CN104825437B - Alkali aster ester A and its derivative preparation and medical usage - Google Patents
Alkali aster ester A and its derivative preparation and medical usage Download PDFInfo
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- CN104825437B CN104825437B CN201510154546.7A CN201510154546A CN104825437B CN 104825437 B CN104825437 B CN 104825437B CN 201510154546 A CN201510154546 A CN 201510154546A CN 104825437 B CN104825437 B CN 104825437B
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- alkali aster
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- methanol
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- 239000003513 alkali Substances 0.000 title claims abstract description 97
- 150000002148 esters Chemical class 0.000 title claims abstract description 84
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 241000490229 Eucephalus Species 0.000 title abstract 8
- 238000000926 separation method Methods 0.000 claims abstract description 18
- 208000032612 Glial tumor Diseases 0.000 claims abstract description 13
- 206010018338 Glioma Diseases 0.000 claims abstract description 13
- 230000000694 effects Effects 0.000 claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims abstract description 9
- 201000002313 intestinal cancer Diseases 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 132
- 241000132092 Aster Species 0.000 claims description 90
- 229940119526 coniferyl alcohol Drugs 0.000 claims description 79
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 35
- 230000014759 maintenance of location Effects 0.000 claims description 25
- 239000012230 colorless oil Substances 0.000 claims description 22
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 claims description 21
- -1 hexamethylene alkane Chemical class 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 19
- 239000000284 extract Substances 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 10
- 238000010898 silica gel chromatography Methods 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 7
- 239000000401 methanolic extract Substances 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- 241000196324 Embryophyta Species 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 241001645016 Tripolium vulgare Species 0.000 claims description 4
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 claims description 4
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000001228 spectrum Methods 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 238000001819 mass spectrum Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 230000003111 delayed effect Effects 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 23
- 230000006907 apoptotic process Effects 0.000 abstract description 14
- 210000004881 tumor cell Anatomy 0.000 abstract description 13
- 230000001939 inductive effect Effects 0.000 abstract description 5
- 201000011510 cancer Diseases 0.000 abstract description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 25
- 239000012071 phase Substances 0.000 description 25
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000010521 absorption reaction Methods 0.000 description 21
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 19
- JMFRWRFFLBVWSI-NSCUHMNNSA-N coniferol Chemical compound COC1=CC(\C=C\CO)=CC=C1O JMFRWRFFLBVWSI-NSCUHMNNSA-N 0.000 description 18
- HHNLQWOVCRXGMP-UHFFFAOYSA-N laricinolic acid Natural products C1C(O)C(=C)C(C(O)=O)C2(C)C1C(C)(C)CCC2 HHNLQWOVCRXGMP-UHFFFAOYSA-N 0.000 description 14
- 150000004702 methyl esters Chemical class 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 230000006698 induction Effects 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 229940009456 adriamycin Drugs 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 229960004964 temozolomide Drugs 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OGNZVIKZDOKDLK-SYTKJHMZSA-N [4-[(E)-3-acetyloxyprop-1-enyl]-2-methoxyphenyl] (2S)-2-methylbutanoate Chemical compound CC[C@H](C)C(=O)OC1=CC=C(\C=C\COC(C)=O)C=C1OC OGNZVIKZDOKDLK-SYTKJHMZSA-N 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 3
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- NPFXDKRGVBMMSL-ZDUSSCGKSA-N (11s)-17-hydroxy-15-methoxy-11-methyl-12-oxabicyclo[12.4.0]octadeca-1(18),14,16-triene-7,13-dione Chemical compound C1CCCCC(=O)CCC[C@H](C)OC(=O)C2=C1C=C(O)C=C2OC NPFXDKRGVBMMSL-ZDUSSCGKSA-N 0.000 description 2
- 108010040476 FITC-annexin A5 Proteins 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- FIUFLISGGHNPSM-UHFFFAOYSA-N 3-(4-methoxyphenyl)propanoic acid Chemical compound COC1=CC=C(CCC(O)=O)C=C1 FIUFLISGGHNPSM-UHFFFAOYSA-N 0.000 description 1
- 108090000663 Annexin A1 Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 241000218691 Cupressaceae Species 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241001645022 Tripolium Species 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides the preparation method that separation alkali aster ester A and synthetic alkali aster ester A and its derivative are extracted from the herb of alkali aster plant.Alkali aster ester A and alkali aster ester A derivative significantly inhibit the propagation of human glioma U87 MG and U251 cell and intestinal cancer HCT 15 and SW620 cells, and inducing apoptosis of tumour cell, can be in the application in preparing tumor.Alkali aster ester A and effect of its derivative to tumour cell are not limited merely to glioma and intestinal cancer, in addition to other various tumours and cancer.The general structure of alkali aster ester A and its derivative is：
Description
Technical field
The invention belongs to field of medicaments, it is related to active compound for anti tumor alkali aster ester A (tripolinolate A) and alkali aster ester
The preparation of A derivative and medical usage.More specifically it is to be extracted from vegetable soda aster (Tripolium vulgare Nees)
Separation alkali aster ester A and alkali aster ester A and alkali aster ester A derivative are prepared with chemical synthesis process and they are preparing antineoplastic
The application in object space face.
Background technology
Alkali aster (Tripolium vulgare Nees) is a kind of unique plant of composite family alkali aster category (Tripolium), point
Be distributed in Europe, Asia, North America and Africa northern, China Jilin, Shanxi, the Inner Mongol, Shaanxi, Gansu, Xinjiang, Shandong, Jiangsu,
The provinces and regions such as Zhejiang are all distributed.Alkali aster is tierra templada obligate halophyte, is grown in low level saline-alkaline spot soil, saline-alkali wetland more
The places such as seashore, lakeside and marsh.At present, the medicinal record in documents and materials also without alkali aster, the chemical composition of alkali aster does not have yet
Studies have reported that.
The content of the invention
It is an object of the present invention to provide a kind of alkali aster ester A and its derivative answering in tumor is prepared
With.Alkali aster ester A and alkali aster ester A derivative significantly inhibit human glioma U87-MG and U251 cell and intestinal cancer HCT-15 and
The propagation of SW620 cells, and inducing apoptosis of tumour cell.It will be appreciated by those skilled in the art that alkali aster ester A and its derivative
Effect to tumour cell is not limited merely to glioma and intestinal cancer, in addition to other various tumours and cancer.
The general structure 2 of the alkali aster ester A and its derivative is：
Wherein：R and R1Acetyl group (- COCH is represented independently of one another3), propiono (- COCH2CH3), isobutyryl [-
COCH(CH3)2], bytyry [- COCH2CH2CH3], 2S- methylbutyryls base [- COCH (CH3)CH2CH3], isovaleryl [-
COCH2CH(CH3)2], valeryl [- COCH2(CH2)2CH3], caproyl [- COCH2(CH2)3CH3], heptanoyl group [- COCH2(CH2)4CH3], caprylyl [- COCH2(CH2)5CH3] or other acyl groups.
Medicine of the present invention be alkali aster ester A and its derivative be each used alone or share or with other drugs or effectively
Composition together, with pharmaceutically acceptable excipient constitute medicine.
The preparation of medicine of the present invention includes liquid preparation, solid pharmaceutical preparation, capsule preparations and sustained release preparation etc..
It is a kind of from alkali aster it is a further object to provide a kind of alkali aster ester A extraction separation method
Extraction separation and purification alkali aster ester A (tripolinolate A) side in the herb of (Tripolium vulgare Nees) plant
Method, described alkali aster ester A chemical structural formula 1 is：
The method of the present invention is realized by following steps：
(1) alkali aster ester A extraction separation and purification：
Dry alkali aster plant herb is cut into segment and powder is ground into medicinal herb grinder, is carried with methanol diacolation
Take, through being concentrated under reduced pressure to give the methanol extract liquid of concentration after the merging of methanol percolate, the methanol extract liquid of concentration is extracted with hexamethylene
Take, merge hexamethylene alkane extract and through being concentrated under reduced pressure to give hexamethylene extract medicinal extract.Hexamethylene extract medicinal extract is through silicagel column
Chromatography, respectively with cyclohexane/ethyl acetate (9:1 and 4:1, v/v) elute successively, cyclohexane/ethyl acetate (4:1) wash
De- component of the liquid through being concentrated under reduced pressure to give inverted silica gel (ODS) column chromatography for separation, is eluted with methanol, the elution of Fractional Collections methanol
Liquid (every 100 milliliters 1 part), each collection group detected respectively with HPLC (Zorbax Bonus-RP ODS HPLC chromatogram posts, 150 ×
4.6mm,5μm；Mobile phase methanol/water, 65：35；Flow velocity 1mL/min；Detection wavelength 256nm), by HPLC chromatogram retention time tR
8.9min component merges, and is concentrated under reduced pressure to give single compound (formula 1).
Solvent used in seepage pressure effects is methanol or ethanol, and the ratio of solvent and medicinal material consumption is 5-7 liters:1 kilogram；Institute
The ratio for stating silica gel consumption and sample size in silica gel column chromatography is 20~50 grams:1 gram；The use of the reversed-phase silica gel column chromatography ODS
The ratio of amount and sample size is 30~60 grams:1 gram.
(2) alkali aster ester A physicochemical property and Structural Identification
The isolated single compound (formula 2) of step (1), according to1H spectrums,13C spectrums, hsqc spectrum, HMBC spectrums and high-resolution
Mass spectral analysis, is accredited as 4- (2S- methylbutyryls base) -9- acetyl group-coniferyl alcohol [4- (2S-methylbutyryl) -9-
Acetyl-coniferol] it is alkali aster ester A, it is a noval chemical compound.
Alkali aster ester A：For colorless oil, molecular formula C17H22O5；Methanol, ethanol, pyridine are dissolved in, ethyl acetate is not dissolved in
Water；[α]D 25+10.6(c 0.10,MeOH)；UVλmax215,256,290nm；HPLC retention times are 8.9min (Zorbax
Bonus-RP ODS HPLC chromatogram posts, 150 × 4.6mm, mobile phase methanol/water, 65:35).
It is also another object of the present invention to provide alkali aster ester A and its chemical synthesis process of derivative.Alkali aster ester A and alkali aster
Ester A derivative has the structure shown in structural formula (2)：
Wherein：R and R1Acetyl group (- COCH is represented independently of one another3), propiono (- COCH2CH3), isobutyryl [-
COCH(CH3)2], bytyry [- COCH2CH2CH3], 2S- methylbutyryls base [- COCH (CH3)CH2CH3], isovaleryl [-
COCH2CH(CH3)2], valeryl [- COCH2(CH2)2CH3], caproyl [- COCH2(CH2)3CH3], heptanoyl group [- COCH2(CH2)4CH3], caprylyl [- COCH2(CH2)5CH3] or other acyl groups.
The chemical preparation process of alkali aster ester A and alkali aster ester A derivative, passes through following reactions steps：
(1) preparation of laricinolic acid (3)：
Vanillic aldehyde (3a) and malonic acid (3b) are dissolved in dioxane, anhydrous pyridine and aniline is added, 90~
95 DEG C of insulation reactions 2~3 hours, are cooled to room temperature.Reactant is added after 20% potassium carbonate and stirred, be adjusted to concentrated hydrochloric acid PH for 2~
3, sediment is separated out, suction filtration is washed with cold water and laricinolic acid (3) is obtained after solid, vacuum drying.Described vanillic aldehyde (3a), third
Diacid (3b), dioxane, anhydrous pyridine, the usage ratio of aniline are 0.02~0.05 (mol):0.03~0.06
(mol):20~30 (ml):10~15 (ml):1.0~2.0 (ml).
(2) preparation of laricinolic acid methyl esters (4)：
Laricinolic acid (3) is dissolved in absolute methanol, thionyl chloride (SOCl is gradually added under the conditions of zero degree2) stirring 10~
After 15 minutes, place do not stop within 7~8 hours stirring at room temperature, reactant obtains laricinolic acid methyl esters through ODS column chromatography for separation
(4).Described laricinolic acid (3), thionyl chloride, the amount ratio of methanol are 0.1 (mol):0.12~0.15 (mol):300~400
(mL)。
(3) preparation of coniferyl alcohol (5)：
Laricinolic acid methyl esters (4) is dissolved in anhydrous tetrahydro furan, tetrahydrochysene calorize lithium is gradually added, it is small that room temperature places 9~10
When and be stirred continuously, reactant obtains coniferyl alcohol (5) through ODS column chromatography for separation.Wherein laricinolic acid methyl esters (4), tetrahydrochysene calorize lithium,
The amount ratio of tetrahydrofuran is 0.1 (mol):0.2~0.3 (mol):500~1000 (mL).
(4) preparation of alkali aster ester A and its derivative：
Wherein：R and R1Acetyl group (- COCH is represented independently of one another3), propiono (- COCH2CH3), isobutyryl [-
COCH(CH3)2], bytyry [- COCH2CH2CH3], 2S- methylbutyryls base [- COCH (CH3)CH2CH3], isovaleryl [-
COCH2CH(CH3)2], valeryl [- COCH2(CH2)2CH3], caproyl [- COCH2(CH2)3CH3], heptanoyl group [- COCH2(CH2)4CH3], caprylyl [- COCH2(CH2)5CH3] or other acyl groups.
Coniferyl alcohol (5) is dissolved in pyridine, the anhydride compound with structural formula (6) is added, after room temperature places 10~24
Add water and stir, reactant is extracted with ethyl acetate, extract is separated through ODS column chromatographies and preparative high performance liquid chromatography
Obtain the alkali aster ester and its derivative of structural formula (2).Described coniferyl alcohol (5), anhydride compound, the amount ratio of pyridine are 0.1
(mol):0.2~0.3 (mol):100~200 (mL).
It will be appreciated by those skilled in the art that in addition to ODS column chromatographies and efficient liquid-phase chromatography method, institute of the present invention
The compound of synthesis can also be isolated and purified by other column chromatography methods and other method.
It will be appreciated by those skilled in the art that the preparation method of the present invention does not limit to above-mentioned reaction, other known skills
The disclosed reaction of art can also be achieved the method for the present invention, and method of the invention should advantageously comprise above-mentioned reaction.
The present invention identifies a kind of new active compound for anti tumor alkali aster ester A from the herb of alkali aster plant
(tripolinolate A), it was found that alkali aster ester A significantly inhibits the activity of tumor cell proliferation and inducing apoptosis of tumour cell.
The invention provides the method and one kind of the extraction separation and purification alkali aster ester A from vegetable soda aster herb be simple, economy, high yield are closed
Into alkali aster ester A and its derivative preparation method；Antineoplastic is being prepared present invention also offers alkali aster ester A and its derivative
The application in object space face.
Brief description of the drawings
Fig. 1 is alkali aster ester A (1) HPLC chromatogram.
Fig. 2 is alkali aster ester A (1) hydrogen spectrum.
Fig. 3 is alkali aster ester A (1) carbon spectrum.
Fig. 4 is alkali aster ester A (1) hsqc spectrum.
Fig. 5 is alkali aster ester A (1) HMBC spectrums.
Fig. 6 is the chemical constitution of compound 7~25.
Fig. 7 is 4,9- diacetyls-coniferyl alcohol (7)1H-NMR spectrum.
Fig. 8 is 4- acetyl group -9- propionos-coniferyl alcohol (8)1H-NMR spectrum.
Fig. 9 is 4- propionos -9- acetyl group-coniferyl alcohol (9)1H-NMR spectrum.
Figure 10 is bis- propionos of 4,9--coniferyl alcohol (10)1H-NMR spectrum.
Figure 11 is 4- acetyl group -9- isobutyryls-coniferyl alcohol (11)1H-NMR spectrum.
Figure 12 is 4- isobutyryls -9- acetyl group-coniferyl alcohol (12)1H-NMR spectrum.
Figure 13 is 4- acetyl group -9- bytyries-coniferyl alcohol (13)1H-NMR spectrum.
Figure 14 is 4- bytyries -9- acetyl group-coniferyl alcohol (14)1H-NMR spectrum.
Figure 15 is 4- acetyl group -9- (2S)-methylbutyryl base-coniferyl alcohol (15)1H-NMR spectrum.
Figure 16 is bis- isobutyryls of 4,9--coniferyl alcohol (16)1H-NMR spectrum.
Figure 17 is 4,9- dibutyryls-coniferyl alcohol (17)1H-NMR spectrum.
Figure 18 is 4- bytyries -9- isovaleryl-coniferyl alcohol (18)1H-NMR spectrum.
Figure 19 is 4- isovaleryl -9- bytyries-coniferyl alcohol (19)1H-NMR spectrum.
Figure 20 is 4,9- bis- (2S)-methylbutyryl base-coniferyl alcohol (20)1H-NMR spectrum.
Figure 21 is 4,9- diisoamyls acyl group-coniferyl alcohol (21)1H-NMR spectrum.
Figure 22 is bis- valeryls of 4,9--coniferyl alcohol (22)1H-NMR spectrum.
Figure 23 is bis- caproyls of 4,9--coniferyl alcohol (23)1H-NMR spectrum.
Figure 24 is bis- heptanoyl groups of 4,9--coniferyl alcohol (24)1H-NMR spectrum.
Figure 25 is bis- caprylyls of 4,9--coniferyl alcohol (25)1H-NMR spectrum.
Figure 26 is alkali aster ester A (1) induction gum knurl U87-MG Apoptosis.
Figure 27 is alkali aster ester A (1) induction gum knurl U251 Apoptosis.
Figure 28 is 4,9- diacetyls-coniferyl alcohol (7) induction gum knurl U87-MG Apoptosis.
Embodiment
The present invention is described in further detail below in conjunction with drawings and examples.It should be appreciated that these embodiments are only
Do not limited the scope of the invention for illustrating the present invention.The experimental method of unreceipted actual conditions in the following example, generally
According to conventional laboratory conditions.
Embodiment 1 extracts separation from plant and prepares alkali aster ester A
(1) alkali aster ester A extraction separation and purification：
Dry alkali aster plant herb is cut into segment and powder (1.5 kilograms) is ground into medicinal herb grinder, is used
Methanol seepage pressure effects 3 times (5000 milliliters 12 hours for the first time, other times it is each 4000 milliliters 5 hours), after methanol percolate merges
Through being concentrated under reduced pressure to give the methanol extract liquid (1000 milliliters) of concentration, the methanol extract liquid of concentration extracts 3 times (every time with hexamethylene
500 milliliters), merge hexamethylene alkane extract and through being concentrated under reduced pressure to give hexamethylene extract medicinal extract (12.5 grams).Hexamethylene is extracted
Thing medicinal extract is separated through silica gel column chromatography, respectively with cyclohexane/ethyl acetate (9:1 and 4:1, v/v) elute successively, hexamethylene/second
Acetoacetic ester (4:1) component (1.3 gram) inverted silica gel (ODS) column chromatography for separation of the eluent through being concentrated under reduced pressure to give, uses first
2000 milliliters of elutions of alcohol, Fractional Collections meoh eluate (every 100 milliliters 1 part), each collection group detects (Zorbax with HPLC respectively
Bonus-RP ODS HPLC chromatogram posts, 150 × 4.6mm, 5 μm；Mobile phase methanol/water, 65：35；Flow velocity 1mL/min；Detect ripple
Long 256nm), single compound alkali aster ester A (HPLC chromatogram retention time t will be containedRComponent 15-16 8.9min) merges, and subtracts
Pressure is concentrated to give alkali aster ester A (8.5 milligrams).
(2) alkali aster ester A physicochemical property and Structural Identification
Alkali aster ester A：For colorless oil, molecular formula C17H22O5；Methanol, ethanol, pyridine are dissolved in, ethyl acetate is not dissolved in
Water；UV absorption：λmax215,256,290nm；HPLC collection of illustrative plates is shown in accompanying drawing 1, its tRIt is worth for 8.9min (Zorbax Bonus-RP
ODS HPLC chromatogram posts, 150 × 4.6mm, mobile phase methanol/water, 65:35).According to alkali aster ester A's1H composes (accompanying drawing 2),13C is composed
(accompanying drawing 3), hsqc spectrum (accompanying drawing 4), HMBC spectrums (accompanying drawing 5) and high resolution mass spectrum, alkali aster ester A are accredited as 4- (2S- methylbutyryls
Base) -9- acetyl group-coniferyl alcohol [4- (2S-methylbutyryl) -9-acetyl-coniferol].Alkali aster ester A NMR data
It is：1H-NMR data (500MHz, pyridine-d5):δ7.22a(1H,H-2),7.23a(1H, H-5), 7.10 (1H, dd, J=
1.8/8.0Hz, H-6), 6.71 (1H, d, J=16.0Hz, H-7), 6.37 (1H, m, H-8), 4.80 (2H, dd, J=1.2/
6.3Hz,H-9),3.76(3H,s,OCH3-3),2.70(1H,m,H-2′),1.61(1H,m,H-3′a),1.86(1H,m,H-3′
B), 1.00 (3H, t, J=7.3Hz, H-4 '), 1.29 (3H, d, J=7.0Hz, H-5 '), 2.05 (3H, s, H-2 ")；13C-NMR numbers
According to (125MHz, pyridine-d5):δ136.2(C,C-1),111.4(CH,C-2),152.4(C,C-3),140.9(C,C-4),
124.2(CH,C-5),120.1(CH,C-6),133.7(CH,C-7),124.9(CH,C-8),65.3(CH2,C-9),56.2
(CH3,OCH3-3),174.9(C,C-1′),41.6(CH,C-2′),27.5(CH2,C-3′),12.0(CH3,C-4′),17.2
(CH3,C-5′),170.9(C,C-1″),21.1(CH3,C-2″)；HRESIMS m/z[M+Na]+329.1360 (calculated values
C17H22NaO5,329.1365).aThe signal overlap of peaks of these signal peaks and deuterated pyridine solvent.
The chemical synthesis of embodiment 2 prepares alkali aster ester A and alkali aster ester A derivative
(1) preparation of laricinolic acid (3)：By 36.51 grams of vanillic aldehyde (3a, 0.24mol), 31.22 grams of malonic acid (3b,
0.30mol), dioxane 60mL, anhydrous pyridine 30mL, aniline 3mL, in 90~95 DEG C of insulation reactions 3 hours, are cooled to room
Temperature, adds after 20% potassium carbonate 200mL and stirs, and it is 2~3 that PH is adjusted to concentrated hydrochloric acid, separates out sediment, and suction filtration is washed with cold water
Solid, obtains the powdered laricinolic acid of yellowish white (3,41.96 grams) after vacuum drying.Molecular formula：C10H10O4；1H-NMR data
(500MHz,methanol-d4):δ 7.13 (1H, d, J=1.9Hz, H-2), 7.03 (1H, dd, J=8.2/1.9Hz, H-6),
6.80 (1H, d, J=8.2Hz, H-5), 7.57 (1H, d, J=15.9Hz, H-7), 6.28 (1H, d, J=15.9Hz, H-8),
3.86(3H,s,OCH3-3)；HRESIMS m/z[M+Na]+217.0452 (calculated value C10H10NaO4,217.0477)。
(2) preparation of laricinolic acid methyl esters (4):Laricinolic acid (3,40.66 grams, 0.21mol) is dissolved in 600mL absolute methanols
In, thionyl chloride (SOCl is gradually added under the conditions of zero degree2) 20.1mL (0.276mol) stir 10~15 minutes after, in room temperature
Lower placement does not stop stirring for 7~8 hours, and reactant is recovered under reduced pressure after solvent to be separated through silica gel column chromatography, with hexamethylene/acetic acid second
Ester (4:1) elute, per 300mL be a component, by component 7~10 merge recycling design after obtain oily laricinolic acid methyl esters (4,
40.59 gram).Molecular formula：C11H12O4；1H-NMR data (500MHz, methanol-d4):δ 7.11 (1H, d, J=1.9Hz, H-
2), 7.01 (1H, dd, J=8.2/1.9Hz, H-6), 6.78 (1H, d, J=8.2Hz, H-5), 7.54 (1H, d, J=15.9Hz,
), H-7 6.29 (1H, d, J=15.9Hz, H-8), 3.83 (3H, s, OCH3-3),3.74(3H,s,OCH3-9)；HRESIMS m/z
[M+Na]+231.0609 (calculated value C11H12NaO4,231.0633)。
(3) preparation of coniferyl alcohol (5):Laricinolic acid methyl esters (4,31.24,0.15mol) is dissolved in the anhydrous tetrahydrochysene furans of 2000mL
In muttering, 11.38 grams of lithium aluminium hydride reduction (LiAlH were slowly added into 60 minutes4,0.30mol).Mixture is stirred continuously at room temperature
9~10 hours.Reactant is extracted with ethyl acetate three times (each 500mL) after adding 750mL 5% hydrochloric acid.Ethyl acetate extracts
Take liquid that the extract obtained after solvent is recovered under reduced pressure to separate through silica gel column chromatography, with hexamethylene and the mixed solvent of ethyl acetate
(3:1) elute, the coniferyl alcohol (5,21.68 grams) that solvent obtains yellowish white is recovered under reduced pressure in eluent.Molecular formula：C10H12O3；1H-
NMR data (500MHz, methanol-d4):δ 6.99 (1H, d, J=1.9Hz, H-2), 6.83 (1H, dd, J=8.1/1.9Hz,
H-6), 6.72 (1H, d, J=8.1Hz, H-5), 6.49 (1H, d, J=15.9Hz, H-7), 6.16 (1H, m, H-8), 4.18 (1H,
Dd, J=5.9/1.4Hz, H-9), 3.86 (3H, s, OCH3-3)；HRESIMS m/z[M+Na]+203.0678 (calculated values
C10H12NaO3,203.0684)。
(4) alkali aster ester A (1) and alkali aster ester A derivative (7~25):Coniferyl alcohol (5,100~200 milligrams) is dissolved in pyrrole
It is different according to target compound in pyridine (3~6mL), different anhydride compounds (6,1.5~3.0mL) are added, mixture is in room
Temperature adds 10mL deionized waters after placing 24 hours, is then extracted with ethyl acetate.Extract is made with ODS chromatographic columns and/or half
Standby type efficient liquid phase (Zorbax SB-C18 chromatographic columns, 250 × 9.4mm, 5 μm) is isolated and purified, and obtains compound (1,50 milligram)
(7~25,25~100 milligrams).The structure (accompanying drawing 6) of these compounds is NMR spectra and high resolution mass spectrometry according to them
Data analysis and confirm, they are 4,9- diacetyls-coniferyl alcohol (4,9-diacetyl-coniferol, 7), 4- acetyl
Base -9- propionos-coniferyl alcohol (4-acetyl-9-propionyl-coniferol, 8), 4- propionos -9- acetyl group-coniferyl alcohol
(4-popionyl-9-acetyl-coniferol, 9), bis- propionos of 4,9--coniferyl alcohol (4,9-dipopionyl-
Coniferol, 10), 4- acetyl group -9- isobutyryls-coniferyl alcohol (4-aetyl-9-isobutyryl-coniferol, 11),
4- isobutyryls -9- acetyl group-coniferyl alcohol (4-isobutyryl-9-acetyl-coniferol, 12), 4- acetyl group -9- fourths
Acyl group-coniferyl alcohol (4-acetyl-9-butyryl-coniferol, 13), 4- bytyries -9- acetyl group-coniferyl alcohol (4-
Butyryl-9-acetyl-coniferol, 14), 4- acetyl group -9- (2S- methylbutyryls base)-coniferyl alcohol (4-acetyl-9-
(2S-methylbutyryl)-coniferol, 15), bis- isobutyryls of 4,9--coniferyl alcohol (4,9-diisobutyryl-
Coniferol, 16), 4,9- dibutyryls-coniferyl alcohol (4,9-dibutyryl-coniferol, 17), 4- bytyry -9- isoamyls
Acyl group-coniferyl alcohol (4-butyryl-9-isovaleryl-conifero, 18), 4- isovaleryl -9- bytyries-coniferyl alcohol (4-
Isovaleryl-9-butyryl-coniferol, 19), 4,9- bis- (2S- methylbutyryls base)-coniferyl alcohol (4,9-di (2S)-
Methylbutyryl-coniferol, 20), 4,9- diisoamyls acyl group-coniferyl alcohol (4,9-diisovaleryl-coniferol,
21), bis- valeryls of 4,9--coniferyl alcohol (4,9-divaleryl-coniferol, 22), bis- caproyls of 4,9--coniferyl alcohol (4,9-
Dicaproyl-coniferol, 23), bis- heptanoyl groups of 4,9--coniferyl alcohol (4,9-diheptanoyl-coniferol, 24), 4,
Bis- caprylyls of 9--coniferyl alcohol (4,9-dioctanoyl-coniferol, 25).Compound 8,9,11,13~15,18~20 is new
Compound.
The alkali aster ester A (4- (2S-methylbutyryl) -9-acetyl-coniferol, 1) of synthesis:Colorless oil,
Molecular formula C17H22O5；Retention time tR20.0min (mobile phase:80%MeOH)；[α]D 25+11.7(c 0.10,MeOH)；It is ultraviolet
Absorb λmax215,256,290nm；1H-NMR data (500MHz, methanol-d4):δ 7.14 (1H, d, J=1.8Hz, H-2),
7.01 (1H, dd, J=8.2/1.8Hz, H-6), 6.94 (1H, d, J=8.2Hz, H-5), 6.66 (1H, d, J=15.9Hz, H-
7), 6.31 (1H, m, H-8), 4.72 (2H, dd, J=6.3/1.3Hz, H-9), 3.82 (3H, s, OCH3-3),2.62(1H,
Sext, J=7.0Hz, H-2 '), 1H, m, H-3 ' b), 1H, m, H-3 ' a), 1.60 2.08 (3H, s, H-2 "), 1.77 ((1.27
(3H, d, J=7.0Hz, H-5 '), 1.02 (3H, t, J=7.4Hz, H-4 ')；13C NMR datas (125MHz, methanol-d4):
δ176.6(C,C-1′),172.8(C,C-1″),152.9(C,C-3),141.2(C,C-4),137.1(C,C-1),134.5(CH,
C-7),125.0(CH,C-8),123.9(CH,C-5),120.4(CH,C-6),111.6(CH,C-2),66.2(CH2,C-9),
56.4(CH3,OCH3-3),42.4(CH,C-2′),28.1(CH2,C-3′),21.0(CH3,C-2″),17.3(CH3,C-5′),
12.0(CH3,C-4′)；HRESI MS m/z[M+Na]+329.1357(calcd for C17H22NaO5,329.1365)。
4,9- diacetyls-coniferyl alcohol (4,9-diacetyl-coniferol, 7):Colorless oil, molecular formula
C14H16O5；Retention time tR14.77min (mobile phase：80%MeOH)；UV absorption λmax216,255,294nm；1H-NMR numbers
According to (500MHz, methanol-d4):δ 7.13 (1H, d, J=1.5Hz, H-2), 6.99 (1H, dd, J=8.2/1.5Hz, H-6),
6.96 (1H, d, J=8.2Hz, H-5), 6.64 (1H, d, J=15.9Hz, H-7), 6.30 (1H, m, H-8), 4.71 (2H, dd, J
=6.4/1.2Hz, H-9), 3.82 (3H, s, OCH3-3),2.25(3H,s,H-2′),and 2.08(3H,s,H-2″)；
HRESIMS m/z[M+Na]+287.0890 (calculated value C14H16NaO5,287.0895)。
4- acetyl group -9- propionos-coniferyl alcohol (4-acetyl-9-propionyl-coniferol, 8):Colorless oil
Thing, molecular formula C15H18O5；Retention time tR43.07min (mobile phase：65%MeOH)；UV absorption λmax 215,256,
294nm；1H-NMR data (500MHz, methanol-d4):δ 7.14 (1H, d, J=1.7Hz, H-2), 7.00 (1H, dd, J=
8.2/1.7Hz, H-6), 6.97 (1H, d, J=8.2Hz, H-5), 6.65 (1H, d, J=15.9Hz, H-7), 6.31 (1H, m, H-
8), 4.73 (2H, dd, J=6.3/1.3Hz, H-9), 3.83 (3H, s, OCH3- 3), 2.37 (2H, q, J=7.5Hz, H-2 "),
2.26 (3H, s, H-2 '), 1.13 (3H, t, J=7.5Hz, H-3 ")；HRESIMS m/z[M+Na]+301.1047 (calculated values
C15H18NaO5,301.1052)。
4- propionos -9- acetyl group-coniferyl alcohol (4-popionyl-9-acetyl-coniferol, 9):Colorless oil,
Molecular formula C15H18O5；Retention time tR44.43min (mobile phase：65%MeOH)；UV absorption λmax215,256,295nm；1H-NMR data (500MHz, methanol-d4):δ 7.14 (1H, d, J=1.8Hz, H-2), 7.00 (1H, dd, J=8.1/
1.8Hz, H-6), 6.96 (1H, d, J=8.1Hz, H-5), 6.65 (1H, d, J=15.9Hz, H-7), 6.31 (1H, m, H-8),
4.72 (2H, dd, J=6.3/1.3Hz, H-9), 3.83 (3H, s, OCH3- 3), 2.57 (2H, q, J=7.5Hz, H-2 '), 2.08
(3H, s, H-2 "), 1.21 (3H, t, J=7.5Hz, H-3 ')；HRESIMS m/z[M+Na]+301.037 (calculated values
C15H18NaO5,301.1052)。
Bis- propionos of 4,9--coniferyl alcohol (4,9-dipopionyl-coniferol, 10):Colorless oil, molecular formula
C16H20O5；Retention time tR21.01min (mobile phase:80%MeOH)；UV absorption λmax214,255,294nm；1H-NMR
Data (500MHz, methanol-d4):δ 7.13 (1H, d, J=1.8Hz, H-2), 6.99 (1H, dd, J=8.1/1.8Hz, H-
6), 6.96 (1H, d, J=8.1Hz, H-5), 6.64 (1H, d, J=16.0Hz, H-7), 6.30 (1H, m, H-8), 4.72 (2H,
Dd, J=6.3/1.3Hz, H-9), 3.82 (3H, s, OCH3- 3), 2.57 (2H, q, J=7.5Hz, H-2 '), 2.37 (2H, q, J=
7.5Hz, H-2 "), 1.21 (3H, t, J=7.5Hz, H-3 '), 1.13 (3H, t, J=7.5Hz, H-3 ")；HRESIMS m/z[M+
Na]+315.1201 (calculated value C16H20NaO5,315.1208)。
4- acetyl group -9- isobutyryls-coniferyl alcohol (4-aetyl-9-isobutyryl-coniferol, 11):Colorless oil
Shape thing, molecular formula C16H20O5；Retention time tR20.14min (mobile phase:80%MeOH)；UV absorption λmax 215,255,
295nm；1H-NMR data (500MHz, methanol-d4):δ 7.14 (1H, d, J=1.7Hz, H-2), 7.00 (1H, dd, J=
8.1/1.7Hz, H-6), 6.97 (1H, d, J=8.1Hz, H-5), 6.65 (1H, d, J=15.9Hz, H-7), 6.31 (1H, m, H-
8), 4.72 (2H, dd, J=6.3/1.3Hz, H-9), 3.82 (3H, s, OCH3- 3), 2.58 (1H, heptet, J=7.0Hz, H-
), 2 " 2.26 (3H, s, H-2 '), 1.18 (6H, d, J=7.0Hz, H-3 ", H-4 ")；HRESIMS m/z[M+Na]+315.1197
(calculated value C16H20NaO5,315.1208)。
4- isobutyryls -9- acetyl group-coniferyl alcohol (4-isobutyryl-9-acetyl-coniferol, 12):Colorless oil
Shape thing, molecular formula C16H20O5；Retention time tR21.55min (mobile phase:80%MeOH)；UV absorption λmax 215,255,
294nm；1H-NMR data (500MHz, methanol-d4):δ 7.14 (1H, d, J=1.7Hz, H-2), 7.00 (1H, dd, J=
8.1/1.7Hz, H-6), 6.95 (1H, d, J=8.1Hz, H-5), 6.65 (1H, d, J=15.9Hz, H-7), 6.31 (1H, m, H-
8), 4.72 (2H, dd, J=6.3/1.2Hz, H-9), 3.82 (3H, s, OCH3- 3), 2.78 (1H, heptet, J=7.0Hz, H-
2 '), 2.08 (3H, s, H-2 "), 1.28 (6H, d, J=7.0Hz, H-3 ', H-4 ')；HRESIMS m/z[M+Na]+315.1194
(calculated value C16H20NaO5,315.1208)。
4- acetyl group -9- bytyries-coniferyl alcohol (4-acetyl-9-butyryl-coniferol, 13):Colorless oil,
Molecular formula C16H20O5；Retention time tR20.67min (mobile phase:80%MeOH)；UV absorption λmax215,255,295nm；1H-NMR data (500MHz, methanol-d4):δ 7.14 (1H, d, J=1.7Hz, H-2), 7.00 (1H, dd, J=8.1/
1.7Hz, H-6), 6.97 (1H, d, J=8.1Hz, H-5), 6.65 (1H, d, J=15.9Hz, H-7), 6.31 (1H, m, H-8),
4.72 (2H, dd, J=6.3/1.3Hz, H-9), 3.83 (3H, s, OCH3- 3), 2.34 (2H, q, J=7.3Hz, H-2 "), 2.25
(3H, s, H-2 '), 1.63 (2H, sext, J=7.3Hz, H-3 "), 0.95 (3H, t, J=7.3Hz, H-4 ")；HRESIMS m/z
[M+Na]+315.1203 (calculated value C16H20NaO5,315.1208)。
4- bytyries -9- acetyl group-coniferyl alcohol (4-butyryl-9-acetyl-coniferol, 14):Colorless oil,
Molecular formula C16H20O5；Retention time tR21.58min (mobile phase:80%MeOH)；UV absorption λmax215,256,295nm；1H-NMR data (500MHz, methanol-d4):δ 7.14 (1H, d, J=1.7Hz, H-2), 7.00 (1H, dd, J=8.1/
1.7Hz, H-6), 6.96 (1H, d, J=8.1Hz, H-5), 6.65 (1H, d, J=15.9Hz, H-7), 6.31 (1H, m, H-8),
4.72 (2H, dd, J=6.3/1.3Hz, H-9), 3.83 (3H, s, OCH3- 3), 2.53 (2H, t, J=7.2Hz, H-2 '), 2.08
(3H, s, H-2 "), 1.73 (2H, sext, J=7.2Hz, H-3 '), 1.03 (3H, t, J=7.2Hz, H-4 ')；13C-NMR data
(125MHz,methanol-d4):δ173.5(C,C-1′),172.8(C,C-1″),152.9(C,C-3),141.2(C,C-4),
137.1(C,C-1),134.5(CH,C-7),125.0(CH,C-8),124.0(CH,C-5),120.4(CH,C-6),111.5
(CH,C-2),66.2(CH2,C-9),56.5(CH3,OCH3-3),36.7(CH2,C-2′),21.0(CH3,C-2″),19.7(CH2,
C-3′),14.0(CH3,C-4′)；HRESIMS m/z[M+Na]+315.1201 (calculated value C16H20NaO5,315.1208)。
4- acetyl group -9- (2S- methylbutyryls base)-coniferyl alcohol (4-acetyl-9- (2S-methylbutyryl) -
coniferol,15):Colorless oil, molecular formula C17H22O5；Retention time tR18.5min (mobile phase:80%MeOH)；It is purple
Outer absorption λmax216,255,295nm；1H-NMR data (500MHz, methanol-d4):δ 7.14 (1H, d, J=1.8Hz, H-
2), 7.00 (1H, dd, J=8.2/1.8Hz, H-6), 6.97 (1H, d, J=8.2Hz, H-5), 6.66 (1H, d, J=16.0Hz,
), H-7 6.32 (1H, m, H-8), 4.73 (2H, dd, J=6.3/1.3Hz, H-9), 3.83 (3H, s, OCH3-3),2.40(1H,
Sext, J=7.0Hz, H-2 "), b), a), 1.47 2.26 (3H, s, H-2 '), 1.64 (1H, m, H-3 " (1H, m, H-3 " 1.16
(3H, d, J=7.0Hz, H-5 "), 0.91 (3H, t, J=7.4Hz, H-4 ")；HRESIMS m/z[M+Na]+329.1358 (calculate
Value C17H22NaO5,329.1365)。
Bis- isobutyryls of 4,9--coniferyl alcohol (4,9-diisobutyryl-coniferol, 16):Colorless oil, molecule
Formula C18H24O5；Retention time tR17.22min (mobile phase:90%MeOH)；UV absorption λmax216,257,295nm；1H-
NMR data (500MHz, methanol-d4):δ 7.12 (1H, d, J=1.8Hz, H-2), 6.99 (1H, dd, J=8.1/1.8Hz,
H-6), 6.94 (1H, d, J=8.1Hz, H-5), 6.64 (1H, d, J=15.9Hz, H-7), 6.30 (1H, m, H-8), 4.72 (2H,
Dd, J=6.3/1.3Hz, H-9), 3.81 (3H, s, OCH3- 3), 2.78 (1H, heptet, J=7.0Hz, H-2 '), 2.58 (1H,
Heptet, J=7.0Hz, H-2 "), 1.28 (6H, d, J=7.0Hz, H-3 ', H-4 '), 1.17 (6H, d, J=7.0Hz, H-3 ",
H-4″)；HRESIMS m/z[M+Na]+343.1513 (calculated value C18H24NaO5,343.1521)。
4,9- dibutyryls-coniferyl alcohol (4,9-dibutyryl-coniferol, 17):Colorless oil, molecular formula
C18H24O5；Retention time tR34.99min (mobile phase:80%MeOH)；UV absorption λmax215,255,295nm；1H-NMR
Data (500MHz, methanol-d4):δ 7.13 (1H, d, J=1.7Hz, H-2), 6.99 (1H, dd, J=8.2/1.7Hz, H-
6), 6.95 (1H, d, J=8.2Hz, H-5), 6.64 (1H, d, J=15.9Hz, H-7), 6.30 (1H, m, H-8), 4.72 (2H,
Dd, J=6.3/1.3Hz, H-9), 3.82 (3H, s, OCH3- 3), 2.53 (2H, t, J=7.3Hz, H-2 '), 2.34 (2H, t, J=
7.3Hz, H-2 "), 1.72 (2H, sext, J=7.3Hz, H-3 '), 1.63 (2H, sext, J=7.3Hz, H-3 "), 1.03 (3H,
T, J=7.3Hz, H-4 '), 0.95 (3H, t, J=7.3Hz, H-4 ")；HRESIMS m/z[M+Na]+343.1512 (calculated values
C18H24NaO5,343.1521)。
4- bytyries -9- isovaleryl-coniferyl alcohol (4-butyryl-9-isovaleryl-conifero, 18):Colorless oil
Shape thing, molecular formula C19H26O5；Retention time tR19.11min (mobile phase:90%MeOH)；UV absorption λmax 215,254,
295nm；1H-NMR data (500MHz, methanol-d4):δ 7.14 (1H, d, J=1.7Hz, H-2), 7.00 (1H, dd, J=
8.1/1.7Hz, H-6), 6.96 (1H, d, J=8.1Hz, H-5), 6.66 (1H, d, J=16.0Hz, H-7), 6.31 (1H, m, H-
8), 4.73 (2H, dd, J=6.3/1.2Hz, H-9), 3.83 (3H, s, OCH3- 3), 2.53 (2H, t, J=7.2Hz, H-2 '),
2.25 (2H, d, J=7.2Hz, H-2 "), 2.07 (1H, m, H-3 "), 1.73 (2H, sext, J=7.2Hz, H-3 '), 1.03 (3H,
T, J=7.2Hz, H-4 '), 0.97 (6H, d, J=6.6Hz, H-4 ", H-5 ")；HRESIMS m/z[M+Na]+357.1669 (meters
Calculation value C19H26NaO5,357.1678)。
4- isovaleryl -9- bytyries-coniferyl alcohol (4-isovaleryl-9-butyryl-coniferol, 19):It is colourless
Grease, molecular formula C19H26O5；Retention time tR19.48min (mobile phase:90%MeOH)；UV absorption λmax 215,253,
294nm；1H-NMR data (500MHz, methanol-d4):δ 7.14 (1H, d, J=1.8Hz, H-2), 7.00 (1H, dd, J=
8.1/1.8Hz, H-6), 6.95 (1H, d, J=8.1Hz, H-5), 6.66 (1H, d, J=16.0Hz, H-7), 6.32 (1H, m, H-
8), 4.73 (2H, dd, J=6.3/1.3Hz, H-9), 3.83 (3H, s, OCH3- 3), 2.43 (2H, d, J=7.1Hz, H-2 '),
2.34 (2H, t, J=7.3Hz, H-2 "), 2.16 (1H, m, H-3 '), 1.65 (2H, sext, J=7.3Hz, H-3 "), 1.06 (6H,
D, J=6.6Hz, H-4 ', H-5 '), 0.95 (3H, t, J=7.3Hz, H-4 ")；HRESIMS m/z[M+Na]+357.1673 (meters
Calculation value C19H26NaO5,357.1678)。
4,9- bis- (2S- methylbutyryls base)-coniferyl alcohol (4,9-di (2S-methylbutyryl)-coniferol, 20):
Colorless oil, molecular formula C20H28O5；Retention time tR14.6min (mobile phase:95%MeOH)；UV absorption λmax 215,
255,295nm；1H-NMR data (500MHz, methanol-d4):δ 7.14 (1H, d, J=1.8Hz, H-2), 7.00 (1H, dd, J
=8.1/1.8Hz, H-6), 6.94 (1H, d, J=8.1Hz, H-5), 6.66 (1H, d, J=15.9Hz, H-7), 6.32 (1H, m,
), H-8 4.73 (2H, dd, J=6.4/1.3Hz, H-9), 3.82 (3H, s, OCH3- 3), 2.61 (1H, sext, J=7.0Hz, H-
1H, m, H-3 ' b), 1.64 1H, m, H-3 ' a), 1.65 2 '), 2.41 (1H, sext, J=7.0Hz, H-2 "), 1.76 (((1H, m,
H-3 " a), 1.47 (b), 1H, m, H-3 " 1.27 (3H, d, J=7.0Hz, H-5 '), 1.16 (3H, d, J=7.0Hz, H-5 "),
1.02 (3H, t, J=7.5Hz, H-4 '), 0.91 (3H, t, J=7.5Hz, H-4 ")；HRESIMS m/z[M+Na]+371.1828
(calculated value C20H28NaO5,371.1834)。
4,9- diisoamyls acyl group-coniferyl alcohol (4,9-diisovaleryl-coniferol, 21):Colorless oil, molecule
Formula C20H28O5；Retention time tR21.99min (mobile phase:90%MeOH)；UV absorption λmax215,255,293nm；1H-
NMR data (500MHz, methanol-d4):δ 7.12 (1H, d, J=1.8Hz, H-2), 6.98 (1H, dd, J=8.1/1.8Hz,
H-6), 6.94 (1H, d, J=8.1Hz, H-5), 6.64 (1H, d, J=15.9Hz, H-7), 6.30 (1H, m, H-8), 4.72 (2H,
Dd, J=6.3/1.3Hz, H-9), 3.81 (3H, s, OCH3- 3), 2.42 (2H, d, J=7.1Hz, H-2 '), 2.24 (2H, d, J=
7.1Hz, H-2 "), 2.16 (1H, m, H-3 '), 2.07 (1H, m, H-3 "), 1.05 (6H, d, J=6.9Hz, H-4 ', H-5 '),
0.96 (6H, d, J=6.9Hz, H-4 ", H-5 ")；HRESIMS m/z[M+Na]+371.1830 (calculated value C20H28NaO5,
371.1834)。
Bis- valeryls of 4,9--coniferyl alcohol (4,9-divaleryl-coniferol, 22):Colorless oil, molecular formula
C20H28O5；Retention time tR22.75min (mobile phase:90%MeOH)；UV absorption λmax216,256,295nm；1H-NMR
Data (500MHz, methanol-d4):δ 7.12 (1H, d, J=1.7Hz, H-2), 6.98 (1H, dd, J=8.1/1.7Hz, H-
6), 6.95 (1H, d, J=8.1Hz, H-5), 6.63 (1H, d, J=15.9Hz, H-7), 6.29 (1H, m, H-8), 4.71 (2H,
Dd, J=6.3/1.3Hz, H-9), 3.81 (3H, s, OCH3- 3), 2.55 (2H, t, J=7.3Hz, H-2 '), 2.35 (2H, t, J=
7.3Hz, H-2 "), 1.68 (2H, quint, J=7.3Hz, H-3 '), 1.59 (2H, quint, J=7.3Hz, H-3 "), 1.44
(2H, sext, J=7.3Hz, H-4 '), 1.33 (2H, sext, J=7.3Hz, H-4 "), 0.96 (3H, t, J=7.3Hz, H-5 '),
0.92 (3H, t, J=7.3Hz, H-5 ")；HRESIMS m/z[M+Na]+371.1829 (calculated value C20H28NaO5,371.1834)。
Bis- caproyls of 4,9--coniferyl alcohol (4,9-dicaproyl-coniferol, 23):Colorless oil, molecular formula
C22H32O5；Retention time tR20.32min (mobile phase:95%MeOH)；UV absorption λmax215,255,294nm；1H-NMR
Data (500MHz, methanol-d4):δ 7.11 (1H, d, J=1.7Hz, H-2), 6.98 (1H, dd, J=8.2/1.7Hz, H-
6), 6.94 (1H, d, J=8.2Hz, H-5), 6.63 (1H, d, J=15.9Hz, H-7), 6.29 (1H, m, H-8), 4.71 (2H,
Dd, J=6.3/1.2Hz, H-9), 3.80 (3H, s, OCH3- 3), 2.53 (2H, t, J=7.4Hz, H-2 '), 2.34 (2H, t, J=
7.4Hz, H-2 "), 1.69 (2H, quint, J=7.4Hz, H-3 '), 1.61 (2H, quint, J=7.4Hz, H-3 "), 1.38
(4H, m, H-4 ', H-5 '), 1.30 (4H, m, H-4 ", H-5 "), 0.93 (3H, t, J=7.1Hz, H-6 '), 0.89 (3H, t, J=
7.1Hz,H-6″)；HRESIMS m/z[M+Na]+399.2145 (calculated value C22H32NaO5,399.2147)。
Bis- heptanoyl groups of 4,9--coniferyl alcohol (4,9-diheptanoyl-coniferol, 24):Colorless oil, molecular formula
C24H36O5；Retention time tR26.03min (mobile phase:95%MeOH)；UV absorption λmax215,256,294nm；1H-NMR
Data (500MHz, methanol-d4):δ 7.11 (1H, d, J=1.7Hz, H-2), 6.98 (1H, dd, J=8.1/1.7Hz, H-
6), 6.94 (1H, d, J=8.1Hz, H-5), 6.63 (1H, d, J=15.9Hz, H-7), 6.29 (1H, m, H-8), 4.71 (2H,
Dd, J=6.3/1.2Hz, H-9), 3.80 (3H, s, OCH3- 3), 2.53 (2H, t, J=7.4Hz, H-2 '), 2.34 (2H, t, J=
7.4Hz, H-2 "), 1.69 (2H, quint, J=7.4Hz, H-3 '), 1.59 (2H, quint, J=7.4Hz, H-3 "), 1.28~
1.38 (12H, H-4 ', H-5 ', H-6 ', H-4 ", H-5 ", H-6 "), 0.92 (3H, t, J=7.0Hz, H-7 '), 0.88 (3H, t, J
=7.0Hz, H-7 ")；HRESIMS m/z[M+Na]+427.2454 (calculated value C24H36NaO5,427.2460)。
Bis- caprylyls of 4,9--coniferyl alcohol (4,9-dioctanoyl-coniferol, 25):Colorless oil, molecular formula
C26H40O5；Retention time tR33.11min (mobile phase:95%MeOH)；UV absorption λmax215,256,294nm；1H-NMR
Data (500MHz, methanol-d4):δ 7.12 (1H, d, J=1.6Hz, H-2), 6.98 (1H, dd, J=8.2/1.6Hz, H-
6), 6.94 (1H, d, J=8.2Hz, H-5), 6.63 (1H, d, J=15.9Hz, H-7), 6.29 (1H, m, H-8), 4.71 (2H,
Dd, J=6.3/1.1Hz, H-9), 3.81 (3H, s, OCH3- 3), 2.54 (2H, t, J=7.4Hz, H-2 '), 2.34 (2H, t, J=
7.4Hz, H-2 "), 1.69 (2H, quint, J=7.4Hz, H-3 '), 1.60 (2H, quint, J=7.4Hz, H-3 "), 1.29~
1.38 (16H, H-4 ', H-5 ', H-6 ', H-7 ', H-4 ", H-5 ", H-6 ", H-7 "), 0.90 (3H, t, J=7.2Hz, H-8 '),
0.87 (3H, t, J=7.2Hz, H-8 ")；HRESIMS m/z[M+Na]+455.2768 (calculated value C26H40NaO5,455.2773)。
The inhibitory action of the alkali aster ester A of embodiment 3 and its derivative to glioma
Human glioma U87-MG and U251 cell are with DMEM and 10%FBS culture mediums in 37 DEG C and 5% carbon dioxide
Cultivated in incubator.Intestinal cancer HCT-15 cells are trained with RPMI-1640 culture mediums in the incubator of 37 DEG C and 5% carbon dioxide
Support, and intestinal cancer SW620 cells are cultivated with Leibovitz ' s L15 culture mediums in 37 DEG C of incubator.It is all to be commissioned to train by three
Foster cell is used for the experimental study of the present invention, with adriamycin (DOX) and the first-line drug of current clinical treatment glioma
Temozolomide (TMZ) is used as positive control.
Tumor cell survival is determined with Sulfonyl rhodamine-B assay (SRB).Cell is inoculated in 96 orifice plates, is added after adherent 24h
Enter the testing drug of various concentrations.Dyed after drug-treated 72h with SRB, the absorption value at 515nm, detection are determined with ELIASA
The survival rate of tumour cell, calculates IC50Value.As a result show alkali aster ester A significantly inhibit glioma U87-MG and U251 cell and
The propagation of intestinal cancer HCT-15 and SW620 cell, its IC50It is worth for 0.48 to 12.9 μM, wherein to intestinal cancer HCT-15 and SW620 cell
With adriamycin (DOX) quite, the inhibitory action bred to glioma U87-MG and U251 cell is significantly strong for the inhibitory action of propagation
In Temozolomide (TMZ) (table 1).Alkali aster ester A derivative 4,9- diacetyls-coniferyl alcohol (7), bis- propionos of 4,9--pine and cypress
Alcohol (10), 4- acetyl group -9- bytyries-coniferyl alcohol (13), 4- bytyries -9- acetyl group-coniferyl alcohol (14), 4- acetyl group -9-
(2S- methylbutyryls base)-coniferyl alcohol (15), bis- isobutyryls of 4,9--coniferyl alcohol (16) and 4,9- dibutyryls-coniferyl alcohol (17)
Also there is obvious inhibitory activity to glioma and the propagation of colon-cancer cell, wherein the activity of 4,9- diacetyls-coniferyl alcohol (7)
By force, it is suitable with alkali aster ester A and adriamycin (DOX) activity, and it is significantly stronger than Temozolomide (TMZ, table 1).Structure and antitumor
Activity analysis shows that compound 1 and its derivative 7-25 suppress in the activity and 4 and 9 two positions of tumor cell proliferation
Acyl moieties size is relevant, with the increase of molecule, and its activity has reduction or even the trend disappeared.
Inhibitory action (the IC of the compound on tumor cell of table 1. propagation50:μM)
NT:Do not test.
The alkali aster ester A (1) of embodiment 4 and 4,9- diacetyls-coniferyl alcohol (7) inducing apoptosis of tumour cell effect
With the double staining analysis methods of Annexin V-FITC/PI to alkali aster ester A (1) and 4,9- diacetyls-coniferyl alcohol (7)
The effect of two compound induced apoptosis of glioma cell has carried out quantitative analysis, and adriamycin (DOX) is used as positive control.
By people's glioma U87-MG and U251 cell alkali aster ester A (1,20.0 μM or 30.0 μM), 4,9- diacetyls-coniferyl alcohol (7,
40.0 μM) or adriamycin (DOX, 10.0 μM) handle 72 hours after, collect 1 × 106Individual cell.Cell is with cold PBS
Be dispersed in again after washing 100 μ L contain 5 μ L Annexin V-FITC and 1 μ L 100 μ g/mL PI working solutions combination buffering
In liquid.Cell is hatched at room temperature adds 400 μ L combination buffers after 15 minutes, with flow cytomery, its fluorescence (is excited
Wavelength：488nm；Launch wavelength：530nm and 575nm).Test result indicates that：The notable induction gum knurl U87-MG of alkali aster ester A and
U251 Apoptosis, is compared with negative control group, and the apoptosis of alkali aster ester A medicine group induction gum knurl U87-MG and U251 cells is thin
Born of the same parents' number increases 38.5% and 11.69% respectively；Moreover, total apoptotic cell hundred of alkali aster ester A induction gum knurl U87-MG cells
31.17% (accompanying drawing 26, accompanying drawing 27 and table 2) of the fraction 45.14% apparently higher than positive drug adriamycin control group.4,9- diacetyl
Base-coniferyl alcohol (7) also highly significant induction gum knurl U87-MG Apoptosis, the apoptosis number of its induction gum knurl U87-MG cell
50.69% is increased than negative control group, is significantly higher than 24.53% (accompanying drawing 28 and table 2) of positive drug adriamycin control group.
The quantitative analysis results (%) of the compound induction gum apoptosis of tumor of table 2.
In a word, the present invention be found that from halophytes alkali aster a kind of new active compound for anti tumor alkali aster ester A there is provided
Separation and Extraction alkali aster ester A (1) method and chemical synthesis first prepare alkali aster ester A and its derivative (7~25) from plant
Method.Because alkali aster ester A and its derivative significantly inhibit a variety of different tumor cell proliferations and inducing apoptosis of tumour cell, institute
So that the related drugs prepared by alkali aster ester A and its derivative have application prospect in terms of tumour is treated.
Claims (6)
1. applications of a kind of alkali aster ester A in tumor is prepared, it is characterised in that with the chemical constitution of formula 1：
2. applications of the alkali aster ester A according to claim 1 in tumor is prepared, it is characterised in that described swollen
Knurl is glioma and intestinal cancer, and the medicine is made up of alkali aster ester A with pharmaceutically acceptable excipient.
3. application according to claim 2, it is characterised in that the preparation of the medicine is liquid preparation, solid pharmaceutical preparation, delayed
Release formulation.
4. a kind of alkali aster ester A extraction separation method, it is characterised in that realized by following steps：
(1) alkali aster ester A extraction separation and purification：
Dry alkali aster (Tripolium vulgare Nees) plant herb is cut into segment and with medicinal herb grinder by its powder
Powder is broken into, methanol seepage pressure effects are used, through being concentrated under reduced pressure to give the methanol extract liquid of concentration after the merging of methanol percolate, concentration
Methanol extract liquid is extracted with hexamethylene, merges hexamethylene alkane extract and through being concentrated under reduced pressure to give hexamethylene extract medicinal extract, hexamethylene
Alkane extract medicinal extract is separated through silica gel column chromatography, respectively with 9:1 and 4:1, v/v cyclohexane/ethyl acetate is eluted successively, and 4:1
Cyclohexane/ethyl acetate the inverted silica gel column chromatography separation of component of the eluent through being concentrated under reduced pressure to give, eluted with methanol,
Fractional Collections meoh eluate, every 100 milliliters 1 part, each collection group is detected with HPLC respectively, by HPLC chromatogram retention time tR
8.9min component merges, and is concentrated under reduced pressure to give the single compound of formula 1；
(2) alkali aster ester A physicochemical property and Structural Identification
The single compound for taking step (1) isolated, according to1H spectrums,13C spectrums, hsqc spectrum, HMBC spectrums and high resolution mass spectrum point
Analysis, is accredited as 4- (2S- methylbutyryls base) -9- acetyl group-coniferyl alcohol [4- (2S-methylbutyryl) -9-acetyl-
Coniferol] it is alkali aster ester A；Alkali aster ester A is colorless oil, molecular formula C17H22O5；It is dissolved in methanol, ethanol, pyridine, acetic acid
Ethyl ester, it is water insoluble；[α]D 25+10.6(c 0.10,MeOH)；UVλmax215,256,290nm；HPLC retention times are
8.9min。
5. a kind of alkali aster ester A according to claim 4 extraction separation method, it is characterised in that step (1) solvent and medicine
The ratio of timber-used amount is 5~7 liters:1 kilogram；The ratio of silica gel consumption and sample size is 20~50 grams in the silica gel column chromatography:1
Gram；The consumption of the reversed-phase silica gel column chromatography and the ratio of sample size are 30~60 grams:1 gram.
6. a kind of alkali aster ester A according to claim 4 extraction separation method, it is characterised in that HPLC is examined in step (1)
Survey condition：Zorbax Bonus-RP ODS HPLC chromatogram posts, 150 × 4.6mm, 5 μm；Mobile phase methanol/water, 65：35；Flow velocity
1mL/min；Detection wavelength 256nm.
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| Anticancer effects of maple syrup phenolics and extracts on proliferation, apoptosis, and cell cycle arrest of human colon cells;Antonio Gonzalez-Sarrıas等;《JOURNAL OF FUNCTIONAL FOODS》;20111111;第4卷;第185-196页 * |
| 松柏醇的合成;王德才等;《化学世界》;19981231(第4期);第182-184页 * |
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