CN101130566A - Method of preparing 23,24-dihydrocucurbitacin B and use of the same in medicament for treating tumour - Google Patents
Method of preparing 23,24-dihydrocucurbitacin B and use of the same in medicament for treating tumour Download PDFInfo
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- CN101130566A CN101130566A CNA200710070792XA CN200710070792A CN101130566A CN 101130566 A CN101130566 A CN 101130566A CN A200710070792X A CNA200710070792X A CN A200710070792XA CN 200710070792 A CN200710070792 A CN 200710070792A CN 101130566 A CN101130566 A CN 101130566A
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- QZJJDOYZVRUEDY-NRNCYQGDSA-N dihydrocucurbitacin B Chemical compound C([C@H]1[C@]2(C)C[C@@H](O)[C@@H]([C@]2(CC(=O)[C@]11C)C)[C@@](C)(O)C(=O)CCC(C)(C)OC(=O)C)C=C2[C@H]1C[C@H](O)C(=O)C2(C)C QZJJDOYZVRUEDY-NRNCYQGDSA-N 0.000 title claims abstract description 18
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses a preparing method of 23,24-dihydrocucurbitacin B and usage to treat tumor disease medicine, which comprises the following steps: using adverse current chromatogram; proceeding primary separation for acetic acid ethyl ester extract of trichosanthes anguina root; choosing two phase dissolvent system from light petroleum, chloroform and acetonitrile; merging and collecting the compound with cell toxic property; proceeding against phase high effective liquid phase color spectrum preparation with flowing phase as methanol and water gradient elution; collecting goal matter; volatilizing dissolvent; getting white crystalline powder; getting the product. This invention can be used to prepare the medicine of breast cancer, liver cancer and large intestine cancer, which possesses wide prospect.
Description
Technical field
The present invention relates to medical technical field, method of extracting effective components and uses thereof from vegetable material specifically, especially from snakegourd (Trichosanthes kirilowli Maxim) root, extract 23, the method for 2-dihydro Cucurbitacin B and the purposes in the preparation antitumor drug thereof.
Background technology
23,24-dihydro Cucurbitacin B (23,24-dihydrocucurbitacin B) is a kind of cucurbit alkanes material that is distributed in widely in the various plants, and its molecular formula is C
32H
48O
8, molecular weight 560, its chemical structure is as follows:
People are at Wilbrandia ebracteata Cogn.
[1], Cayaponia tayuya
[2,3], Begonia nantornsis
[4], Bryonia Verrucosa
[5]And Trichosanthes Kirilowli
[6]All finding in the plants such as (snakegourds) has 23, the distribution of 24-dihydro Cucurbitacin B.But, traditional separation preparation 23, the method for 24-dihydro Cucurbitacin B such as purification on normal-phase silica gel thin-layer chromatography
[5], normal phase silica gel column chromatography
[1], gel filtration chromatography
[3]Etc. method because the dead absorption of solid phase carrier makes isolating productive rate and efficient all very low, and the efficient liquid-phase chromatography method of development only is used for its purity check and evaluation, therefore, also do not have a kind ofly can prepare 23 in a large number quickly and efficiently, the method for 24-dihydro Cucurbitacin B.
At present, 23, the similar material of 24-dihydro Cucurbitacin B such as Cucurbitacin B, cucurbitacin I and cucurbitacin Q etc. find that strong anti-tumor activity is arranged, but for 23, the antitumor research report of 24-dihydro Cucurbitacin B seldom, one of its reason is 23, and 24-dihydro Cucurbitacin B is compared with its these similar cucurbit alkanes materials, and its cytotoxicity is much lower relatively.But development low toxicity antitumor drug efficiently is the main flow direction of current tumour medicine development.Existing studies show that, 23,24-dihydro Cucurbitacin B has good anti-inflammatory activity
[1,3], can reduce the arthritic damage of adjuvant type
[2]Simultaneously, 23,24-dihydro Cucurbitacin B is HONE-1 to SGC-7901 NUGC-3, KB cell
[4], human lung adenocarcinoma A549, ovarian cancer SK-OV-3, melanoma SK-MEL-2, central nerve neuroma XF498 and colorectal carcinoma HCT15
[6]Deng having certain cytotoxicity, but do not appear in the newspapers for its restraining effect, do not see yet it is studied by the mechanism that inducing apoptosis of tumour cell suppresses tumor growth breast cancer cell line Bcap37, breast cancer cell line MCF-7, hepatoma cell line SMMC-7721, colorectal carcinoma cell line SW620, erythroleukemia cell line k562 and cervical cancer tumer line HeLa.
Summary of the invention
An object of the present invention is to provide and a kind ofly prepare 23 fast, efficiently, in a large number, the method for 24-dihydro Cucurbitacin B (23,24-dihydrocucurbitacin B).This 23, the molecular formula of 24-dihydro Cucurbitacin B is C
32H
48O
8, molecular weight 560, CAS nmuber:13201-14-4 belongs to the cucurbitane compounds.
Another object of the present invention provides 23, the purposes of 24-dihydro Cucurbitacin B in treatment tumor disease medicine.
23, the preparation method of 24-dihydro Cucurbitacin B, its step is as follows:
At first use adverse current chromatogram to carry out initial gross separation the ethyl acetate extract of radices trichosanthis, used two phase solvent system is sherwood oil, chloroform, acetonitrile, merge the cytotoxic component of collection then and carry out C8 or the preparation of C18 RPLC, moving phase is the methanol-water gradient elution of 10%-100%, collect target substance, get white crystalline powder behind the solvent flashing, be purpose compound 23,24-dihydro Cucurbitacin B.
Of the present invention 23, the application of 24-dihydro Cucurbitacin B in treatment tumor disease medicine.
The prepared antitumor drug of the present invention is 23, the composition that the single preparation of 24-dihydro Cucurbitacin B or the pharmaceutical excipient that allows with other preparation, carrier or its synergistic agent are formed, these medicines be smelting treatment mammary cancer, cervical cancer, liver cancer, large bowel cancer, erythroleukemia by cell death inducing.
Medicine provided by the invention also can comprise other synergistic agent in its preparation, comprise antitumor drug.
Medicine provided by the invention can be made following dosage form by this formulation art perception method in the sixth of the twelve Earthly Branches: comprise liquid preparation, granule, tablet, electuary, soft capsule, soft capsule, pill or injection.
Medicine provided by the invention, the administering mode of preparation comprises oral administration or drug administration by injection.
Beneficial effect of the present invention is:
1) technology of preparing that adopts adverse current chromatogram and reversed-phase preparative chromatography to combine innovatively prepare high-purity 23,24-dihydro Cucurbitacin B.Advantages such as the preparation amount that utilizes the adverse current chromatogram technology of preparing to have is big, sample is harmless are carried out the primary separation of sample, can guarantee the acquisition of quick, the high yield of target components; The target components that is obtained uses efficiently C8 or C18 RPLC to carry out purifying again, can guarantee high purity, the high-level efficiency preparation of target component.
2) provided 23,24-dihydro Cucurbitacin B antitumor drug has the effect of external strongly inhibited tumor cell proliferation, detects through tetramethyl-azo azoles salt (abbreviation mtt assay), and the half of mammary cancer Bcap37 is suppressed proliferation rate IC
50Be about 0.5 μ g/ml, to the half inhibition proliferation rate IC of cervical cancer Hela, erythroleukemia K562
50Be about 1.5 μ g/ml, to the half inhibition proliferation rate IC of mammary cancer MCF-7, large bowel cancer SW620
50Be about 2.5 μ g/ml, to the half inhibition proliferation rate IC of liver cancer SMMC-7721
50Be about 5 μ g/ml.And, antitumor drug provided by the invention, its main mechanism that suppresses tumor proliferation is inducing apoptosis of tumour cell, its apoptotic process is finished by the plastosome approach, and 23,24-dihydro Cucurbitacin B acts on the G of Bcap37
2Thereby/M the phase causes apoptosis of tumor cells.Therefore it makes up as the single preparation or with drug dressing, all can use in preparation treatment malignant tumor medicine.The present invention provides scientific basis for developing new anti-malignant tumor medicine, and is significant to development and use China traditional Chinese medicine.
Description of drawings
Fig. 1 is prepared 23, the liquid-phase chromatographic analysis of the pure product of 24-dihydro Cucurbitacin B;
Fig. 2 is under the different concns 23, and 24-dihydro Cucurbitacin B is to mammary cancer Bcap37, erythroleukemia K562, liver cancer SMMC-7721, large bowel cancer SW620, mammary cancer MCF-7, the in-vitro multiplication inhibiting rate broken line graph of 6 strain tumour cells such as cervical cancer Hela;
Fig. 3 is under the different concns 23, and 24-dihydro Cucurbitacin B is to the time-dependent curve of breast cancer cell line Bcap37;
Fig. 4 is 23 of 3.6 μ M, and 24-dihydro Cucurbitacin B causes the gel electrophoresis figure of the dna ladder shape band of the form fluorogram of mammary cancer Bcap37 apoptosis and generation;
Fig. 5 is 23 of 3.6 μ M, and 24-dihydro Cucurbitacin B acts on the cell cycle analysis of mammary cancer Bcap37;
Fig. 6 is 23 of 3.6 μ M, and 24-dihydro Cucurbitacin B different time acts on the two apoptosis figure that dye of AnnexinV-PI of mammary cancer Bcap37;
Fig. 7 is 23 of 3.6 μ M, the apoptosis-related protein caspase-1 of mammary cancer Bcap37 under the effect of 24-dihydro Cucurbitacin B, 3,8,9 active broken line graph and adding caspase-family thereof, caspase-3 influences the histogram of the external survival rate of mammary cancer Bcap37 under the caspase-9 inhibitor situation;
Fig. 8 is 23 of 3.6 μ M, and 24-dihydro Cucurbitacin B acts on the western blot figure that cuts PARP, cytochrome c release conditions in the mammary cancer Bcap37 process.
Embodiment
Further specify the present invention below in conjunction with drawings and Examples.These examples only are used to illustrate the present invention, and are not used in the restriction scope of the invention.
Embodiment 1:23, the prepared in high purity of 24-dihydro Cucurbitacin B
At first will use sherwood oil (2L) and ethyl acetate (3L) to extract after fresh radices trichosanthis (3950g) freeze-drying successively.Gained acetic acid ethyl acetate extract low temperature removes and desolvates, and obtains ethyl acetate extract.(source natural drug and the development of biotoxin research centre are thought by Zhejiang University with three shaft vertical counter current chromatographs to get the 2.5g ethyl acetate extract then, column capacity 600ml) carries out initial gross separation, used two phase solvent system is sherwood oil, chloroform, acetonitrile (volume ratio, 6: 1: 3), merge component then.At last cytotoxic component in the collected component is carried out the preparation of C8 or C18 RPLC, moving phase is the methanol-water gradient elution of 10%-100%, collect target substance, get white crystalline powder (15.3mg) behind the solvent flashing, through mass spectrum, a peacekeeping two dimensional NMR spectrum analysis, and and document
[4,7-9]The comparison, determine that its structure is 23,24-dihydro Cucurbitacin B, its liquid phase analysis as shown in Figure 1, its purity reaches more than 98.5%.It is highly purified 23 that the result shows that this method only needs two step chromatographic runs to obtain easily, and 24-dihydro Cucurbitacin B is convenient to the production of mass-producing.
Embodiment 2:23,24-dihydro Cucurbitacin B is tested the human tumor cell line proliferation inhibition activity
Experimental technique
(1) human tumor cell line and source: doing six tumor lines altogether is respectively mammary cancer Bcap37, mammary cancer MCF-7, cervical cancer HeLa, liver cancer SMMC-7721, large bowel cancer SW620, erythroleukemia K562, all comes from the Zhejiang University institute of oncology.
(2) 23,24-dihydro Cucurbitacin B is dissolved in and is made into the 1mg/ml mother liquor among the DMSO, place-20 ℃ of refrigerators, being diluted to final concentration with nutrient solution during experiment is that 0,0.6,1.1,2.2,4.5,8.9,35.7 μ M are for using, MTT (AMRESCO company product) is made into the 2mg/ml mother liquor with phosphoric acid buffer (Phosphate-buffered Saline is called for short PBS), places 4 ℃ of refrigerators standby.
(3) cell cultures: all cells all is incubated at the RPMI-1640 complete culture solution, (SIGMA), adds 10% new-born calf serum (Hangzhou Sijiqing Biological Engineering Material Co., Ltd.), 100U/ml Streptomycin sulphate and 100U/ml penicillin.Select the logarithmic phase cell, with 1 * 10
4Density be inoculated in 96 orifice plates, add medicine by concentration, put 37 ℃, in 5% incubator, cultivate usefulness Olympus IX70 universal microscope (penguin 600CL CCD, Pixera) Taking Pictures recording after 48 hours.
(4) adopt tetramethyl-azo azoles salt (abbreviation mtt assay) to detect the influence of tumour cell, select the logarithmic phase cell, with 1 * 10 to medicine propagation
4Density be inoculated in 96 orifice plates, every hole 200 μ l put 37 ℃, cultivate in 5% incubator after 4 hours to add medicine by concentration, each concentration is established 6 in multiple hole, establishes blank simultaneously, puts 37 ℃, 5%CO
2Cultivated 48 hours in the incubator, nutrient solution in the sucking-off orifice plate (attached cell), adding concentration in every hole is the MTT 50 μ l of 2mg/ml, putting into incubator continues to cultivate 4 hours, taking-up added 96 orifice plates of MTT, 2000rpm, 4 ℃ are carried out centrifugal 5min, sucking-off MTT solution gently, unnecessary MTT is cleaned with 2 of PBS solution in every hole, sucking-off PBS washing lotion, and every hole adds the DMSO of 200 μ l, light shaking orifice plate 10min, after the crystallisate for the treatment of hole bottom dissolves fully, orifice plate is put into microplate reader survey the absorbance value of wavelength, record result: experiment triplicate in each hole of 490nm.
Getting the multiple hole OD of each concentration is worth mean value, is calculated as follows cell proliferation inhibition rate:
Inhibiting rate=(OD blank-OD sample)/OD blank * 100%
Experimental result
Referring to accompanying drawing 2 and 3, the result shows 23, and 24-dihydro Cucurbitacin B suppresses tumor cell proliferation and is dosage dependence and time-dependent relation.
Embodiment 3:23,24-dihydro Cucurbitacin B suppresses the apoptosis related mechanism of mammary cancer Bcap37 propagation
(1) DNA LADDER experiment: some cell is after accepting drug effect, DNA can be cut off in the nucleosome junction by nuclease, produce the DNA fragment of 180-200bp or its integral multiple size, present well-regulated scalariform body band during agarose gel electrophoresis, this is apoptotic characteristic feature, also be to distinguish apoptosis and downright bad important symbol, whole experiment is carried out according to the operation steps of DNA apoptosis band extraction agent box (Biovision), observation experiment result under ultraviolet lamp.
Result (Fig. 4 C) shows 23 of 3.6 μ M, and 24-dihydro Cucurbitacin B is at 24h, and 36h and 48h can cause obviously that mammary cancer Bcap37 transfers and die and produce distinctive dna ladder shape band.
(2) apoptosis morphology experiment: 23 of mammary cancer Bcap37 and 3.6 μ M, after 24-dihydro Cucurbitacin B is hatched 24 hours jointly, ice ethanol fixed cell with 70%, PBS cleans twice, then dye with fluorescence dye Hoechst 33342 pair cells nuclear, lucifuge is cleaned with PBS after handling 15min again, use Olympus IX70 universal microscope (penguin 600CL CCD, Pixera) Taking Pictures recording at last.
Referring to Fig. 4 B, compare with contrast Fig. 4 A, 23 of 3.6 μ M, 24-dihydro Cucurbitacin B can cause obviously that at 24h mammary cancer Bcap37 nucleus produces the features of apoptotic form.
(3) cell cycle analysis: about 10
6The mammary cancer Bcap37 of individual logarithmic phase and 1.8,3.6 23 of μ M, 24-dihydro Cucurbitacin B was hatched 24 hours jointly, 1000rpm, 4 ℃, 5min collecting cell, PBS clean twice back and fix with 70% ice ethanol, and PBS cleans twice, 1000rpm, 4 ℃, 5min, abandoning supernatant, DNA dye liquor (20 μ g/ml ofPI with 1ml, and 100 μ g/ml ofRNase A) resuspension cell 30min is with FACScan flow cytometer (Becton Dickinson) analyzing DNA content, with the CellModiFIT software statistics cell quantity (Becton Dickinson) in each period.
Referring to accompanying drawing 5, experimental result shows 23, and 24-dihydro Cucurbitacin B acts on the G of Bcap37
2Thereby/M the phase causes apoptosis of tumor cells.
(4) AnnexinV-PI is two dyes experiment: apoptosis is early stage, phosphatidylserine on the cytolemma (PS) can be turned to outside the cytolemma in cytolemma, AnnexinV can combine with it, and the cytolemma of apoptotic cell still is kept perfectly, dyestuff PI can not enter cell and dye, therefore dye experiment by AnnexinV-PI is two, can distinguish apoptosis and non-viable non-apoptotic cell.About 10
623 of the mammary cancer Bcap37 of individual logarithmic phase and 2 μ g/ml, 24-dihydro Cucurbitacin B is hatched jointly, centrifugal collecting cell, PBS cleans twice, the AnnexinV-FITC binding buffer liquid that adds 100 μ l, the PI damping fluid of the AnnexinV-FITC of 5 μ l and 10 μ l, lucifuge is hatched 15min then, behind the Annexin V-FITC binding buffer liquid that adds 400 μ l, with FACScan flow cytometer (Becton Dickinson) analytical results.
Experimental result was seen accompanying drawing 6, shows 23 of 3.6 μ M, and 24-dihydro Cucurbitacin B just caused the Bcap37 apoptosis significantly since 6 hours.
(5) caspase-1,3,8,9 activity experiments: about 10
623 of the mammary cancer Bcap37 of individual logarithmic phase and 3.6 μ M, 24-dihydro Cucurbitacin B was hatched 0-24 hour jointly, centrifugal collecting cell is resuspended in the 50 μ l cell pyrolysis liquids, hatch 10min on ice, 10, behind the centrifugal 1min of 000xg supernatant liquor is transferred in the new 1.5ml centrifuge tube, places stand-by on ice.Extracting albumen with 50-200 μ g dilutes with 50 μ l cell pyrolysis liquids then, YVAD-pNA (caspase-1)/DEVD-pNA (caspase-3)/IETD--pNA (the caspase-8)/LEHD--pNA (caspase-9) that adds 50 μ l 2 * reaction buffers and 5 μ l 4mM again, 37 ℃ of temperature were bathed 1-2 hour, 400 or the 405nm wavelength under read the sample test data; The elementary operation of the active inhibition experiment of caspase is the same, is just adding 23, and 24-dihydro Cucurbitacin B added the caspase inhibitor of 2 μ M in advance before 6 hours.
Referring to accompanying drawing 7, experimental result shows 23 of 3.6 μ M, and 24-dihydro Cucurbitacin B can obviously activate the apoptosis-related protein caspase-1 of mammary cancer Bcap37,3,8,9 activity;
(6) Western blot experiment: 3 * 0
623 of the mammary cancer Bcap37 of individual logarithmic phase and 2 μ g/ml, 24-dihydro Cucurbitacin B was hatched 36 hours jointly, with RIPA lysate cracking 15min, 12, behind the centrifugal 20min of 000xg, measure protein concentration with Bradford, on 10%SDS-PAGE glue, carry out electrophoresis, spot on the glue spends the night and transfers on the film with PBST damping fluid (PBS containing 0.1%Tween-20) room temperature treatment, at room temperature hatch with the antibody of PARP, cytochrome c then, anti-hatch jointly with two again after the cleaning.Use ECL test kit (Amersham) observation that develops the color at last.
Referring to accompanying drawing 8, the result shows 23 of 3.6 μ M, and 24-dihydro Cucurbitacin B acts on PARP, the cytochrome c that mammary cancer Bcap37 produces and is time-dependent relation, shows 23, and 24-dihydro Cucurbitacin B is by exciting Caspase-3,9 and play apoptosis.
In sum, 23,24-dihydro Cucurbitacin B is the medicine of a kind of very effective energy smelting treatment mammary cancer, cervical cancer, liver cancer, large bowel cancer, erythroleukemia by cell death inducing, has very big potential applicability in clinical practice.
The partial reference document that the present invention relates to:
[1]J.M.Siqueira，R.R.Peters，A.C.Gazola，P.B.Krepsky，M.R.Farias，G.A.Rae，A.J.Brum-Fernandes，R.M.Ribeiro-do-Valle，Anti-inflammatory?effects?of?atriterpenoid?isolated?from?Wilbrandia?ebracteata?Cogn，Life?Sci.80(2007)1382-1387.
[2]J.M.Escandell，M.C.Recio，S.Má
ez，R.M.Giner，M.Cerdá-Nicolás，J.L.Ríos，Dihydrocucurbitacin?B，isolated?from?Cayaponia?tayuya，reduces?damage?inadjuvant-induced?arthritis，Eur.J.Pharmacol.532(2006)145-154.
[3]M.C.Recio，M.Prieto，M.Bonucelli，C.Orsi，S.Manez，R.M.Giner，M.Cerda-Nicolas，J.L.Rios，Anti-inflammatory?activity?of?two?cucurbitacinsisolated?from?Cayaponia?tayuya?roots，Planta?Medica?70(2004)414-420.
[4]P.L.Wu，F.W.Lin，T.S.Wu，C.S.Kuoh，K.H.Lee，S.J.Lee，Cytotoxic?andanti-HIV?principles?from?the?rhizomes?of?Begonia?nantoensis，Chem.Pharmaceut.Bulletin?52(2004)345-349.
[5]A.Galindo，N.Villegas，H.Mansilla，Nat.Product?Lett.13(199)285-292.
[6]Y.R.Shi，H.L.Seung，U.C.Sang，O.L.Chong，N.Zaesung，W.A.Jong，Antitumor?activity?of?Trichosanthes?kirilowii.，Arch.Pharm.Res.17(1994)348-353.
[7]M.R.Farias，E.P.Schenkel，R.Mayer，G.Rücker，Cucurbitacins?as?constituents?ofWilbrandia?ebracteata，Planta?Medica?59(1993)272-275.
[8]W.Jiratchariyakul，A.W.Frahm，Cucurbitacin?B?and?dihydrocucurbitacin?B?fromTrichosanthes?cucumerina?L.，Warasan?Phesatchasat?19(1992)5-12.
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Claims (9)
1.23, the preparation method of 24-dihydro Cucurbitacin B, said 23, the molecular formula of 24-dihydro Cucurbitacin B is C
32H
48O
8Molecular weight 560, belong to the cucurbitane compounds, it is characterized in that at first using adverse current chromatogram to carry out initial gross separation the ethyl acetate extract of radices trichosanthis, used two phase solvent system is sherwood oil, chloroform, acetonitrile, merge the cytotoxic component of collection then and carry out C8 or the preparation of C18 RPLC, moving phase is the methanol-water gradient elution of 10%-100%, collects target substance, gets white crystalline powder behind the solvent flashing, be purpose compound 23,24-dihydro Cucurbitacin B.
2.23 the purposes of 24-dihydro Cucurbitacin B in treatment tumor disease medicine is characterized in that the dihydro Cucurbitacin B makes up the application in the preparation antitumor drug as the single preparation or with medical dressing.
3. according to claim 2 23, the purposes of 24-dihydro Cucurbitacin B in treatment tumor disease medicine is characterized in that the application in preparation treatment breast cancer medicines.
4. according to claim 2 23, the purposes of 24-dihydro Cucurbitacin B in treatment tumor disease medicine is characterized in that the application in preparation treatment cervical cancer medicine.
5. according to claim 2 23, the purposes of 24-dihydro Cucurbitacin B in treatment tumor disease medicine is characterized in that the application in preparation treatment liver-cancer medicine.
6. according to claim 2 23, the purposes of 24-dihydro Cucurbitacin B in treatment tumor disease medicine is characterized in that the application in preparation treatment large bowel cancer medicine.
7. according to claim 2 23, the purposes of 24-dihydro Cucurbitacin B in treatment tumor disease medicine is characterized in that the application in preparation treatment erythroleukemia medicine.
8. according to claim 2 23, the purposes of 24-dihydro Cucurbitacin B in treatment tumor disease medicine is characterized in that the dosage form of said medicine comprises liquid preparation, granule, tablet, electuary, soft capsule, soft capsule, pill or injection.
9. according to claim 2 23, the purposes of 24-dihydro Cucurbitacin B in treatment tumor disease medicine is characterized in that the administering mode of said medicine comprises oral administration or drug administration by injection.
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| CN102659888A (en) * | 2012-03-02 | 2012-09-12 | 张南 | Cucurbitacin derivatives and preparation method thereof |
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| CN102659888A (en) * | 2012-03-02 | 2012-09-12 | 张南 | Cucurbitacin derivatives and preparation method thereof |
| CN102659888B (en) * | 2012-03-02 | 2014-07-30 | 张南 | Cucurbitacin derivatives and preparation method thereof |
| CN102659889A (en) * | 2012-03-16 | 2012-09-12 | 石河子大学 | Preparation of 23, 24-dihydro-epi-iso-cucurbitacin D and use in antitumor drug thereof |
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