CN1274705C - Compounds with anti neurocyte apoptosis function - Google Patents
Compounds with anti neurocyte apoptosis function Download PDFInfo
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- CN1274705C CN1274705C CN 200310122417 CN200310122417A CN1274705C CN 1274705 C CN1274705 C CN 1274705C CN 200310122417 CN200310122417 CN 200310122417 CN 200310122417 A CN200310122417 A CN 200310122417A CN 1274705 C CN1274705 C CN 1274705C
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Abstract
In the present invention, various separation methods comprising positive and reversed phase silica gel column chromatography, macroporous adsorptive resin column chromatography, sephadexLH-20 column chromatography, preparative high performance liquid chromatography and the like are used for separating plant polygala root to obtain five new compounds comprising phenolic ketone and saponin compounds. Activity determination experiments show that the five compounds have the efficacy for resisting neuronal apoptosis and can be used for preparing medicaments for preventing and treating senile dementia.
Description
Technical field
The present invention relates to one group of compound, specifically extraction, isolating phenolic ketone and saponins compound from the polygala root plant with anti-nerve cell apoptosis effect.
Background technology
Polygala root is the common Chinese medicine material, and the beginning is stated from Shennong's Herbal, classifies as top gradely, is regarded as supporting the key medicine of life." Chinese pharmacopoeia (2000 editions) has been recorded 2 kinds of basic source plants: polygala root Polygala tenuifolia and ovum leaf polygala root P.sibirica, its medicinal part is a root.This product bitter, suffering, temperature, the thoughts of returning home, kidney, the spleen channel, have the intelligence development of calming the nerves, eliminate the phlegm, effect such as detumescence (Chinese Pharmacopoeia Commission compiles, one one of Pharmacopoeia of People's Republic of China, 2000:123).
It is reported, mainly contain in the polygala root compositions such as ketone, sugar esters, saponins and alkaloid (Jiang Yong etc. herbal medicine, 32 (8): 759,2001; Phytochemistry, 2002,60 (8): 813; Herbal medicine, 2002,33 (10): 874).But the research about its activeconstituents is reported but seldom.
Summary of the invention
The objective of the invention is to by multiple extraction, separation means, further from the polygala root plant, extract, separate the reactive monomer compound that makes new advances with intelligence development and anti-senile dementia effect.
The objective of the invention is to realize by the following technical solutions:
Utilize multiple extraction, separation means, comprise methods such as solvent-extraction process, solvent extration, macroporous adsorbent resin method, positive and negative silica gel column chromatography, sephadex LH-20 column chromatography and preparation HPLC, systematic study the chemical ingredients of polygala root.Therefrom separate having obtained more than 50 compound, wherein new compound is 19, has 5 of active monomers, is respectively:
Polygala root tropolones Compound C has structure shown in the structural formula I:
Polygala root tropolones Compound D has structure shown in the structural formula II:
Structural formula (II)
Polygalic acid compounds L has structure shown in the structural formula II I:
Structural formula (III)
Wherein, R
1=
Polygalic acid compounds J has structure shown in the structural formula IV:
Wherein, R
2=
Or
Polygalic acid compounds K has structure shown in the structural formula V:
The structure formula V
Wherein, R
3=
Above-mentioned 5 kinds of compounds are to be prepared by following method:
The pulverizing of rattlesnaker oot skin is back with 95% EtOH refluxing extraction, and decompression and solvent recovery obtains solid extract.This solid extract is suspended in water, use sherwood oil, chloroform and n-butanol extraction successively.
Chloroform extract through silica gel column chromatography, is used CHCl
3-MeOH is collected in sherwood oil-acetone (7: 1) and launches R as elutriant
fBe positioned at about 0.2, and spot presents stream part of orange under the UV lamp, after this stream part concentrated successively through hydroxypropyl dextrane gel (sephadex LH-20) purifying (use methanol-eluted fractions) and silica gel column chromatography (usefulness sherwood oil-acetone wash-out), be collected in sherwood oil-acetone (7: 1) and launch R
fBe positioned at stream part of 0.23, obtain compound Tenuiphenone D (tenuiphenone D) through acetone recrystallization; Be collected in sherwood oil-acetone (7: 1) and launch R
fBe positioned at stream part of 0.21, obtain compound Tenuiphenone C (tenuiphenoneC) through acetone recrystallization.
N-butyl alcohol extract is dissolved in the water last macroporous resin D
101, use H respectively
2O, 20% EtOH, 50% EtOH and 70% EtOH carry out wash-out, and each elutriant that obtains concentrates respectively, freeze-drying.Get 50% EtOH eluate, through silica gel column chromatography, CHCl
3-MeOH-H
2The O wash-out is collected the stream part to the saponin(e spot of sulfuric acid displaing amaranth; Then through ODS post (C
18The alkyl reverse phase silica gel) separates, use MeOH-H
2The O wash-out is collected in n-BuOH: HCOOH: H
2Launch R among the O (60: 3: 37 upper stratas)
fStream part between 0.30-0.58; And then, use n-BuOH-EtOAc-H through the separation of decompression silica gel column chromatography
2The upper strata of O (4: 1: 2) is that elutriant carries out wash-out, is collected in n-BuOH: HCOOH: H
2O (launches R in 60: 3: 37 upper stratas
fStream part 0.30,0.37 and 0.55; Each flows part through the HPLC purifying at last, MeOH: H
2O (61: 39, H
2Contain 0.05% TFA among the O) be moving phase, flow velocity 3ml/min, collecting retention time respectively is 30min, stream part of 48min and 60min, each the stream part that obtains is through decompression and solvent recovery, lyophilize promptly gets each compound, is determined as polygalic acid compounds L (onjisaponin L) through IR, NMR and MS, polygalic acid compounds J (onjisaponin J) and polygalic acid compounds K (onjisaponin K).
5 compounds provided by the invention show to have the effect of anti-nerve cell apoptosis through the determination of activity experiment, can be used to prepare the medicine of intelligence development and anti-senile dementia effect.
Embodiment
The preparation of embodiment 1, compound
Rattlesnaker oot skin 11kg is pulverized the back with 95% EtOH 70L refluxing extraction 3h, extract altogether 3 times.Decompression and solvent recovery obtains solid extract 4.91kg.Get 2kg medicinal extract and suspend in water, use sherwood oil, chloroform and n-butanol extraction successively.
Chloroform extract through silica gel column chromatography, is used CHCl
3-MeOH (volume ratio is 500: 1 to 60: 40) is as elutriant gradient elution, wherein CHCl
3Stream part of 90: 10 o'clock wash-outs of-MeOH volume ratio is launched in sherwood oil-acetone (7: 1), R
fBe positioned at about 0.2, and spot presents orange under the UV lamp, collect this stream part, after this stream part concentrated successively through hydroxypropyl dextrane gel (sephadex LH-20) purifying (use methanol-eluted fractions) and silica gel column chromatography (usefulness sherwood oil-acetone wash-out), be collected in sherwood oil-acetone (7: 1) and launch R
fBe positioned at stream part of 0.23, obtain polygala root tropolones Compound D (tenuiphenone D) 24.1mg; Be collected in sherwood oil-acetone (7: 1) and launch R
fBe positioned at stream part of 0.21, obtain polygala root tropolones Compound C (tenuiphenone C) 15.3mg.
Tenuiphenone C, off-white color solid (acetone), mp 197-200 ℃.HR SI-MS(positive)：m/z559.4724(C
36H
63O
4 [M+H]
+，requires 559.4721，581.4540[M+Na]
+。IR ν
Max KBrCm
-1: 3281 (OH), 2918,2850 (CH
2,-CH
3), 1657 (conjugation-C=O), 1602,1525,1469 (aromatic rings), 720 ((CH
2) n, n 〉=4).EI-MS(m/e)：43[C
3H
7]
+，57[C
4H
9]
+，71[C
5H
11]
+，97[C
5H
11-CH＝CH-]
+，111[C
5H
11-CH＝CH-CH
2]
+...，153[C
7H
5O
4]
+，168[C
8H
7O
4+H]
+，181[C
9H
9O
4]
+...。
1HNMR (acetone): δ 11.81 (2,6-OH), 9.14 (4-OH), 5.90 (2H, s, H-3,5), 5.33 (2H, t, J=4.8Hz, H-24), 3.05 (2H, t, J=7.5Hz ,-COCH
2-), 2.04 (m ,-CH
2CH=), 1.65 (2H, m ,-COCH
2CH
2-), 1.27 (brs ,-CH
2-), 0.87 (3H, t, J=6.9Hz, CH
3).
13C NMR (acetone): δ 206.33 (CO-, overlapped), 164.27,165.40 (C-2 ', 5 ', 4 ', can exchange between the signal), 95.69 (C-3 ', 5 '), 130.44 (C-24,25), 44.39 (CH
2CO), 32.53,30.57-29.03,27.69,25.44,23.23 (CH
2-), 14.31 (CH
3).
Tenuiphenone D, off-white color solid (acetone), mp 197-200 ℃.HR SI-MS(positive)：m/z587.5057(C
38H
67O
4 [M+H]
+，requires 587.5034)，609.4823[M+Na]
+。IR ν
Max KBrCm
-1: 3285 (OH), 2918,2850 (CH
2,-CH
3), 1659 (conjugation-C=O), 1603,1525,1472 (aromatic rings), 720 ((CH
2) n, n 〉=4).EI-MS(m/e)：43[C
3H
7]
+，57[C
4H
9]
+，71[C
5H
11]
+，97[C
5H
11-CH＝CH-]
+，111[C
5H
11-CH＝CH-CH
2]
+...，153[C
7H
5O
4]
+，168[C
8H
7O
4+H]
+，181[C
9H
9O
4]
+...。
1HNMR (acetone): δ 11.70 (2,6-OH), 9.14 (4-OH), 5.91 (2H, s, H-3,5), 5.35 (2H, t, J=4.8Hz, H-26), 3.05 (2H, t, J=7.5Hz ,-COCH
2-), 2.04 (m ,-CH
2CH=), 1.65 (2H, m ,-COCH
2CH
2-), 1.29 (brs ,-CH
2-), 0.87 (3H, t, J=6.9Hz, CH
3).
13C NMR (acetone): δ 206.33 (CO-, overlapped), 164.96,164.92 (C-2 ', 5 ', 4 ', can exchange between the signal), 95.60 (C-3 ', 5 '), 130.44 (C-26,27), 44.36 (CH
2CO), 32.53,30.78-29.00,27.67,25.49,23.28 (CH
2-), 14.32 (CH
3).
N-butyl alcohol extract is dissolved in the water last macroporous resin D
101, use H respectively
2O, 20% EtOH, 50% EtOH and 70% EtOH carry out wash-out, and each elutriant that obtains concentrates respectively, freeze-drying.Get 50% EtOH eluate, through silica gel column chromatography, CHCl
3-MeOH-H
2The O wash-out is collected the stream part to the saponin(e spot of sulfuric acid displaing amaranth; Then through ODS post (C
18The alkyl reverse phase silica gel) separates, use MeOH-H
2The O wash-out is collected in n-BuOH: HCOOH: H
2Launch R among the O (60: 3: 37 upper stratas)
fStream part between 0.30-0.58; And then, use n-BuOH-EtOAc-H through the separation of decompression silica gel column chromatography
2The upper strata of O (4: 1: 2) is that elutriant carries out wash-out, is collected in n-BuOH: HCOOH: H
2O (launches R in 60: 3: 37 upper stratas
fStream part 0.30,0.37 and 0.55; Each flows part through the HPLC purifying at last, MeOH: H
2O (61: 39, H
2Contain 0.05% TFA among the O) be moving phase, flow velocity 3ml/min, collecting retention time respectively is 30min, stream part of 48min and 60min, each the stream part that obtains is through decompression and solvent recovery, lyophilize promptly gets each compound, is determined as polygalic acid compounds L (onjisaponin L) through IR, NMR and MS, J (onjisaponin J) and K (onjisaponin K).
Polygalic acid L, white unformed powder, Liebermann-Burchard and Molish reacting positive.TOF-MS(m/e)：1866[M+NH
4]
+。
1H NMR(C
5D
5N)：δ7.91(1H，d，J＝16.0Hz，H-β ofE-cinnamoyl)，6.50(1H，d，J＝15.5Hz，H-α of E-cinnamoyl)/6.87(1H，d，J＝12.5Hz，H-β ofZ-cinnamoyl)，5.95(1H，d，J＝13.0Hz，H-α of Z-cinnamoyl)；7.36(1H，d，J＝8.5Hz，H-2，6of E-cinnamoyl)，6.95(1H，d，J＝8.5Hz，H-3，5 of E-cinnamoyl)/7.97(1H，d，J＝9.0Hz，H-2，6 of Z-cinnamoyl)，7.01(1H，d，J＝8.5Hz，H-3，5 of Z-cinnamoyl)，3.65(3H，s，OCH
3 ofE-cinnamoyl)/3.60(3H，s，OCH
3 of Z-cinnamoyl)，4.90(1H，d，J＝8.0Hz，Gal-1)，5.01(1H，d，J＝8.0Hz，Glc-1)，5.18(1H，d，J＝8.0Hz，Xyl-1)，5.52(1H，brs，Rha-1′)，5.79(1H，brs，Rha-1)，6.08(1H，overlapped，Api-1)，6.07(1H，overlapped，Fuc-1)。
13C NMR data see Table 1.
Polygalic acid J, white unformed powder, Liebermann-Burchard and Molish reacting positive.TOF-MS(m/e)：1836[M+NH
4]
+。
1H NMR(C
5D
5N)：δ7.93(1H，d，J＝15.9Hz，H-β ofE-cinnamoyl)，6.50(1H，d，J＝15.9Hz，H-α of E-cinnamoyl)/6.90(1H，d，J＝12.9Hz，H-β ofZ-cinnamoyl)，6.00(1H，d，J＝12.9Hz，H-α of Z-cinnamoyl)；7.38(1H，d，J＝8.4Hz，H-2，6of E-cinnamoyl)，6.97(1H，d，J＝8.7Hz，H-3，5 of E-cinnamoyl)/8.00(1H，d，J＝8.4Hz，H-2，6 of Z-cinnamoyl)，7.03(1H，d，J＝9.0Hz，H-3，5 of Z-cinnamoyl)，3.66(3H，s，OCH
3 ofE-cinnamoyl)/3.62(3H，s，OCH
3 of Z-cinnamoyl)，5.03(1H，d，J＝7.6Hz，Glc-1)，5.16(1H，d，J＝6.9Hz，Ara-1)，5.25(1H，d，J＝7.5Hz，Xyl-1)，5.54(1H，brs，Rha-1′)，5.78(1H，brs，Rha-1)，6.04(1H，overlapped，Api-1)，6.07(1H，d，J＝7.7Hz，Fuc-1)。
13C NMR data see Table 1.
Polygalic acid K, white unformed powder, Liebermann-Burchard and Molish reacting positive.TOF-MS(m/e)：1623.6[M+Na]
+。
1H NMR(C
5D
5N)：δ7.93(1H，d，J＝16.0Hz，H-β ofE-cinnamoyl)，6.58(1H，d，J＝15.5Hz，H-α of E-cinnamoyl)/6.85(1H，d，J＝13.0Hz，H-βof Z-cinnamoyl)，5.99(1H，d，J＝12.5Hz，H-α of Z-cinnamoyl)，6.81(2H，s，H-2，6 ofE-cinnamoyl)/7.37(2H，s，H-2，6 of Z-cinnamoyl)，3.85(3H，s，OCH
3 of E-cinnamoyl)/3.83(3H，s，OCH
3 of Z-cinnamoyl)，3.78(6H，s，OCH
3 of E-cinnamoyl)/3.75(6H，s，OCH
3of Z-cinnamoyl)，5.04(1H，d，J＝7.5Hz，Glc-1)，5.31(1H，d，J＝7.5Hz，Xyl-1)，6.03(1H，d，J＝4.0Hz，Api-1)，6.13(1H，d，J＝8.5Hz，Fuc-1)，6.25(1H，brs，Rha-1)。
13C NMR data see Table 1.
Table 1 polygalic acid L's
13(solvent is C to C NMR data
5D
5N)
| L | J | K | L | J | K | ||
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Cinn. 1 2 3 4 5 6 7 8 9 OMe | 44.0 69.9 85.7 52.6 52.3 21.0 33.7 41.0 49.1 36.8 23.3 127.5 138.8 46.8 24.3 23.9 47.7 41.9 45.3 30.6 33.7 32.0 180.8 14.0 17.4 18.9 64.3 176.4 32.9 23.9 127.2/127.5 130.3/133.1 114.6/113.9 161.8/160.9 114.6/113.9 130.3/133.1 145.5/144.6 115.5/116.2 167.0/166.2 55.2/55.0 | 44.1 70.2 85.9 52.8 52.4 21.2 33.8 41.2 49.2 37.0 23.5 127.7 138.9 46.9 24.5 24.1 47.9 42.1 45.5 30.8 33.8 32.2 180.9 14.1 17.6 19.1 64.4 176.4 33.1 24.1 127.4/127.6 130.4/133.2 114.8/114.1 162.0/161.1 114.8/114.1 130.4/133.2 145.6/144.7 115.7/116.3 167.1/166.3 55.4/55.1 | 44.0 70.6 85.7 52.7 52.4 21.0 33.5 41.8 49.0 36.8 23.9 127.6 138.7 46.7 24.2 23.9 47.6 41.8 45.1 30.6 33.5 32.1 180.9 14.1 17.2 18.9 64.4 176.6 32.8 23.9 130.5 /130.2 106.1 /108.9 140.8 /139.9 153.9 /153.1 140.8 /139.9 106.1 /108.9 145.8 /144.2 117.5 /118.5 167.4 /166.4 56.1 /55.9 56.1 | C-3sugar Glc-1 2 3 4 5 6 C-28sugar Fuc-1 2 3 4 5 6 Rha-1(F-2) 2 3 4 5 6 Rha-1(F-3) 2 3 4 5 6 Xyl-1 2 3 4 5 Api-1 2 3 4 5 Gal-1 2 3 4 5 6 | 105.1 75.0 78.1 71.2 78.1 62.4 94.8 76.4 80.1 73.2 70.7 16.9 101.9 71.5 82.3 78.1 68.7 18.6 104.8 72.1 73.2 72.4 70.8 18.7 104.7 75.0 76.3 78.0 64.6 111.3 77.3 78.1 74.3 66.4 104.3 71.7 74.9 70.0 77.3 62.2 | 105.2 75.1 78.2 71.5 78.2 62.6 94.8 76.8 79.7 73.2 70.9 16.8 102.1 71.7 82.2 78.0 68.7 18.6 104.7 72.1 72.7 73.6 70.7 18.6 104.7 74.2 86.2 69.3 66.4 111.5 78.0 78.4 74.4 66.6 | 105.0 75.0 78.1 71.5 78.1 62.4 94.2 75.8 74.3 74.7 70.6 16.4 102.0 /102.1 71.5 81.9 78.3 68.3 18.6 105.1 75.4 78.3 71.3 67.0 111.2 77.6 78.1 74.7 66.6 |
| HMG-1 2 3 4 5 OMe | 171.5 46.2 69.9 46.3 174.7 28.2 | 171.5 46.3 70.0 46.9 174.9 28.2 | /55.9 60.5 /60.3 171.4 46.1 69.9 46.1 174.4 28.0 | Ara-1 2 3 4 5 | 105.4 72.4 74.5 69.2 67.0 |
Embodiment 2, determination of activity
One, experimental technique
Get rat cerebellar granule cell, with 1 * 10
6Individual cell/cm
3Be inoculated in 96 orifice plates of the poly-lysine covering of using 10mg/L in advance, 200 μ L/ holes place 37 ℃ to contain 5% (volume fraction) CO
2Incubator in cultivate.Be replaced by the nutrient solution that contains 10 μ mol/L cytosine arabinosides behind the 24h, to suppress the propagation of non-neurocyte.Experiment is divided into high and low two the dosage groups of blank group, model group and medicine, establishes 6 holes for every group.In cultivating the 4th day, drug component does not add the medicine that final concentration is 40 μ g/L, 20 μ g/L; Behind the dosing 24h, model group and drug component do not add the MPP that final concentration is 100 μ mol/L
+, the blank group adds isopyknic substratum; 37 ℃ contain 5%CO
2Incubator in continue to cultivate 24h after, take out 96 orifice plates, the MTT (final concentration is 0.5mg/mL) that in every hole, adds 20 μ L 5mg/mL, behind the reaction 4h, nutrient solution is removed in suction, adds the DMSO of 200 μ l in every hole, gently piping and druming, make the blue particle dissolving, survey its optical density value (OD value) at wavelength 570nm place with full-automatic microplate reader.The experiment triplicate, the optical density value height shows the cell survivaling number height.
Two, statistical analysis
Establish 6 multiple holes for every group, the result is with means standard deviation (X ± SD) expression; Significance of difference paired t-test.
Three, experimental result
By table 2 data as can be seen; compound Onjisaponin L, Onjisaponin J, Onjisaponin K, Tenuiphenone C and Tenuiphenone D relatively have significant difference to the influence and the model group of nerve cell apoptosis, point out these compounds that neurocyte is had provide protection.And show that according to the pharmaceutical research in modern times nerve cell apoptosis is one of inducement that causes senile dementia, point out these compounds having good prospect aspect control and the treatment senile dementia thus.
Table 2 compound is to the influence of nerve cell apoptosis (40 μ g/mL, X ± SD)
| Medicine name | The OD value | Cell survival rate (%) |
| Blank group | 1.224±0.082 | 100 |
| Model group | 0.846±O.053 ### | 69.12 |
| Onjisaponin L | 1.018±0.061*** | 83.17 |
| Onjisaponin J | 0.987±0.054** | 80.64 |
| Onjisaponin K | 0.984±0.082** | 80.39 |
| Tenuiphenone C | 1.000±0.049*** | 81.70 |
| Tenuiphenone D | 1.006±0.049*** | 82.19 |
Paired t-test: compare ###P＜0.001 with the blank group;
Compare with model group,
*P＜0.01,
* *P＜0.001
The present invention utilizes multiple separation means, comprise positive reversed-phase silica gel column chromatography, macroporous adsorbent resin column chromatography, hydroxypropyl dextrane gel column chromatography and preparative high-performance liquid chromatographic method etc., from the plant of polygala root, separate having obtained 5 new compounds, comprise phenolic ketone and saponins compound.These new compounds be found to be from now on further pharmacologically active screening and clinical study, develop determined curative effect, novel control and treatment senile dementia medicine that toxic side effect is little have been established basic substance.
Claims (6)
1, a kind of saponins compound has structure shown in the structural formula II I:
Structural formula (III)
Wherein, R
1=
2, the purposes of the described saponins compound of a kind of claim 1 in preparation intelligence development and anti senile dementia drug.
3, a kind of saponins compound has structure shown in the structural formula IV:
Structural formula (IV)
Wherein, R
2=
4, the purposes of the described saponins compound of a kind of claim 3 in preparation intelligence development and anti senile dementia drug.
5, a kind of saponins compound has structure shown in the structural formula V:
The structure formula V
Wherein, R
3=
6, the purposes of the described saponins compound of a kind of claim 5 in preparation intelligence development and anti senile dementia drug.
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|---|---|---|---|
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310122417 CN1274705C (en) | 2003-12-23 | 2003-12-23 | Compounds with anti neurocyte apoptosis function |
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| Publication Number | Publication Date |
|---|---|
| CN1631865A CN1631865A (en) | 2005-06-29 |
| CN1274705C true CN1274705C (en) | 2006-09-13 |
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ID=34844491
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|---|---|---|---|
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| EP3134421B1 (en) * | 2014-04-24 | 2022-04-20 | Institut National de la Santé et de la Recherche Médicale (INSERM) | New lipophenol compounds and uses thereof |
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