CN100429219C - Celosia argentea suponin compound and its pharmaceutical use - Google Patents
Celosia argentea suponin compound and its pharmaceutical use Download PDFInfo
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- CN100429219C CN100429219C CNB2006100267893A CN200610026789A CN100429219C CN 100429219 C CN100429219 C CN 100429219C CN B2006100267893 A CNB2006100267893 A CN B2006100267893A CN 200610026789 A CN200610026789 A CN 200610026789A CN 100429219 C CN100429219 C CN 100429219C
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Abstract
The present invention discloses the structures of celosin A and celosin B as two new celosin saponin compounds having the chemical structure general formula disclosed in formula (1) in the specification and an extraction separation method thereof, which belong to the technical fields of natural medicine chemistry and medicines. The celosin A and the celosin B are separated from celosia argentea as an amaranthcea plant. The present invention also discloses a celosin saponin compound comprising the two new compounds and the application of derivatives of the celosin saponin compound at the aspect of the preparation of medicines for treating and preventing diseases, such as fatty liver, hepatic injury, hepatic fibrosis, hepatic cirrhosis, coronary disease, myocardial infarction, myocardial ischemia, cerebral ischemia, cerebral infarction, cerebral apoplexy, diabetes, hyperinsulinemia, insulin resistance disease, adiposis, glucose intolerance, and/or hypertension obesity, hyperlipoidemia, aphrenia, depression or dysphoria, insomnia, etc. The chemical structure general formula of the celosin saponin compound is disclosed in formula (1) in the specification.
Description
Technical field
The present invention relates to Natural Medicine Chemistry and medical technical field, relate to the feather cockscomb saponins All new compounds of extraction separation from feather cockscomb (Celosia argentea L.), and the application of feather cockscomb saponins aspect preparation treatment and prevention of liver disease, cardiovascular and cerebrovascular disease, metabolic disease, dementia, depression or anxiety medicine that comprises this new compound and derivative thereof.
Background technology
Hepatopathy, cardiovascular and cerebrovascular disease, metabolic disease and dementia, depression or anxiety etc. all are the common disease and the frequently-occurring disease of harm humans health.Therefore, the active drug of the above-mentioned all diseases of research and development control is the direction that researcher is made great efforts all the time.
Semen Celosiae (Semen Celosiae) is the dry mature seed of Amaranthaceae (Amaranthcea) feather cockscomb (Celosia argentea L.).Bitter, cold nature has clearing liver, effect hot, hypotensive, anti-inflammatory makes eye bright, dispels the wind.Be usually used in the treatment of conjunctival congestion with pain and swelling of the eye, keratitis, nebula, iridocyclitis, dizzy, skin wind-heat itch, mange.But, up to the present, do not have one piece of bibliographical information the feather cockscomb saponin constituent in the feather cockscomb to be used to prepare the report of prevention and treatment hepatopathy, cardiovascular and cerebrovascular disease, metabolic disease, dementia, depression or anxiety medicine.
Summary of the invention
The objective of the invention is to from natural product, seek the natural product that is used to prepare prevention and treatment prevention and treatment hepatopathy, cardiovascular and cerebrovascular disease, metabolic disease, dementia, depression or anxiety safely and effectively, through continuous effort, finally from Amaranthaceae (Amaranthcea) plant feather cockscomb, be separated to the feather cockscomb saponin constituent, respectively called after feather cockscomb glycosides A, feather cockscomb glycosides B; Simultaneously, find that saponin component and the derivative thereof in feather cockscomb total saponins, all feather cockscombs all has tangible prevention and therapeutic action to above-mentioned disease, thereby finished the present invention.
Saponin component in feather cockscomb total saponins of the present invention, all feather cockscombs and derivative thereof can be used for prevention and treatment hepatopathy, cardiovascular and cerebrovascular disease, metabolic disease, dementia, depression or anxiety.These diseases comprise fatty liver, liver injury, hepatic fibrosis, liver cirrhosis, coronary heart disease, myocardial infarction, myocardial ischemia, cerebral ischemia, cerebral infarction, cerebral apoplexy, diabetes, hyperinsulinemia, insulin resistance disease, obesity, glucose intolerance and/or hypertensive obesity disease, hyperlipidaemia; Dull-witted; Depression or anxiety, insomnia.
The present invention finishes by following technical solution, and particular content comprises: the extraction separation of two kinds of feather cockscomb saponin(e new compounds, and structure is identified; The research of the pharmacological effect research of saponin component in feather cockscomb total saponins, the feather cockscomb and derivative prevention thereof and treatment hepatopathy, cardiovascular and cerebrovascular disease, metabolic disease, dementia, depression or anxiety and associated medicinal use.
(1) extraction separation
The present inventor utilizes the feather cockscomb dry mature seed (medicinal material claims Semen Celosiae) that is collected in the Haozhou, Anhui, pulverizing the back extracts with the aqueous ethanol diacolation, the extracting solution concentrating under reduced pressure gets concentrated solution, and concentrated solution is by macroporous resin column, water, 30% ethanol, 60% ethanol and 95% ethanol gradient elution successively.Ethanol eluate with 30% and 60% is concentrating under reduced pressure, drying respectively, respectively feather cockscomb total saponins (feather cockscomb extract) I and feather cockscomb total saponins (feather cockscomb extract) II, with feather cockscomb total saponins (feather cockscomb extract) I and feather cockscomb total saponins (feather cockscomb extract) II merge feather cockscomb total saponins (feather cockscomb extract).The feather cockscomb total saponins through acid hydrolysis and decolouring, is obtained 3 kinds of aglycons, be respectively 2-hydroxyl-23-aldehyde radical-Oleanolic Acid, 2-hydroxyl-23-carboxyl-Oleanolic Acid, 2-hydroxyl-23-methyl-Oleanolic Acid.The feather cockscomb total saponins is carried out silica gel column chromatography repeatedly, and, finally obtain 2 new compounds with Sephadex LH-20 or reverse silica gel purification.
(2) structure is identified
New compound 1
New compound 1 is a white powder, FAB-MSS:m/z 793[M]
-, determine that compound molecular weight is 794.UV (MeOH) shows that compound does not have obvious uv-absorbing.
1H-NMR (C
5D
5N+D
2O, δ, ppm) in, show that this compound has 6 methyl substituted, and be unimodal: 0.95,0.98,1.02,1.29,1.45,1.66 (s, 6 * CH
3); There is a reactive hydrogen at low place: 9.76 (s, 1H); 5.48 (s, 1H) supposition may be the hydrogen on two keys; 5.22 (d, J=7.2Hz) and 4.94 (d J=7.8Hz) infers it may is two anomeric protons on the sugar; 3.5-4.5 hydrogen may be hydrogen signal on the sugar.From
13During composing, C-NMR spectrum and DEPT contain 9 quaternary carbons, 16-CH, 10-CH as can be known in this compound
2, 6-CH
3, can determine that in conjunction with its molecular weight the molecular formula of this compound is: C
41H
62O
15From
13C-NMR (C
5D
5N+D
2O, δ, ppm) spectrum in as can be seen, 3 carbonyls (207.4,180.6,174.4) are arranged in this compound, and one of them is aldehyde radical (207.4); One group of two key (143.7,121.3) is arranged; 103.7 and 102.4 be two end group carbon signals on the sugar.Comprehensive above information can infer that this compound is a Pentacyclic triterpene saponins, and its aglycon is an oleanane type, and is connected with two sugar.
Can further belong to the hydrocarbon of compound 1 according to the HMQC spectrum.
In HMBC spectrum, 1.66 (3H, (1H, hydrogen s) are relevant with 53.4 quaternary carbon, show that this methyl and aldehyde radical all are connected on 4 the quaternary carbon for hydrogen s) and 9.76.174.4 carbon and hydrogen signal on the sugar have relevantly, show that it is glucuronic acid that a sugar is arranged in this compound.5.22 (1H, d, sugared terminal hydrogen J=7.2Hz) and 84.0 carbon have relevant, show that two sugar in this compound are 1 → 2 connections; 4.94 (1H, d, sugared terminal hydrogen J=7.8Hz) and 82.3 carbon have relevant, show that two sugar in the compound are to be connected on 3 of aglycon.Contrast reference [FUMIKO A., TATSUO Y., HmOTAKA S.et al.Triterpenoid glycosides from bark of Meliosma Lanceolata.Phytochemistry1996,42 (3): 809-814] and compound
13C-NMR and
1The H-NMR spectrum can determine that contained sugar is a part β-D-glucuronic acid and a part α-L-arabinose in the compound 1.
The contrast Oleanolic Acid
13C-NMR composes data, can find that this compound does not have methylene signals at the 38ppm place, so 1 or 2 of this compound of deduction has hydroxyl to replace.Compound
13C-NMR spectrum and reference [KOHDA H., TANAKA S., YAMAOKA Y.et al.Saponins from Amaranthus Hypochondriacus.Chem.Pharm.Bull.1991,39 (10): 2609-2612] Bao Dao data basically identical so determine the aglycon structure of compound is: 2-hydroxyl-23-aldehyde radical-Oleanolic Acid.
Comprehensive above the analysis determines that the structure of compound 1 is: 2-hydroxyl-23-aldehyde radical-3-O-[α-L-arabopyranose base (1 → 2)-beta d glucopyranosiduronic acid base]-Oleanolic Acid.Be a new compound, called after feather cockscomb glycosides A (Celosin A).
New compound 1
Table 1 new compound 1
1HNMR,
13C-NMR and HMBC data (600MHZ, C
5D
5N+D
2O, δ, ppm)
New compound 2
New compound 2 is a white powder, FAB-MS:m/z 839[M]
-, determine that compound molecular weight is 840.UV (MeOH) shows that compound does not have obvious uv-absorbing.
1H-NMR (C
5D
5N+D
2O, δ, ppm) in, show that this compound has 6 methyl substituted, and be unimodal: 1.80,1.38,1.09,1.05,1.26,0.86 (s, 6 * CH
3); 5.50 (s, 1H) supposition may be the hydrogen on two keys; 5.08 (d, J=7.2Hz) and 5.01 (d J=7.8Hz) infers it may is two anomeric protons on the sugar; 3.5-4.5 hydrogen be hydrogen signal on the sugar.From
13During composing, C-NMR spectrum and DEPT contain 9 quaternary carbons, 17-CH, 10-CH as can be known in this compound
2, 6-CH
3, can determine that in conjunction with its molecular weight the molecular formula of this compound is: C
42H
64O
17From
13C-NMR (C
5D
5N+D
2O, δ, ppm) spectrum in as can be seen, 3 carbonyls (184.2,184.2,174.3) are arranged in this compound; One group of two key (143.7,121.3) is arranged; 103.7 and 102.4 be two end group carbon signals on the sugar.Comprehensive above information can infer that this compound is the oleanane type pentacyclic triterpene saponin.
Control compounds 2 and compound 1
13C-NMR and
1H-NMR spectrum can find, in the compound 2 on the parent nucleus 23 aldehyde radical (207.4) signal become carboxyl (184.2) signal, other substantially change.Control compounds 2 and reference [MARIEA., BERNARD H., ZHEN H.et al.Jenisseensosides C and D biologically active acylatedtriterpene saponins from Silene Jenisseensis, Phytochemistry 1997,45 (5): 985-990]
13C-NMR and
1The H-NMR spectrum can determine that contained sugar is a part β-D-glucuronic acid and a part β-D-semi-lactosi in the compound 2.
Can further belong to the hydrocarbon of compound 2 according to the HMQC spectrum.In sum, determine that the structure of new compound 2 is: 2-hydroxyl-23-carboxyl-3-O-[β-D-galactopyranose base (1 → 2)-beta d glucopyranosiduronic acid base]-Oleanolic Acid, be new compound, called after feather cockscomb glycosides B (Celosin B).
New compound 2
Table 2 new compound 2
1H NMR,
13C-NMR and HMBC data (600MHZ, C
6D
5N+D
2O, δ, ppm)
More than two kinds of feather cockscomb saponin compounds, up to now, find relevant patent or bibliographical information as yet, be new compound.
(3) activity test of feather cockscomb saponin(e
The present invention has as the compound of the pharmacology and the test of pesticide effectiveness: feather cockscomb total saponins, feather cockscomb glycosides A, feather cockscomb glycosides B, sapogenin 2-hydroxyl-23-aldehyde radical-Oleanolic Acid, 2-hydroxyl-23-carboxyl-Oleanolic Acid, 2-hydroxyl-23-methyl-Oleanolic Acid etc., all obtained good result.These compounds all contain the mother's ring shown in the formula (1), and their chemical structure of general formula is:
Formula (1)
R wherein
1, R
2Representative respectively:
R1:-H ,-CH
3, pectinose glucal acidic group (GlcA-Ara), semi-lactosi glucal acidic group (GlcA-Gal), ethanoyl (CH
3CO-), ethyl (CH
3CH
2-), glucosyl group (Glc), the rhamnosyl glucosyl group (Glc-Rha), (Rha-Glc), (Gal), glucal (glycosides) acidic group (GlcA) for galactosyl for the glucose rhamanopyranosyl, Arabic glycosyl (Ara), xylosyl (Xyl), the Arabic glycosyl (feruloyl-Ara-) of asafoetide acyl, the Arabic glycosyl (coumaroyl-Ara-) of coumaric acyl;
R
2: aldehyde radical (CHO), carboxyl (COOH), methyl (CH
3).
The chemical structure of feather cockscomb saponin(e and derivative thereof determines that its female ring is gone up each R group and seen Table 3.
The female ring of table 3 feather cockscomb saponin(e and derivatives chemical structural formula thereof is gone up each R group
| Numbering | The compound title | R 1 | R 2 |
| 1 | 2-hydroxyl-23-aldehyde radical-Oleanolic Acid | -H | -CHO |
| 2 | 2-hydroxyl-23-carboxyl-Oleanolic Acid | -H | -COOH |
| 3 | 2-hydroxyl-Oleanolic Acid | -H | -CH 3 |
| 4 | 2-hydroxyl-23-aldehyde radical-3-O-(pectinose-glucal acidic group)-Oleanolic Acid | -GlcA-Ara | -CHO |
| 5 | 2-hydroxyl-23-carboxyl-3-O-(pectinose-glucal acidic group)-Oleanolic Acid | -GlcA-Ara | -COOH |
| 6 | 2-hydroxyl-3-O-(pectinose-glucal acidic group)-Oleanolic Acid | -GlcA-Ara | -CH 3 |
| 7 | 2-hydroxyl-23-aldehyde radical-3-O-(semi-lactosi-glucal acidic group)-Oleanolic Acid | -GlcA-Gal | -CHO |
| 8 | 2-hydroxyl-23-carboxyl-3-O-(semi-lactosi-glucal acidic group)-Oleanolic Acid | -GlcA-Gal | -COOH |
| 9 | 2-hydroxyl-3-O-(semi-lactosi-glucal acidic group)-Oleanolic Acid | -GlcA-Gal | -CH 3 |
| 10 | 2-hydroxyl-23-aldehyde radical-3-O-methyl-Oleanolic Acid | -CH 3 | -CHO |
| 11 | 2-hydroxyl-23-carboxyl-3-O-methyl-Oleanolic Acid | -CH 3 | -COOH |
| 12 | 2-hydroxyl-3-O-methyl-Oleanolic Acid | -CH 3 | -CH 3 |
| 13 | 2-hydroxyl-23-aldehyde radical-3-O-ethanoyl-Oleanolic Acid | CH 3CO- | -CHO |
| 14 | 2-hydroxyl-23-carboxyl-3-O-ethanoyl-Oleanolic Acid | CH 3CO- | -COOH |
| 15 | 2-hydroxyl-3-O-ethanoyl-Oleanolic Acid | CH 3CO- | -CH 3 |
| 16 | 2-hydroxyl-23-aldehyde radical-3-O-ethyl-Oleanolic Acid | CH 3CH 2- | -CHO |
| 17 | 2-hydroxyl-23-carboxyl-3-O-ethyl-Oleanolic Acid | CH 3CH 2- | -COOH |
| 18 | 2-hydroxyl-3-O-ethyl-Oleanolic Acid | CH 3CH 2- | -CH 3 |
| 19 | 2-hydroxyl-23-aldehyde radical-3-O-glucosyl group-Oleanolic Acid | -Glc | -CHO |
| 20 | 2-hydroxyl-23-carboxyl-3-O-glucosyl group-Oleanolic Acid | -Glc | -COOH |
| 21 | 2-hydroxyl-3-O-glucosyl group-Oleanolic Acid | -Glc | -CH 3 |
| 22 | 2-hydroxyl-23-aldehyde radical-3-O-(rhamnosyl-glucosyl group)-Oleanolic Acid | -Glc-Rha | -CHO |
| 23 | 2-hydroxyl-23-carboxyl-3-O-(rhamnosyl-glucosyl group)-Oleanolic Acid | -Glc-Rha | -COOH |
| 24 | 2-hydroxyl-3-O-(rhamnosyl-glucosyl group)-Oleanolic Acid | -Glc-Rha | -CH 3 |
| 25 | 2-hydroxyl-23-aldehyde radical-3-O-(glucose-rhamanopyranosyl)-Oleanolic Acid | -Rha-Glc | -CHO |
| 26 | 2-hydroxyl-23-carboxyl-3-O-(glucose-rhamanopyranosyl)-Oleanolic Acid | -Rha-Glc | -COOH |
| 27 | 2-hydroxyl-3-O-(glucose-rhamanopyranosyl)-Oleanolic Acid | -Rha-Glc | -CH 3 |
| 28 | 2-hydroxyl-23-aldehyde radical-3-O-galactosyl-Oleanolic Acid | -Gal | -CHO |
| 29 | 2-hydroxyl-23-carboxyl-3-O-galactosyl-Oleanolic Acid | -Gal | -COOH |
| 30 | 2-hydroxyl-3-O-galactosyl-Oleanolic Acid | -Gal | -CH 3 |
| 31 | 2-hydroxyl-23-aldehyde radical-3-O-(glucose-aldehydic acid base)-Oleanolic Acid | -GlcA | -CHO |
| 32 | 2-hydroxyl-23-carboxyl-3-O-(glucose-aldehydic acid base)-Oleanolic Acid | -GlcA | -COOH |
| 33 | 2-hydroxyl-3-O-(glucose-aldehydic acid base)-Oleanolic Acid | -GlcA | -CH 3 |
| 34 | Arabic glycosyl-the Oleanolic Acid of 2-hydroxyl-23-aldehyde radical-3-O- | -Ara | -CHO |
| 35 | Arabic glycosyl-the Oleanolic Acid of 2-hydroxyl-23-carboxyl-3-O- | -Ara | -COOH |
| 36 | Arabic glycosyl-the Oleanolic Acid of 2-hydroxyl-3-O- | -Ara | -CH 3 |
| 37 | 2-hydroxyl-23-aldehyde radical-3-O-xylosyl-Oleanolic Acid | -Xyl | -CHO |
| 38 | 2-hydroxyl-23-carboxyl-3-O-xylosyl-Oleanolic Acid | -Xyl | -COOH |
| 39 | 2-hydroxyl-3-O-xylosyl-Oleanolic Acid | -Xyl | -CH 3 |
| 40 | Arabic glycosyl-the Oleanolic Acid of 2-hydroxyl-23-aldehyde radical-3-O-asafoetide acyl | feruloyl- Ara- | -CHO |
| 41 | Arabic glycosyl-the Oleanolic Acid of 2-hydroxyl-23-carboxyl-3-O-asafoetide acyl | feruloyl- Ara- | -COOH |
| 42 | Arabic glycosyl-the Oleanolic Acid of 2-hydroxyl-3-O-asafoetide acyl | feruloyl- Ara- | -CH 3 |
| 43 | Arabic glycosyl-the Oleanolic Acid of 2-hydroxyl-23-aldehyde radical-3-O-coumaric acyl | coumaroyl- Ara- | -CHO |
| 44 | Arabic glycosyl-the Oleanolic Acid of 2-hydroxyl-23-carboxyl-3-O-coumaric acyl | coumaroyl- Ara- | -COOH |
| 45 | Arabic glycosyl-the Oleanolic Acid of 2-hydroxyl-3-O-coumaric acyl | coumaroyl- Ara- | -CH 3 |
The mixture of a kind of or arbitrary combination of above-mentioned compound comprises the feather cockscomb extract, and its efficient part is a total saponins, also is the feather cockscomb total saponins, and the total content of saponins compound is 0.01%-100% in this described mixture.
All saponins compounds of the present invention all can be used for preparing the medicine of treatment hepatopathy, cardiovascular and cerebrovascular disease, metabolic disease, dementia, depression or anxiety.These diseases comprise fatty liver, liver injury, hepatic fibrosis, liver cirrhosis, coronary heart disease, myocardial infarction, myocardial ischemia, cerebral ischemia, cerebral infarction, cerebral apoplexy, diabetes, hyperinsulinemia, insulin resistance disease, obesity, glucose intolerance and/or hypertensive obesity disease, hyperlipidaemia; Dull-witted; Depression or anxiety, insomnia.
Embodiment
Now the invention will be further described in conjunction with the embodiments, but the not merely cited embodiment of content of the present invention.Experiment is collected in the Haozhou, Anhui with feather cockscomb in September, 2004, and identifies through the inventor.
Embodiment 1. feather cockscomb glycosides A extract
The present inventor utilizes the feather cockscomb dry mature seed (medicinal material claims Semen Celosiae) that is collected in the Haozhou, Anhui, pulverizing the back extracts with the aqueous ethanol diacolation, the extracting solution concentrating under reduced pressure gets concentrated solution, concentrated solution passes through macroporous resin column, water successively, 30% ethanol, 60% ethanol and 95% ethanol gradient elution, ethanol eluate with 30% and 60% is concentrating under reduced pressure respectively, dry, respectively feather cockscomb total saponins (feather cockscomb extract) I and feather cockscomb total saponins (feather cockscomb extract) II, with feather cockscomb total saponins (feather cockscomb extract) I and feather cockscomb total saponins (feather cockscomb extract) II merge feather cockscomb total saponins (feather cockscomb extract).The feather cockscomb total saponins through acid hydrolysis and decolouring, is obtained 3 kinds of aglycons, be respectively 2-hydroxyl-23-aldehyde radical-Oleanolic Acid, 2-hydroxyl-23-carboxyl-Oleanolic Acid, 2-hydroxyl-23-methyl-Oleanolic Acid.I carries out silica gel column chromatography repeatedly with the feather cockscomb total saponins, with chloroform-methanol (30: 1～1: 1) solvent systems wash-out, collect the elutriant of chloroform-methanol (2: 1～1: 1), after this elutriant concentrated, go up silicagel column again, with the solvent systems wash-out of methanol-water (5: 1～1: 1), and use Sephadex LH-20, get feather cockscomb glycosides A.
Embodiment 2. feather cockscomb glycosides B extract
Semen Celosiae is extracted with the aqueous ethanol heating, the extracting solution concentrating under reduced pressure gets concentrated solution, concentrated solution is by macroporous resin column, water, 30% ethanol, 60% ethanol and 95% ethanol gradient elution successively, the ethanol eluate concentrating under reduced pressure with 60%, dry feather cockscomb total saponins (feather cockscomb extract) II.II carries out silica gel column chromatography repeatedly with the feather cockscomb total saponins, with chloroform-methanol (30: 1～1: 1) solvent systems wash-out, collect the elutriant of chloroform-methanol (2: 1～1: 1), after this elutriant concentrated, go up silicagel column again, with the solvent systems wash-out of methanol-water (5: 1～1: 1), and use reverse silica gel purification, get feather cockscomb glycosides A, feather cockscomb glycosides B successively.
The test of embodiment 3. pharmacological effects
The method of above-mentioned each compound pharmacology and pharmacodynamics test is basic identical, is that example is described in detail as follows with feather cockscomb total saponins (feather cockscomb extract), feather cockscomb glycosides A, feather cockscomb glycosides B below:
One, saponins compound is to the preventive and therapeutic effect of hepatopathy
For investigating the feather cockscomb saponin(e in the curative effect aspect the treatment acute and chronic hepatitis, the present invention has done deep pharmacodynamic experiment research, and pharmacodynamic study has been selected tetracol phenixin (CCl for use
4) inductive chmice acute liver injury model, rat chronic Liver Fibrosis Model and the chronic fatty liver model of high lipid food inductive.Preceding two models are that classical screening protects the liver and the model of hepatic fibrosis control medicine, and it is similar to human body hyperlipidemia fatty liver mechanism that the third model is generally acknowledged by everybody, is used for the classical model that research of hyperlipidaemia fatty liver and lipid lowering agent are developed.
(1) provide protection of the chmice acute liver injury that tetracol phenixin is caused
1. experimental animal and method:
60 of Kunming mouses, be divided into 6 groups, 10 every group, be respectively: the normal control group, model control group, positive controls Biphenylylmethylcarbinol group, medicine group: feather cockscomb total saponins (1#), feather cockscomb glycosides A (2#), feather cockscomb glycosides B (3#): dosage is respectively 3mg/Kg, 2mg/Kg, 2mg/Kg.Continuous oral administration 3 days, volume is 0.2ml/10g, 1h abdominal injection 0.1% tetracol phenixin 10ml/kg after the administration in the 3rd day plucks the eyeball blood sampling, centrifugal determination of serum aspartic transaminase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) after 18 hours.
4. result and conclusion
After the tetracol phenixin modeling, serum AST, ALT and the ALP of mouse obviously raise, and with the normal control group difference of highly significant are arranged.1#, 2#, the administration of 3# continuous oral 3 days, AST, ALT and ALP rising that tetracol phenixin is caused have tangible prophylactic effect (seeing Table 4).
Conclusion: the feather cockscomb saponins compound has tangible prophylactic effect to the mouse liver injury of tetrachloro-methane induction.
Table 4 feather cockscomb saponins compound causes the provide protection blood parameters of liver injury to tetracol phenixin
Compare with model group: * p＜0.05**p＜0.01
(2) to the therapeutic action of fatty liver
Along with the raising of people's living standard and the variation of dietary structure, fatty liver has become a kind of common disease, frequently-occurring disease.This disease is common in patients such as obesity, alcoholic liver disease, hepatitis, diabetes and hyperlipidemia, has become a public health problem at present, the serious harm human health.Fatty liver is the early stage performance of multiple liver toxicity damage, can form fat hepatitis and hepatic fibrosis, even liver cirrhosis.Therefore, Prevention and Management of Fatty Liver is very important to the development of control chronic hepatopathy.Yet, still lack effective lipotropic medicine at present, therefore be necessary to carry out fatty liver prevention drug research.One of purpose of the present invention provides lipotropic active drug.
1, laboratory animal and method:
70 of Wister rats, body weight 180-230g is divided into two groups at random, and first group 10, be normal group, give and normal feed; All the other animals are divided into second group, give and high lipid food after 60 days, put to death wherein 10, do the hepatic pathology section, determine that the fatty liver model is set up after, be divided into following 5 groups at random, 1. the fatty liver model group: give continuously and high lipid food; 2. non-treatment group: animal changes the food normal diet, 3. 3 medicine groups: animal changes the food normal diet, give and medicine 1#-feather cockscomb total saponins (feather cockscomb extract), 2#-feather cockscomb glycosides A, 3#-feather cockscomb glycosides B, dosage is respectively 3mg/Kg/d, 2mg/Kg/d 2mg/Kg/d, successive administration 30 days.
2, observation index:
A body weight: in the time of 0,30,60,90 day, weigh respectively
B blood parameters: Serum ALT, AST, serum total cholesterol, triglyceride level
The c pathological examination: paraffin section, HE dyeing, observe fatty liver and inflammation degree of necrosis.
3, experimental result:
The result shows: saponin(e 1#, 2#, 3# can obviously reduce cholesterol and triglyceride level in the serum, effectively alleviate the fatty liver sex change that high lipid food causes, improve the hepatic disorder (table 5, table 6, table 7) that causes because of steatosis.
The variation of blood fat in each experimental group animal serum of table 5
Compare with model control group,
*P＜0.01
The variation of each experimental group animal serum transaminase content of table 6
Compare with model control group,
*P＜0.01
The degree (%) of each experimental group animal livers steatosis of table 7
(3) to tetracol phenixin (CCl
4) effect of the rat chronic hepatic fibrosis brought out
1, laboratory animal and method;
120 of male Wister rats are divided into 6 groups at random, 20 every group; Except that the normal control group, all the other each treated animals are the CCl of subcutaneous injection 10% weekly all
4(5ml/Kg) 2 times, totally 12 weeks; From start injection CCl
4Rise, press the drug dose administration every day 1 time, in totally 12 weeks, administering mode: gastric infusion, dosage: positive drug Biphenylylmethylcarbinol 160mg/Kg/d, 1#, 2#, 3#, dosage are respectively 3mg/Kg/d, 2mg/Kg/d, 2mg/Kg/d.
2, observation index:
When a. experiment finishes, press the kit method blood sampling and measure each index;
B. get hepatic tissue, press kit method and measure oxyproline (HP) content;
C.. get hepatic tissue, the pathology histological examination is done in HE dyeing, calculates the collagen volume integral.
3, experimental result:
(1) liver function, biochemical indicator the results are shown in Table 8, table 9: model control group AST, ALT, TP, PIIIP, CIV compare with the normal control group; there is highly significant difference (P＜0.01); positive control is compared with model control group with each group medicine group and is all had highly significant difference (P＜0.01), illustrates that 1#, 2#, 3# all have provide protection to liver.
(2) pathological examination result: see Table 10, the collagen volume integral of model control group is compared with the normal control group, there is highly significant difference (P＜0.01), positive control is compared with model control group with each medicine group and is all had highly significant difference (P＜0.01), illustrates that 1#, 2#, 3# all have tangible effect to anti-hepatic fibrosis.
Test-results shows that saponins compound of the present invention is to CCl
4Due to the rat chronic hepatic fibrosis obvious therapeutic action is arranged.
Table 8 saponins compound is to CCl
4Due to the rat chronic liver injury after the influence of liver function
Compare with model control group,
*P＜0.01
Table 9 saponins compound is to CCl
4Due to the influence of rat chronic liver injury heptic fibrosis
Compare with model control group,
*P＜0.01
Table 10 saponins compound is to CCl
4Due to the rat chronic liver injury after the influence of collagen volume integral
Compare with model control group,
*P＜0.01
Two, the cardiovascular and cerebrovascular activity of saponins compound
(1) to Racemic isoproterenol (ISO) to the therapeutic action of rat heart muscle ischemic
1, laboratory animal and method
40 of Healthy female SD rats are divided into 5 groups at random, 8 every group, are respectively normal control group, model control group and medicine 1#, 2#, 3# group.Normal control group and model control group are irritated stomach respectively in advance and are given physiological saline, the other gastric infusion of drug component, and every day 1 time, dosage is respectively 3mg/Kg/d, 2mg/Kg/d, 2mg/Kg/d, successive administration three days.Subcutaneous injection ISO (1ml/Kg body weight) behind model control group and medicine group second day and the 3rd day administration 1h, the normal control group waits the physiological saline of capacity, respectively record last give be subjected to before the reagent thing and give for the 2nd time with ISO after the electrocardiogram(ECG of 30min, measure the J point value, calculate give with ISO after respectively organize the absolute value of rat J point displacement.The rat aorta blood sampling, centrifugal separation plasma behind the anticoagulant heparin, LDH activity unit in the spectrophotometry blood plasma.Each administration group statistics and model group are relatively carried out the t-check.Serum lactic dehydrogenase (LDH) calculation formula is as follows:
2, result and conclusion
Each group causes rat heart muscle ischemic II lead electrocardiogram J point change in displacement to ISO and sees Table 11.Each group causes the variation of rat heart muscle ischemic LDH activity unit to ISO and sees Table 12.
Table 11 compound is to the influence (n=8) of rat heart muscle ischemic J point displacement due to the ISO
Compare with model control group,
*P＜0.05,
*P＜0.01,
Table 12 compound is to the influence (n=8) of ISO rat LDH activity unit
Compare with model control group,
*P＜0.05,
*P＜0.01,
Experimental result shows that behind rat skin lower injection (s.c.) ISO, the model group animal displacement of J point occurs and increases, and the significance myocardial ischemia that the LDH unit of activity increases in the blood plasma changes.Medicine 1#, 2#, 3# group can significantly reduce LDH level in J point displacement and the blood plasma; compare with model control group and to have significant difference (p＜0.05); show that the rat heart muscle ischemic that ISO is caused has significant inhibitory effect; and the damage that can alleviate ischemic myocardium, therefore cardiac muscle there is tangible ischemic provide protection.
(2) saponins compound is to the provide protection of rat coronary artery caused by ligature acute myocardial ischemia
1, laboratory animal and method
Get 40 of healthy SD rats about body weight 200g, male and female half and half are divided into 4 groups at random by body weight: model control group (physiological saline 10ml/kg), positive drug group Proprasylyte group (8mg/Kg), medicine 1#, 2#, 3# group.All samples oral administration gastric infusion, administration volume are 10ml/kg, every day 1 time, 2d continuously.
1h after the last administration, abdominal injection 12% Chloral Hydrate 3ml/kg anaesthetizes, the record normal ECG, chest unhairing, sterilization, along the about 2cm of left mid-clavicular line longitudinal incision skin, separate the flesh layer in the 4th or the 5th intercostal passivity, open the thoracic cavity, cut off pericardium, the light right side thorax of pressing is extruded heart, behind ligation arteria coroaria sinistra in coronary vein place between right side circular cone and the left auricle of heart, heart is put back to the thoracic cavity, fully discharge air in the thoracic cavity, sew up and close thoracic cavity, respirator assisted respiartion, frequency 20 times/minute, Tidal volume 5ml.At once, 1h, 24h, 48h trace one section electrocardiogram(ECG respectively after the ligation, and in 24h, 48h difference oral administration gavage medicine 1#, 2#, 3# and physiological saline, dose is the same.
Behind coronary ligation 50h, rat is anaesthetized once more, takes out heart rapidly, uses normal saline flushing, removes blood stains, rejects non-cardiac muscular tissues such as blood vessel, fat, inhales the branch that anhydrates with thieving paper, claims weight in wet base whole-heartedly.Along coronary sulcus excision atrium, stay ventricle, weigh, along coronary sulcus from the apex of the heart to heart base portion 4 of parallel myocardium sheets with ventricular muscles crosscut Cheng Houyue 0.1cm, clean with normal saline flushing, myocardium sheet is placed in 0.1% the N-BT solution, the 15min that under 37 ℃ of water bath condition, dyes, unnecessary dyestuff is removed in water flushing immediately after the dyeing.Infarcted region is not painted, and non-infarcted region is dyed blueness by N-BT solution.Cut off infarcted myocardium, claim weight in wet base, account for whole-heartedly the per-cent of weight in wet base with the infarcted region weight in wet base and represent myocardial infarct size, the results are shown in Table 13.
2, result and conclusion
Saponins compound can highly significant the tissue necrosis that causes of reduction myocardial ischemia, ischemia group is woven with significant protective effect.
Table 13 saponins compound causes the influence (n=10) of Model Rats with Acute Myocardial Ischemia ischemic scope to coronary artery ligation
Compare with model control group,
*P＜0.01
(3) saponins compound is to the provide protection of focal brain ischemia-reperfusion injury in rats
The focal brain ischemia-reperfusion injury in rats model, be generally acknowledge prevent and treat cerebral ischemia (or cerebral apoplexy, cerebral infarction) model, therefore, what the present invention adopted this model research saponins compound prevents and treats the cerebro-vascular diseases activity.
1. experimental animal and method:
Get totally 48 of male SD rats, be divided into 6 groups at random, every group 8, the 1st group is sham operated rats, the 2nd group is model group (injection equal-volume physiological saline), the 3rd group of positive medicine Nimoldipine injection liquid group (Bayer A.G's production), dosage 2mg/Kg, 4th, 5,6 groups is 1#, 2#, 3# group, and dosage is respectively 3mg/Kg, 2mg/Kg, 2mg/Kg.Administration time is ischemic tail vein injection after 1 hour.
With reference to the line bolt model of Longa EZ report prepare cerebral ischemia re-pouring injured model (Longa EZ, et al:Reversablemiddle cerebral artery occlusion without craniectomy in rat.Stroke, 1989,20:84).Ischemic poured into to break end after 24 hours in 2 hours again gets brain, TTC dyeing is left and taken sample and is carried out cerebral infarct volume and measure and (see the Zhang Juntian chief editor for details: modern pharmacology experimental methodology, the 1241st page, combined publication society of China Concord Medical Science University of Beijing Medical University, October in 1998 the 1st edition).
2, experimental result sees Table 14:
Table 14 saponins compound is to the provide protection of focal brain ischemia-reperfusion injury in rats
Compare with model group,
*P＜0.05,
*P＜0.01
As can be seen from Table 14,1#, 2#, 3# all significantly dwindle brain infarction area, alleviate ischemic side brain hemisphere oedema degree.Show that 1#, 2#, 3# have strong provide protection to focal brain ischemia-reperfusion injury in rats.
Three, saponins compound is to the preventive and therapeutic effect of metabolic disease
1, laboratory animal and method:
Get body weight and be 50 of the rats of 180～240g, male and female half and half are left and taken 10 at random as the normal control group, and all the other are experimental group.After the experimental group rat fasting 12, with abdominal cavity, lower-left disposable injection streptozotocin (STZ, u s company) 65mg/Kg (is dissolved in PH4.5,0.1mmol/L citrate buffer), control group is injected isometric citrate buffer, inject after 48 hours, the glucose in urine of all blood sugar concentration＞13mmol/L is strong positive person, and occur drinking more, many foods, the diuresis person is a diabetes model, diabetes rat is divided into 4 groups more at random, every group 10, diabetic model group, saponins compound 1#, 2#, 3# treatment group, control group and model group are fed and are raised normal diet, except that freely drinking water, irritate stomach (2ml/d) with distilled water every day.Saponins compound 1#, 2#, 3#, every rat is according to dosage irritated 4 weeks of stomach, during standard feed and drinking-water unrestricted, the experiment end, with Sodital anesthesia, heart extracting blood detects relevant biochemical indicator: 1. whole blood blood sugar detection: the afterbody 20 μ L that take a blood sample, measure by blood glucose meter with blood sugar test paper.2. measure LPO, adopt the TBA method.3. SOD adopts xanthine oxidase.
2, result and conclusion
The results are shown in Table 15, table 16, table 17, compare with diabetic model group, 1#, 2#, 3# whole blood blood sugar obviously descend (P＜0.01), more rat drinks, eats more, the diuresis symptom is obviously improved, whole blood LPO content obviously descends, the plasma SOD level obviously improves, and the hypoglycemic activity that shows 1#, 2#, 3# may have oxidation-resistant active ingredient with it and suppress the generation of free radical and accelerate the removing of free radical relevant.
The key of metabolic disease is lipid metabolism and carbohydrate metabolism disturbance, compound of the present invention not only can reducing cholesterol, regulating blood fat (see Table 5, table 6), improves lipid metabolism, can also lowering blood glucose, reconcile carbohydrate metabolism, thereby to metabolic disease performance prevention and result of treatment.
Table 15 saponins compound is to the influence of experimental diabetic rats blood sugar
Compare with model group,
*P＜001
Table 16 saponins compound is to the influence of experimental diabetic rats whole blood LPO content
Table 17 saponins compound is to the influence of experimental diabetic rats activity of plasma SOD
Four, saponins compound is to the therapeutic action of dementia
One of clinical main performance of senile dementia is exactly a damage in learning and memory.Learning and memory is one of critical function of brain, the intellectual level of its reaction brain.And what can weigh the ability of its learning and memory by the mistake made in the animal behavior.Scopolamine inductive Model of Dementia in Rats is exactly to utilize this principle to study the influence of medicine to animal intelligence.
We adopt MORRIS water maze method and keep away two kinds of methods of dark experiment, use Scopolamine learning memory disorder model, observe 1#, 2#, the 3# influence to learning and memory in rats.
1.MORRIS water maze method
1.1 animal and method
The MORRIS water maze laboratory: 60 of SD rats (providing) by the The 2nd Army Medical College Experimental Animal Center, be divided into 6 groups at random, be respectively blank group, model group, positive controls and 1#, 2#, 3# medicine group.Its empty group and model group are irritated stomach with 0.5% Xylo-Mucine, and positive controls is irritated stomach and given Hup A 4mg/kg, and the medicine group is pressed the 20mg/kg gastric infusion, every day 2 times, totally 8 days.After the every day of the administration for the first time 1 hour, begin to carry out the training of MORRIS water maze.Experiment allows rat free swimming 2 minutes to adapt to surrounding environment the day before yesterday, since first day, train every day 4 times, select a place of entry at random at every turn, rat is put into water towards pool wall, observe and write down route map and the required time (latent period) that rat sought and climbed up platform.4 trained rat, need it is caused platform if rat was not found platform in 120 seconds respectively from four different people's water spot people water.At this moment be designated as 120 seconds latent period, each training 60 seconds at interval, continuous 7 days.After the last administration in the 8th day 1 hour, blank group rats by intraperitoneal injection physiological saline 1ml/kg, all the other respectively organize rats by intraperitoneal injection scopolamine hydrobromide 2mg/kg.Every rat injection end back 25min is fixed into water spot by one and is dropped in the water towards pool wall, observes and write down the time (latent period) that it is sought platform route and finds platform.
Keep away dark experiment: 60 of SD rats, be divided into 6 groups at random by the aforementioned groupings method, wherein blank group and model group are irritated stomach with 0.5% Xylo-Mucine, control group is irritated stomach and is given Hup A 4mg/kg, the medicine group is pressed the 20mg/kg gastric infusion, every day 2 times, totally 8 days.1 hour begins training after the last administration in the 8th day, except that the blank group, and every group of rat 25min abdominal injection scopolamine hydrobromide 2.0mg/kg before training, blank group is physiological saline 1.0ml/kg.During training rat is put into case endoadaptation 3min earlier, connect power supply then, animal back is placed to the hole keep away the bright chamber of camera bellows, observe animal and enter the total degree (number of times of making a mistake) that enters the darkroom in time (latent period) in darkroom and the 5min first.Repeated to keep away dark experimental implementation on the 9th day and write down latent period and make mistakes the number as the memory indexs.
2 results and conclusion see Table 18 and table 19
As can be seen from Table 20, compare with model group, obviously shorten the latent period that the rat of 1#, 2#, 3# seeks platform, and difference has statistical significance.
Table 18 is respectively organized the latent period that rat seeks platform
*P＜0.05,
*Compare with model group P＜0.01
As shown in Table 19, in keeping away dark experiment, the rat of 1#, 2#, the 3# digital display work of making mistakes is lower than model group, and then prolong greatly latent period.
Table 19 is respectively organized rat and is made a mistake number of times and latent period relatively
Compare with model group,
*P＜0.05,
*P＜0.01
Above-mentioned result of study shows that 1#, 2#, 3# can obviously improve the learning and memory function of dementia rats, and dementia is had certain prevention and therapeutic action.
Five, the antidepressant of saponins compound or anxiety activity
Mouse forced swimming experiment (mouse forced swimming test) is classical depressed animal model, so investigate the preventive and therapeutic effect of saponins compound to the experimental animal models dysthymia disorders with it.
1, laboratory animal and method
Method by Zhang Juntian chief editor " modern pharmacology experimental technique " (first volume) the 104th page is carried out.Mouse (Kunming kind, male, 20-23 gram) is put into 10 centimetres of the depth of waters, and swimming in the graduated cylinder that water temperature is 25 ± 1 ℃ (20 centimetres high, 14 cm diameters) makes it produce the feared state of mind, takes out after 5 minutes, and 32 ℃ down will be hairy dried.Give the laboratory animal gastric infusion in 24 hours respectively, again mouse is put into above-mentioned environment, measure mouse and in 6 minutes back 4 minutes, keeps the motionless time of swimming, with the shortening of dead time standard as judgement medicine antidepressant effect.This tests 10 of every group of mouse.1. the blank group gives the physiological saline with drug study group equivalent; 2. positive controls gives medicine fluorine west tincture, and dosage is 6mg/Kg; 3. 1# of the present invention, 2#, 3# dosage are respectively: 3mg/Kg, 2mg/Kg, 2mg/Kg, the identical time in 24 hours after each is organized administration time and is that mouse is hairy and does.Route of administration is divided into gastric infusion three times, and gastric infusion carries out the forced swimming experiment after 60 minutes the last time.
2, result and conclusion: experimental result sees Table 20.
Table 20 saponins compound is to the result that influences of mouse forced swimming experiment behavior
Compare with the blank group
*P＜0.05,
*P＜0.01
As can be seen from Table 20, medicine 1#, 2#, 3#, all can significantly reduce the mouse forced swimming dead time, show that this compounds all has antidepressant activity, therefore can be used to prepare the medicine of preventing and treating depression or anxiety disorder.
Claims (2)
1, a kind of feather cockscomb saponins compound is characterized in that this compound has the chemical structure shown in the chemical structure of general formula (1):
Formula (1)
Wherein: R
1=pectinose glucal acidic group, R
2=-CHO is a compound 1;
Or R
1=semi-lactosi glucal acidic group, R
2=-COOH is a compound 2;
The chemical structure of compound 1 is: 2-hydroxyl-23-aldehyde radical-3-O-[α-L-arabopyranose base (1 → 2)-beta d glucopyranosiduronic acid base]-Oleanolic Acid, called after feather cockscomb glycosides A;
The structure of compound 2 is: 2-hydroxyl-23-carboxyl-3-O-[β-D-galactopyranose base (1 → 2)-beta d glucopyranosiduronic acid base]-Oleanolic Acid, called after feather cockscomb glycosides B;
Its structure is respectively:
Compound 1 compound 2.
2, feather cockscomb saponins compound according to claim 1 is used to prevent and treat the purposes of the medicine of fatty liver, liver injury, hepatic fibrosis, liver cirrhosis, coronary heart disease, myocardial infarction, myocardial ischemia, cerebral ischemia, cerebral infarction, cerebral apoplexy, diabetes, hyperinsulinemia, insulin resistance disease, obesity, glucose intolerance, hypertensive obesity disease, hyperlipidaemia, senilism or vascular dementia, depression or anxiety in preparation.
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| CN104341478B (en) * | 2014-10-27 | 2017-06-30 | 中国药科大学 | Triterpene saponin componds feather cockscomb glycosides K and its medical application in the seed of feather cockscomb |
| CN104387438B (en) * | 2014-10-27 | 2017-03-01 | 中国药科大学 | New triterpene saponin componds Herba Celosiae argenteae glycosides L in Semen Celosiae and its medical application |
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| CN105669793B (en) * | 2015-12-30 | 2018-08-03 | 上海市奉贤区中心医院 | Oleanane-type triterpene saponin class compound, preparation method and its application |
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| CN110204589B (en) * | 2019-06-28 | 2021-04-09 | 河南大学 | Effective component of feather cockscomb seed, extraction method and application thereof in preparing neuroprotective medicament |
| CN115385978A (en) * | 2022-07-12 | 2022-11-25 | 成都乐美天医药科技有限公司 | Feather cockscomb seed compound and preparation method and application thereof |
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