound in water.
Experimental result: the solubleness of plumbagin-5-O-glucose is 0.65g/100g water;
The experimental technique of plumbagin solubleness is the same, and experimental result shows that plumbagin is water-soluble hardly at normal temperatures, and solubleness is approximately 0.
Thus it is clear that, the water-soluble plumbagin that obviously is superior to of plumbagin of the present invention-5-O-glucose.

Claims (9)

1. plumbagin-5-O-glucose, its structural formula is shown below:
2. the preparation method of the described plumbagin of claim 1-5-O-glucose is characterized in that: get plumbagin and silver suboxide and place acetonitrile to form suspension, get 2-bromo glucose ester then and drip in above-mentioned suspension after with the acetonitrile dissolving; Lucifuge stirring reaction 12～48h, reacting liquid filtering, recovery solvent, the gained resistates dissolves with methylene dichloride; With the saturated sodium bicarbonate solution extraction, extract surplus washing mutually, anhydrous magnesium sulfate drying; Reclaim solvent then, obtain the dark brown solid product; With silica gel column chromatography on the dark brown solid product, be that 3～10: 1 sherwood oil and ETHYLE ACETATE mixed solution are eluent with volume ratio, obtain intermediate product plumbagin-5-O-glucose ester; The gained intermediate product uses volume ratio, and mixed solvent that to be 1: 1～5 methylene dichloride form with methyl alcohol dissolves; Add sodium methylate stirring reaction 4～12h then; Concentrating under reduced pressure boils off most of solvent; Silica gel column chromatography on the residuum wet method is that 15～50: 1 chloroform and methyl alcohol mixed liquor are eluent with volume ratio, promptly gets title product plumbagin-5-O-glucose.
3. the preparation method of plumbagin according to claim 2-5-O-glucose is characterized in that: may further comprise the steps:
1) by plumbagin: the proportioning of silver suboxide: acetonitrile=10mmol: 10mmol: 50～200mL takes by weighing each raw material, places acetonitrile to form suspension plumbagin and silver suboxide, gets then to drip in above-mentioned suspension after 8～20mmol 2-bromo glucose ester dissolves with an amount of acetonitrile; Lucifuge stirring reaction 12～48h, reacting liquid filtering, filtrating is reclaimed solvent; The gained resistates dissolves with methylene dichloride; With saturated sodium bicarbonate solution extraction 3～4 times, extract surplus washing mutually, anhydrous magnesium sulfate drying; Reclaim solvent then, obtain the dark brown solid product;
2) with silica gel column chromatography on the dark brown solid product, be that 3～10: 1 sherwood oil and ETHYLE ACETATE mixed solution are eluent with volume ratio, the elutriant solvent evaporated obtains intermediate product plumbagin-5-O-glucose ester;
3) the intermediate product plumbagin-5-O-glucose ester mixed solvent that to use volume ratio be 1: 1～5 methylene dichloride forms with methyl alcohol is dissolved; The sodium methylate that adds 1～3 times of intermediate product molar weight then stirs 4～12h; Concentrating under reduced pressure is removed 80～95% solvent, and silica gel column chromatography on the residuum wet method is that 15～50: 1 chloroform and methyl alcohol mixed liquor are eluent with volume ratio; The elutriant solvent evaporated promptly gets title product plumbagin-5-O-glucose.
4. the preparation method of plumbagin according to claim 3-5-O-glucose; It is characterized in that: in the step 1); Before adding 2-bromo glucose ester, add
Figure FDA0000153281790000021
molecular sieve of 5～10g earlier.
5. the preparation method of plumbagin according to claim 3-5-O-glucose is characterized in that: in the step 1), the acetonitrile consumption that is used to dissolve 2-bromo glucose ester is 30～100mL.
6. the preparation method of plumbagin according to claim 3-5-O-glucose is characterized in that: step 2) in, the volume ratio of sherwood oil and ETHYLE ACETATE is 5: 1.
7. the preparation method of plumbagin according to claim 3-5-O-glucose is characterized in that: in the step 3), the volume ratio of chloroform and methyl alcohol is 20～30: 1.
8. the application of the described plumbagin of claim 1-5-O-glucose in the preparation antitumor drug.
9. with the described plumbagin of claim 1-5-O-glucose the antitumor drug of effective ingredient preparation.
CN2012101087323A 2012-04-14 2012-04-14 Plumbagin-5-O-glucose and synthetic method and application thereof Pending CN102617664A (en)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
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Publication number Priority date Publication date Assignee Title
CN101037447A (en) * 2006-03-17 2007-09-19 广西师范大学 Metal complex using plumbagin as ligand, synthesizing method and usage thereof
WO2012018948A2 (en) * 2010-08-04 2012-02-09 Pellficure Pharmaceuticals, Inc. Novel treatment of prostate carcinoma

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SUBHASH PADHYE，等: "Perspectives on Medicinal Properties of Plumbagin and Its Analogs", 《MEDICINAL RESEARCH REVIEWS》 *
卫生部药政管理局: "《新药（西药）临床前研究指导原则汇编（药学 药理学 毒理学）》", 31 July 1993 *
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Application publication date: 20120801