CN101372491A - Lignan sauchinone antipode, preparation thereof and liver protection application - Google Patents
Lignan sauchinone antipode, preparation thereof and liver protection application Download PDFInfo
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- CN101372491A CN101372491A CNA2008101987439A CN200810198743A CN101372491A CN 101372491 A CN101372491 A CN 101372491A CN A2008101987439 A CNA2008101987439 A CN A2008101987439A CN 200810198743 A CN200810198743 A CN 200810198743A CN 101372491 A CN101372491 A CN 101372491A
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Abstract
The invention relates to lignans lizardtail ketone enantiomorph which is expressed by the following formula (1), a method for preparing the compound and the application in the aspect of protecting liver. The method is characterized in that Saururus Chinensis (Lour.) bail1 is refluxed and extracted by methanol or ethanol; after the methanol or the ethanol is recycled, the extract is placed at the room temperature; after being separated and dried, the separated precipitation is dissolved by the mixed solvent of chloroform and methanol, and then silicagel column chromatography is carried out; sherwood oil-ethyl acetate is taken as eluant, and gradient elution is carried out from 20:1-3:1; flow separation with the rf value of 0.5 is carried out on collecting thin-laver chromatography by using the sherwood oil-ethyl acetate with the volume ratio of 10:1, the separated granularcrystaline is placed, and the product is obtained by recrystal. The experiment proves that the compound of the invention has better protective function for liver which is suffered from acute injury. Formula (1).
Description
Technical field
The present invention relates to a kind of Lignanoids compounds, relate in particular to a kind of Rhizoma Saururi (Herba Saururi) ketone enantiomorph, the preparation method who also relates to this compound with and in the application aspect the protection liver.
Background technology
Rhizoma Saururi (Herba Saururi) (Saururus Chinensis (Lour.) baill) is Saururaceae (Saururaceae) per nnial herb, mainly be distributed in east Asia, in Hubei of China, all there is distribution in province such as Guangdong, Guangxi, Yunnan, Sichuan, Zhejiang, Jiangsu, Jiangxi, Anhui, it is grown in the place of low humidity and nearly water, all can gather the whole year, and after clean drying, herb all can be used as medicine, have clearing heat and detoxicating, the effect of diuresis anti-inflammation detumescence.According to research, Rhizoma Saururi (Herba Saururi) also has hypoglycemic, protects the liver, and effects such as anti-oxidant activity are to epoxidase Rel cancer protein, nitricoxide synthase, tumor necrosis factor alpha, PGE
2Deng all restraining effect is arranged, be used for illnesss such as urinary tract infections, nephritic edema, jaundice, women's leukorrhagia more clinically.
The lizardtail lignan class mainly contains three white fat elements (Saucernetin), Ao Sichubai fat element-5 (Austrobailignan-5), three white fat elements-8 (Saucernetin-8) and three white fat elements-7 (Saucernetin-7), Rhizoma Saururi (Herba Saururi) element (Sauchinin), Rhizoma Saururi (Herba Saururi) ketone (Sauchinone) and diastereomer Rhizoma Saururi (Herba Saururi) ketone A (Sauchinone A) thereof and 1 '-Biao Rhizoma Saururi (Herba Saururi) ketone (l '-epi-sauchinone), 2-O-methyl tetrahydrochysene guaiacin (Di-O-methltetrahydrofuriguaiacin) B, red nanmu element (Machilin) D, plain D of the red nanmu of 4-methoxyl group and the Rhizoma Saururi (Herba Saururi) alcohol A (Saucerneol A) of tetrahydrofuran (THF) type sesquilignan, Rhizoma Saururi (Herba Saururi) alcohol B (Saucerneol B), Rhizoma Saururi (Herba Saururi) alcohol C (Saucerneol C), Rhizoma Saururi (Herba Saururi) alcohol D (Saucerneol D), Rhizoma Saururi (Herba Saururi) alcohol E (Saucerneol E), tetrahydrofuran (THF) type two lignanoids (Manassantin A and Manassantin B), SaururinA, 8-O-4 ' type neolignan, Virolin, Saurufuran A and Saurufuran B.In recent years, China has also carried out the research of some to the chemical ingredients of Rhizoma Saururi (Herba Saururi), but its screening and pharmacological research at anti-liver injury and Fibrotic reactive site still is in blank, and the Separation Research of the chemical ingredients of the reactive site that Shang Weiyou is relevant is appeared in the newspapers.
Summary of the invention
The objective of the invention is to isolate from Rhizoma Saururi (Herba Saururi) the active substance that is used for anti-liver injury, another purpose provides the preparation method of this compound, and further purpose is its application aspect the protection liver injury of exploitation.
We are raw material with the Rhizoma Saururi (Herba Saururi), by the refluxing extraction of alcohol, and silica gel column chromatography, the compound that obtains is opposite with the specific rotation of Rhizoma Saururi (Herba Saururi) ketone (Sauchinone), and the liver that is subjected to acute injury is had good provide protection, thereby realizes purpose of the present invention.
Lignan sauchinone enantiomorph of the present invention is represented by following formula (1):
Formula (1)
The preparation method of lignan sauchinone enantiomorph of the present invention, its feature comprises the steps:
(1) with Rhizoma Saururi (Herba Saururi) (Saururus Chinensis (Lour.) baill) with methyl alcohol or alcohol reflux, extracting solution reclaim methyl alcohol or ethanol to the Rhizoma Saururi (Herba Saururi) mass ratio be 2:1～1:2, room temperature is placed the post precipitation of separating out and it is separated drying;
(2) the precipitation volume ratio that step (1) is obtained is the mixed solvent dissolving of 2:1～1:2 chloroform and methyl alcohol, carry out silica gel column chromatography then, as elutriant, gradient elution is carried out in variation from volume ratio 20:1 to 3:1 with petroleum ether-ethyl acetate, and thin-layer chromatography is followed the trail of and merged component; Collecting on the thin layer and launching Rf value with volume ratio 10:1 petroleum ether-ethyl acetate is 0.5 flow point, and coarse crystal is separated out in placement, and purifying obtains formula (1) compound.
Described methyl alcohol of step (1) or alcohol concn are volume fraction 60%～100%, and extraction time can be 2～3 times, and each 2～5 hours, described room temperature was placed 12～18 hours, and described separation can be adopted for example suction filtration of conventional method.
The employed silica gel particle diameter of the described silica gel column chromatography of step (2) is 40～50 microns, and described purifying can carry out recrystallization with methyl alcohol.
The product that obtains by above-mentioned preparation method is colourless needle crystal, and getting molecular formula by the high resolution electrospray ionization mass spectrum is C
20H
20O
6, 2 aromatic ring hydrogen (δ appear in nuclear magnetic resonance spectrum
H6.45 and 6.85) and two (methylenedioxy) groups, one of them (methylenedioxy) group (δ
H5.93,5.90; δ
C101.2) be connected on the aromatic nucleus another (methylenedioxy) group (δ
H5.68,5.63; δ
C98.5) be connected on the fatty carbon.Compose existing signal δ at carbon
C143.1 144.9 and 146.6 show the carbon-oxygen bond of the (methylenedioxy) group on aromatic ring, also have an oxygen to be connected on the aromatic ring in addition.The carbon spectrum signal appears at δ
C199.5 be contribution owing to enol ketone, and δ
C168.5 showing the (methylenedioxy) group connects on the γ-carbon of enol ketone.The hydrogen spectrum signal is at δ
H1.22 (d is J=7.2Hz) with 0.74 (d, J=7.2Hz) two methyl of appearance, each methyl and ortho-hydrogens coupling.Therefore the structure of the product that obtains of above-mentioned preparation method is represented by formula (1).The hydrogen spectrum and the carbon spectrum that contrast this compound and Rhizoma Saururi (Herba Saururi) ketone (Sauchinone) show that these two compounds are steric isomers, and the hydrogen spectrum is nearly all identical with carbon spectrum and mass spectrum, except ketone group carbon (1: δ in the carbon spectrum
C199.5; Rhizoma Saururi (Herba Saururi) ketone: δ
C193.3).But the just in time opposite (product of the present invention: [α] of the specific rotation of product of the present invention with Rhizoma Saururi (Herba Saururi) ketone
25 D-112.8 °, 0.022, chloroform; Rhizoma Saururi (Herba Saururi) ketone: [α]
D+ 97.8 °, 0.022, chloroform), this phenomenon shows that product of the present invention is the enantiomorph of Rhizoma Saururi (Herba Saururi) ketone.The relative steric configuration of compound is clearly confirmed by the monocrystalline X-ray diffraction.Compound is accredited as enantiomorph ent-sauchinone (Wang EC, Shih MH, Liu MC, Chen MT, Lee GH.Heterocycles, 1996,43,969 of Rhizoma Saururi (Herba Saururi) ketone sauchinone; Wang L, Zhao D, Cheng D, Liu Y.ent-sauchinone from saururus chinensis Heterocycles, 2008,75 (5) online available), be the compound that formula (1) is represented.The detailed nuclear magnetic spectrum attribution data of this compound sees Table 1.
Through test, lignan sauchinone enantiomorph of the present invention can be used for protecting liver.
The paddy third conversion enzyme (ALT) of the mouse that lignan sauchinone enantiomorph of the present invention causes tetracol phenixin and the rising of mda (MDA) content all have significant reduction effect; the rising of the paddy third conversion enzyme of the mouse that thioacetyl is caused also has tangible reduction effect in addition, and therefore lignan sauchinone enantiomorph of the present invention has the better protecting effect to the liver that is subjected to acute injury.
Embodiment
Following embodiment further specifies of the present invention, but the invention is not restricted to following embodiment.
Embodiment 1: the preparation of the lignan sauchinone enantiomorph of formula (1) expression
Get Rhizoma Saururi (Herba Saururi) 5kg, with volume fraction 70% alcohol reflux secondary, each 3 hours, each alcohol adding amount is 30L, filters, and collects extracting solution, ethanol is reclaimed in distillation, make extracting solution residue 2L, room temperature is placed and was spent the night 15 hours, has pale brown look precipitation to separate out, suction filtration, divide and get the precipitation part,, obtain pale brown look precipitation 100g in 55 ℃ of dryings.
Chloroform-methanol mixing solutions with volume ratio 1:1 dissolves pale brown look precipitation, adding particle diameter then is that 40～50 microns silica gel 100g mix sample, through silicagel column (1000g, particle diameter is 40～50 microns, the chromatographic separation of 10cm * 100cm) is an eluent with petroleum ether-ethyl acetate, carries out gradient elution at 20:1～3:1, TLC detects and merges same section, obtains 5 parts altogether.Collecting on the thin-layer chromatography and launching Rf value with volume ratio 10:1 petroleum ether-ethyl acetate is 0.5 flow point, and distillating recovering solvent is placed to a small amount of, the needle-like coarse-grain, through recrystallizing methanol, get product 300mg.Confirm it is the compound of formula (1) through the said structure analysis.
Embodiment 2: the compound of formula (1) is to the hepatoprotective effect of tetracol phenixin induced mice acute liver damage
Get 50 of mouse, divide 5 groups at random, every group 10, use 10mL/kg distilled water to irritate stomach for first group,, use 10mL/kg distilled water to irritate stomach for second group as the blank group, as model group, use WulingGanfu capsule 2.0g content/kg to irritate stomach for the 3rd group, the 4th group of compound 5mg/kg that obtains with embodiment 1 irritates stomach, and the 5th group of compound 2.5mg/kg that obtains with embodiment 1 irritates stomach.Except that the blank group, other each group is abdominal injection 0.1% tetracol phenixin peanut oil solution 10mL/kg before irritating stomach all.Irritate the stomach frequency and all be every day 1 time, continuous irrigation stomach 10 days.Last administration fasting in preceding 16 hours.Irritate stomach after 10 days vena ophthalmica get blood, measure average paddy third conversion enzyme of each group, round a liver and weigh, measure average liver coefficient of each group, get mouse lobus dexter liver, measure average mda content of each group.Get the Mouse Liver lobus sinister and do the pathology inspection, use paraffin section, HE dyeing, microscope light microscopy checking.The cardinal principle inspection standard: normal mouse liver tunicle is smooth, and color and luster is ruddy, and good springiness be subjected to the mouse liver or the color of tetracol phenixin damage darker, or color and luster is greyish white, and volume is a bit larger tham normal liver, and fragility is big.Lesion degree is pressed the document classification ,-expression normal liver cell, and+expression hepatocellular degeneration (mainly being cloudy swelling) or spotty necrosis, ++ expression hepatocellular degeneration or focal necrosis, +++expression liver lobule is less than 1/3 hepatic necrosis.Sex change: no sex change of-expression or only central vein extravasated blood expansion, + expression accounts for below 1/3 of liver cell sum with the loose liver cell that turns to main or steatosis of liver cytoplasm, ++ expression based on the liver cell of ballooning degeneration of liver cells or steatosis account for the liver cell sum 1/3～1/2 in, +++represent to account for more than 1/2 of liver cell sum based on the liver cell of ballooning degeneration of liver cells or steatosis.Downright bad :-expression does not have downright bad; The downright bad liver cell of+expression accounts for total liver cell below 10%, ++ the expression liver cell accounts for 10～20% of liver cell sum based on the small pieces necrosis, +++expression liver cell accounts for more than 20% of liver cell sum based on large stretch of necrosis.The results are shown in Table 2.Statistical study, the liver damage degree adopts SPSS12.0 software, with in the nonparameter test, the ranked data rank test, P is the asymptotic probable value of bilateral, and * represents P＜0.05 with the model group comparison, and * * represents P＜0.01, and * * * represents P＜0.001.
The compound of table 2 formula of the present invention (1) is to the hepatoprotective effect of acute liver damage mouse due to the tetracol phenixin
Embodiment 3: the compound of formula (1) is to the hepatoprotective effect of thioacetamide induced mice liver injury
Get 50 of mouse, divide five groups at random, every group 10, first group with 10mL/kg distilled water filling stomach, as the blank group, use 10mL/kg distilled water to irritate stomach for second group, as model group, use WulingGanfu capsule 2.0g content/kg to irritate stomach for the 3rd group, as the positive drug group, the 4th group of product 5mg/kg that obtains with embodiment 1 irritates stomach (being equivalent to crude drug 15g/kg), and the 5th group of product 2.5mg/kg that obtains with embodiment 1 irritates stomach (being equivalent to crude drug 7.5g/kg).Except that the blank group, all the other each groups equal abdominal injection 50mg/kg thioacetamide before irritating stomach, every day 1 time, continuous 10 days, last administration fasting in preceding 16 hours.Irritate stomach after 10 days vena ophthalmica get blood, measure the paddy third conversion enzyme content, and get the Mouse Liver lobus sinister and do the pathology inspection, carry out paraffin section, HE dyeing, microscope light microscopy checking.Lesion degree is pressed the document classification.Check substantially: normal mouse liver tunicle is smooth, and color and luster is ruddy, good springiness, and the color that thioacetamide damage mouse liver has is dark, and volume is big slightly, and fragility is big.The liver damage degree adopts SPSS12.0 software, with nonparameter test middle grade data rank test statistics.The liver injury grading :-expression normal liver cell ,+expression hepatocellular degeneration (mainly being cloudy swelling) or spotty necrosis, ++ expression hepatocellular degeneration or focal necrosis, +++represent liver lobule less than 1/3 hepatic necrosis, ++ ++ the expression liver lobule is downright bad to surpass 1/3.P is the asymptotic probable value of bilateral, and * represents P＜0.05 with the model group comparison, and * * represents P＜0.01, and * * * represents P＜0.001.The results are shown in Table 3.
The compound of table 3 formula of the present invention (1) is to the hepatoprotective effect of acute liver damage mouse due to the thioacetyl
Claims (4)
1. the compound of formula (1):
Formula (1)
2. the preparation method of the described compound of claim 1, its feature comprises the steps:
(1) with Rhizoma Saururi (Herba Saururi) (Saururus Chinensis (Lour.) baill) with methyl alcohol or alcohol reflux, extracting solution reclaim methyl alcohol or ethanol to the Rhizoma Saururi (Herba Saururi) mass ratio for being 2:1～1:2, room temperature is placed the post precipitation of separating out and it is separated drying;
(2) the precipitation volume ratio that step (1) is obtained is the mixed solvent dissolving of 2:1～1:2 chloroform and methyl alcohol, carry out silica gel column chromatography then, as elutriant, gradient elution is carried out in variation from volume ratio 20:1 to 3:1 with petroleum ether-ethyl acetate, and thin-layer chromatography is followed the trail of and merged component; Collecting on the thin-layer chromatography and launching Rf value with volume ratio 10:1 petroleum ether-ethyl acetate is 0.5 flow point, and coarse crystal, purifying are separated out in placement.
3. the preparation method of the compound of formula according to claim 1 (1), it is characterized in that the described extraction time of step (1) is 2～3 times, each 2～5 hours, described room temperature was placed 12～18 hours, described separation is a suction filtration, the employed silica gel particle diameter of the described silica gel column chromatography of step (2) is 40～50 microns, and described purifying carries out recrystallization with methyl alcohol.
4. the application of the described compound of claim 1 in the liver-protective medicine of preparation.
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| CNA2008101987439A CN101372491A (en) | 2008-09-25 | 2008-09-25 | Lignan sauchinone antipode, preparation thereof and liver protection application |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102764359A (en) * | 2012-07-18 | 2012-11-07 | 唐启裕 | Traditional Chinese medicine for treating enteritis and dysentery |
| CN106749311A (en) * | 2017-01-05 | 2017-05-31 | 中国药科大学 | Reflect-Sauchinone analog derivative and its preparation method and application |
| CN106810565A (en) * | 2017-01-05 | 2017-06-09 | 中国药科大学 | Reflect-Sauchinone analog derivative and its application in antineoplastic is prepared |
| CN106866696A (en) * | 2017-01-20 | 2017-06-20 | 张忠立 | The composition of Sauchinone sulfonate or Sauchinone and geniposide and its applied in hepatic or medicine for senile dementia is prepared |
-
2008
- 2008-09-25 CN CNA2008101987439A patent/CN101372491A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102764359A (en) * | 2012-07-18 | 2012-11-07 | 唐启裕 | Traditional Chinese medicine for treating enteritis and dysentery |
| CN102764359B (en) * | 2012-07-18 | 2013-09-18 | 唐启裕 | Traditional Chinese medicine for treating enteritis and dysentery |
| CN106749311A (en) * | 2017-01-05 | 2017-05-31 | 中国药科大学 | Reflect-Sauchinone analog derivative and its preparation method and application |
| CN106810565A (en) * | 2017-01-05 | 2017-06-09 | 中国药科大学 | Reflect-Sauchinone analog derivative and its application in antineoplastic is prepared |
| CN106810565B (en) * | 2017-01-05 | 2018-04-17 | 中国药科大学 | Reflect Sauchinone analog derivative and its application in antitumor drug is prepared |
| CN106866696A (en) * | 2017-01-20 | 2017-06-20 | 张忠立 | The composition of Sauchinone sulfonate or Sauchinone and geniposide and its applied in hepatic or medicine for senile dementia is prepared |
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Open date: 20090225 |