CN101235060B - Isograndidentatin, preparation method thereof and application of the same in preparing antineoplastic medicament - Google Patents
Isograndidentatin, preparation method thereof and application of the same in preparing antineoplastic medicament Download PDFInfo
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- CN101235060B CN101235060B CN200810052362XA CN200810052362A CN101235060B CN 101235060 B CN101235060 B CN 101235060B CN 200810052362X A CN200810052362X A CN 200810052362XA CN 200810052362 A CN200810052362 A CN 200810052362A CN 101235060 B CN101235060 B CN 101235060B
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Abstract
The invention discloses a specific cog populin, a corresponding preparation method and an application in anti-tumor drug, wherein the specific cog populin is represented as follow and named as 2-hydroxyl cyclohexyl-4-O-p-1-(p-coumaroyl)-beta-glucopyranoside. The preparation method has simple process, while tests prove that cog populin can inhibit the growth of tumor cell lines.
Description
Technical field
The invention belongs to pharmacy field, relate to a kind of 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside (different grandidentoside) and Preparation method and use particularly.
Background technology
Human beings'health in the cancer serious threat, affects people's quality of life.Though some antitumor drugs of present clinical use have restraining effect to tumour cell, but when acting on tumour cell, the particularly mushroom cell of normal human body cell is also had obvious suppression growth or killing effect, and its serious toxic side effect causes patient's life quality to descend.Therefore, the research of new antitumor drug has become the important topic that scientists faces.
The anticancer component that many curative effects are obvious and security is good is arranged in the plant, thereby from the natural product of plant, seek compound and become the new research direction of countries in the world cancer drug exploitation scientific workers with anti-tumor activity.
Summary of the invention
The purpose of this invention is to provide a kind of compound 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside with anti-tumor activity.
Another object of the present invention provides the method for extracting 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside from Salicaceae (Salicaceae) Populus (Populus) plant bark.
The 3rd purpose of the present invention provides the application of 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside in the preparation antitumor drug.
Technical scheme of the present invention is summarized as follows:
The compound of following structural formula:
Chemistry 2-hydroxyl cyclohexyl by name-4-O-ρ-coumaric acyl-β-D-glucopyranoside.
The preparation method of 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside comprises the steps:
(1) being raw material with the aspen bark of pulverizing, is that 1: 2～20 adding concentration expressed in percentage by volumes are 5%～95% aqueous acetone solution by mass ratio, normal temperature or heating or ultrasonic extraction 1～5 time, each 1～24 hour, filter, filtrate decompression is concentrated into 1%～10% of original volume, gets crude extract;
(2) add the water of 2～5 times of crude extract quality, stir, the n-hexane extraction that adding crude extract quality is 2～8 times 1～5 time, separate, the residue water layer is added the dichloromethane extraction 2～4 times of 2～8 times of crude extract quality, separate, add the ethyl acetate extraction 1～5 time of 2～8 times of crude extract quality remaining water layer once more, separating ethyl acetate layer and last water layer get the ethyl acetate extraction position with the ethyl acetate layer concentrating under reduced pressure;
(3) the ethyl acetate extraction position is through at least a 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside for preparing of silica gel column chromatography and gel filtration chromatography.
Preferably: the concentration expressed in percentage by volume of acetone is 70%.
The number of times that extracts is preferably 3 times.
The application of 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside in the preparation antitumor drug.
Preparation technology of the present invention is simple, and evidence compound molecule formula of the present invention is C
21H
28O
9Chemistry 2-hydroxyl cyclohexyl by name-4-O-ρ-coumaric acyl-β-D-glucopyranoside, be 2-hydroxycyclohexyl-4-O-p-coumaryol-β-D-glucopyr-anoside, the different grandidentoside isograndidentatin of called after, different grandidentoside can suppress the growth of tumor cell line, detect in the anti-tumor activity test medium lethal dose IC of different grandidentoside in the MTT reduction method that with human hepatoma cell strain Bel-7204 and human stomach cancer cell line SGC-7901 is target cell
50Be respectively 5.380 and 2.243 μ g/ml, show that different grandidentoside has anti-tumor activity, can be used for preparing antitumor drug.
Description of drawings
Fig. 1 is the Positive FAB-MS collection of illustrative plates of different grandidentoside;
Fig. 2 is different grandidentoside
1The H-NMR collection of illustrative plates;
Fig. 3 is different grandidentoside
13The C-NMR collection of illustrative plates;
Fig. 4 is the DEPT collection of illustrative plates of different grandidentoside;
Fig. 5 is the HETCOR collection of illustrative plates of different grandidentoside;
Fig. 6 is the extraction separation schema of different grandidentoside.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
The present invention extracts 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside from Salicaceae (Salicaceae) Populus (Populus) plant aspen (Populus davidiana Dode) or Populus alba L. * Populus glandulosa Uyeki bark.Also can from other the plant of Salicaceae Populus, adopt method of the present invention to prepare compound of the present invention.
Embodiment 1
2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside preparation
(1) be raw material with 2kg aspen Populus davidiana Dode bark, after the pulverizing, use 6kg 70% aqueous acetone solution at every turn, extract at room temperature 3 times, each 5 hours, to filter, filtrate decompression is concentrated into 5% of original volume, gets crude extract;
(2) add the water of 3 times of crude extract quality, stir, add the n-hexane extraction of 3 times of crude extract quality, extract 3 times, separate, dichloromethane extraction with 3 times of residue water layer adding crude extract quality extracts 3 times, separates, the ethyl acetate of 3 times of water layer adding crude extract quality will be remained once more, extract 3 times, separating ethyl acetate layer and last water layer get the ethyl acetate extraction position with the ethyl acetate layer concentrating under reduced pressure;
(3) the ethyl acetate extraction position prepares 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside, promptly different grandidentoside through silica gel column chromatography and Portugal's coagel Sephadex LH-20 column chromatography.See Fig. 6.
The structure of this compound is identified: the Positive FAB-MS collection of illustrative plates (see figure 1) of compound [M+H] of this compound as can be known thus
+Be 425, [M+Na]
+Be 447, in conjunction with
1The H-NMR (see figure 2) and
13C-NMR spectrum (see figure 3) provides molecular formula C
21H
28O
9 1H-NMR and
13The C-NMR spectrum shows that this compound is by a β-D-glucopyranoside [1 terminal hydrogen δ
H(4.45 1H, d, J=7.5Hz, H-1 ') and δ
H3.36～4.89 (6H, m, H-2 ', 3 ', 4 ', 5 ', 6 '); An end group carbon δ
C101.16 and δ
C61.40～75.01 (C-2 ', 3 ', 4 ', 5 ', 6 ')], 4-O-ρ-coumaric acyl [δ
H7.66 (1H, d, J=15.7Hz, H-7 "), 6.36 (1H, d, J=15.7Hz, H-8 "), 7.46 (2H, d, J=7.9Hz, H-2 ", 6 "), 6.81 (2H, d, J=7.9Hz, H-3 ", 5 "); δ
C126.13 (C-1 "), 130.35 (C-2 ", 6 "), 115.93 (C-3 ", 5 "), 160.39 (C-4 "), 146.31 (C-7 "), 113.80 (C-8 "), 167.61 (C-9 ")] and a 2-hydroxyl cyclohexyl [δ
H3.85 (2H, m, H-1﹠amp; 2), 1.31～1.79 (8H, m, H-3,4,5,6); δ
C78.42 (C-1), 69.93 (C-2), 26.64 (C-3), 21.43 (C-4), 22.09 (C-5), 30.42 (C-6)].In the HMBC spectrum, observe proton signal δ
H(4.89 1H, m, H-4 ') and carbon signal δ
C167.61 (C-9 "), proton signal δ
H(4.45 1H, d, J=7.5Hz, H-1 ') and carbon signal δ
C78.42 (C-1) Long-Range Correlation is arranged, determine β-D-glucopyranoside and 4-O-ρ-coumaric acyl 4 ' with 9 " position links to each other, and β-D-glucopyranoside and 2-hydroxyl cyclohexyl 1 ' link to each other with 1.The DEPT spectrum (see figure 4) and the HETCOR (see figure 5) of this compound have all confirmed above structural analysis.This compound and grandidentoside grandidentatin's
1H reaches
13Show that once more this compound is the isomer of grandidentoside after C-NMR spectrum data (the seeing Table 1) contrast, just 4-O-ρ-coumaric acyl links to each other with 4 of β-D-glucopyranoside ' number position in this compound.So far, the structure of this compound is confirmed as 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside.Retrieving this compound through CA is new compound, belongs to phenolic glycoside (phenolic glycoside) compounds, is named as different grandidentoside (isograndidentatin).This compound has uv-absorbing under ultraviolet lamp 254nm wavelength, iron trichloride ethanolic soln (mass percent) the spraying color reaction with 1% is deep green, R when launching with the trimethyl carbinol-glacial acetic acid-solvent systems of 3: 1: 1 of water volume ratio
fBe worth about 0.81, R when launching with 6: 94 solvent systems of glacial acetic acid-water volume ratio
fBe worth about 0.51.
Embodiment 2
(1) being raw material with Populus alba L. * Populus glandulosa Uyeki bark of pulverizing, is that to add concentration expressed in percentage by volume at 1: 4 be 95% aqueous acetone solution by mass ratio, ultrasonic extraction 1 time, each 1 hour, filter, filtrate decompression is concentrated into 1% of original volume, gets crude extract;
(2) add the water of 2 times of crude extract quality, stir, the n-hexane extraction that adding crude extract quality is 2 times 5 times, the dichloromethane extraction 4 times that the residue water layer is added 2 times of crude extract quality, add the ethyl acetate extraction 5 times of 2 times of crude extract quality, separating ethyl acetate layer and last water layer with remaining water layer once more;
(3) ethyl acetate layer is obtained 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside through silica gel column chromatography.
Embodiment 3
(1) being raw material with the aspen bark of pulverizing, is that to add concentration expressed in percentage by volume at 1: 20 be 5% aqueous acetone solution by mass ratio, heat 35-40 ℃ and extract 5 times, and each 10 hours, to filter, filtrate decompression is concentrated into 10% of original volume, gets crude extract;
(2) add the water of 5 times of crude extract quality, stir, the n-hexane extraction that adding crude extract quality is 8 times 1 time, the dichloromethane extraction 2 times that the residue water layer is added 8 times of crude extract quality, add the ethyl acetate extraction 1 time of 8 times of crude extract quality with remaining water layer once more, separating ethyl acetate layer and last water layer get the ethyl acetate extraction position with the ethyl acetate layer concentrating under reduced pressure;
(3) the ethyl acetate extraction position obtains 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside through gel filtration chromatography.
Embodiment 4
(1) being raw material with the aspen bark of pulverizing, is that to add concentration expressed in percentage by volume at 1: 2 be 50% aqueous acetone solution by mass ratio, extract at room temperature 3 times, each 24 hours, filter, filtrate decompression is concentrated into 6% of original volume, crude extract;
(2) add the water of 4 times of crude extract quality, stir, the n-hexane extraction that adding crude extract quality is 4 times 3 times, the dichloromethane extraction 3 times that the residue water layer is added 4 times of crude extract quality, add the ethyl acetate extraction 3 times of 2～84 times of crude extract quality with remaining water layer once more, separating ethyl acetate layer and last water layer get the ethyl acetate extraction position with the ethyl acetate layer concentrating under reduced pressure;
(3) the ethyl acetate extraction position obtains 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside through silica gel column chromatography and gel filtration chromatography.
Different grandidentoside of table 1. (isograndidentatin) and grandidentoside (grandidentatin)
1H (400MHz) reaches
13CNMR (100MHz) spectrum data (MeOH-d
4)
| Grandidentatin | Isograndidentatin | |||
| Position | δ C | δ HmJ(Hz) | δ C | δ HmJ(Hz) |
| 1 2 3 4 5 6 1′ 2′ 3′ 4′ 5′ 6′ 1″ 2″ 3″ 4″ 5″ 6″ 7″ 8″ 9″ | 80.04 71.47 30.87 21.63 23.70 28.92 101.15 78.05 75.46 71.71 76.14 62.60 127.22 131.27 116.89 161.40 116.89 131.27 146.91 115.28 168.55 | _ a _ b 1.14～1.60(2H，m) 1.14～1.60(2H，m) 1.14～1.60(2H，m) 1.14～1.60(2H，m) 3.22～5.23(1H，m) 3.22～5.23(1H，m) 3.22～5.23(1H，m) 3.22～5.23(1H，m) 3.22～5.23(1H，m) 3.22～5.23(2H，m) 7.55(1H，d，7.5) 6.78(1H，d，7.5) 6.78(1H，d，7.5) 7.55(1H，d，7.5) 7.57(1H，d，16.0) 6.37(1H，d，16.0) | 78.42 69.93 26.64 21.43 22.09 30.42 101.16 74.09 74.60 71.51 75.01 61.40 126.13 130.35 115.93 160.39 115.93 130.35 146.31 113.80 167.61 | 3.85(1H，m) 3.85(1H，m) 1.31～1.79(2H，m) 1.31～1.79(2H，m) 1.31～1.79(2H，m) 1.31～1.79(2H，m) 4.45(1H，d，7.5) 3.36(1H，m) 3.52～3.69(1H，m) 4.89(1H，m) 3.52～3.69(1H，m) 3.52～3.69(2H，m) 7.46(1H，d，7.9) 6.81(1H，d，7.9) 6.81(1H，d，7.9) 7.46(1H，d，7.9) 7.66(1H，d，15.7) 6.36(1H，d，15.7) |
aOverlapped?with?glucose?signal.
bOverlapped?with?solvent?signal.
Embodiment 5:
The MTT reduction method detects different grandidentoside anti-tumor activity test
1. material:
1.1 tetramethyl-azo azoles salt (MTT): with phosphate buffered saline buffer (PBS) the dissolving MTT[3-(4 of 0.01mol/L, 5)-and dimethylthiahiazo (z-yl)-3,5-di-phenytetrazoliumromide, Sigma] final concentration 5mg/ml, filtration sterilization, packing is kept in Dark Place for 4 ℃.
1.2MTT (SDS Sigma) is dissolved in the N-N-dimethylformamide (Sigma) of 200ml the sodium laurylsulfonate of the preparation of lysate: 80g, and the heating in water bath hydrotropy adds 200ml distilled water, mixes with 1N hydrochloric acid (1: 1) with 80% ethanol and transfers pH to 4.7.
1.3 cell strain is selected for use: people's normal liver cell L-02, human hepatoma cell strain Bel-7204 and human stomach cancer cell line SGC-7901 (Korean Genebank).
2. operation steps:
2.1 being inoculated in 96 orifice plates, single cell suspension (use the RPMI-1640 basic medium with cell dilution to 3 * 10
4/ ml, every hole adds 200 μ l and dilutes good cell), 37 ℃, 5%CO
2, cultivated 24 hours under the saturated humidity; Every group of six parallel samples;
2.2 the removal substratum is got new preparation substratum and prepared the different grandidentoside of compound (embodiment 1) solution by series concentration, every hole 200 μ l cultivated 48 hours;
2.3 every hole adds the MTT 20 μ l of 2mg/ml, fosters 4 hours;
2.4 nutrient solution in the sucking-off hole, every hole add 150 μ l DMSO liquid (Sigma), vibrate 10 minutes, and crystallisate is fully dissolved;
2.5 microplate reader detects each hole OD value (under the wavelength 570nm);
2.6 draw the cell viability graphic representation, obtain IC
50Value.
Test-results is as shown in table 2.The result shows that the different grandidentoside of compound (2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside) has stronger cytotoxicity, and its toxicity has certain selectivity to normal cell and cancer cells; The different grandidentoside of compound can be used for preparing antitumor drug.
The cell toxicity test result of the different grandidentoside of table 2. (isograndidentatin)
| The test cell | People's normal liver cell strain L-02 | Human hepatoma cell strain Bel-7204 | Human stomach cancer cell line SGC-7901 |
| IC 50(μg/ml) | 13.422 | 5.380 | 2.243 |
Claims (5)
1. the compound of following structural formula:
Chemistry 2-hydroxyl cyclohexyl by name-4-O-ρ-coumaric acyl-β-D-glucopyranoside.
2. the preparation method of claim 1 compound is characterized in that comprising the steps:
(1) being raw material with the aspen bark of pulverizing, is that 1: 2～20 adding concentration expressed in percentage by volumes are 5%～95% aqueous acetone solution by mass ratio, normal temperature or heating or ultrasonic extraction 1～5 time, each 1～24 hour, filter, filtrate decompression is concentrated into 1%～10% of original volume, gets crude extract;
(2) add the water of 2～5 times of crude extract quality, stir, the n-hexane extraction that adding crude extract quality is 2～8 times 1～5 time, separate, the residue water layer is added the dichloromethane extraction 2～4 times of 2～8 times of crude extract quality, separate, add the ethyl acetate extraction 1～5 time of 2～8 times of crude extract quality remaining water layer once more, separating ethyl acetate layer and last water layer get the ethyl acetate extraction position with the ethyl acetate layer concentrating under reduced pressure;
(3) the ethyl acetate extraction position is through at least a 2-hydroxyl cyclohexyl-4-O-ρ-coumaric acyl-β-D-glucopyranoside for preparing of silica gel column chromatography and gel filtration chromatography.
3. method according to claim 2, the concentration expressed in percentage by volume that it is characterized in that described acetone is 70%.
4. method according to claim 2, the number of times that it is characterized in that described extraction is 3 times.
5. the application of claim 1 compound in the preparation antitumor drug is characterized in that described tumour is liver cancer or cancer of the stomach.
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| Bonnie Rasmussen, et al..Dovyalicin-Type Spermidine Alkaloids from DoWyalis Species.《J. Nat. Prod.》.American Chemical Society and American Society of Pharmacognosy,2006,第69卷(第9期),1300-1304. * |
| 王欣等.山杨的化学成分研究.《中草药》.2000,第31卷(第12期),891-892. * |
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