CN102258516A - Application of 13-methylamino-18-sulfo matrine compound in preparing medicines for resisting liver fibrosis or fibrosis of other tissues and organs - Google Patents
Application of 13-methylamino-18-sulfo matrine compound in preparing medicines for resisting liver fibrosis or fibrosis of other tissues and organs Download PDFInfo
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Abstract
The invention, relating to the technical field of medicine, relates to a 13-methylamino-18-sulfo matrine compound (I) and application of its salts and its application in preparing medicines for resisting fibrosis. Cytological experiments prove that the 13-methylamino-18-sulfo matrine compound can prevent the activation and proliferation of hepatic stellate cell of extracellular matrix (ECM) producing cells, prevent the transition of the intercellular substance of fibrotic liver epithelial cells, and can prevent other ECM-producing cells which cause fibrosis of tissues or organs. Animal experiments prove that the 13-methylamino-18-sulfo matrine compound has outstanding effects of resisting the hepatic fibrosis. The results show that the 13-methylamino-18-sulfo matrine compound has exact effects of resisting hepatic fibrosis or fibrosis of other tissues and organs, and can be used for preparing medicines for controlling and curing hepatic fibrosis or fibrosis of other tissues and organs.
Description
Technical field
The present invention relates to medical technical field, be specifically related to 13-methylamino-18-sulfo-matrine chemical compound and pharmaceutically acceptable salt class thereof the purposes in the preparation anti-fibrosis medicine.
Background technology
Hepatic fibrosis is a liver to the reparation reaction of chronic hepatic injury due to the various causes of disease, and principal character is extracellular matrix (extracellular matrix, over-deposit ECM).Hepatic fibrosis is the total pathological characters of various chronic hepatopathys, is further to develop to liver cirrhosis, even the dead main intermediate link that cancerates.Because the treatment of liver cirrhosis is very difficult, mortality rate is high, and thinks that at present hepatic fibrosis has reversibility, therefore block or delay developing of hepatic fibrosis, for the multiple treatment of following the chronic hepatopathy of hepatic fibrosis, have significant application value.At present, treating liver fibrosis comprises at the etiological treatment of protopathy with at the treatment of fibrosis itself clinically.But remove protopathy because of can not suppressing the development of hepatic fibrosis fully, and Fibrotic existence also can influence the therapeutic effect to protopathy, therefore, outstanding apparent important at Fibrotic treatment.At present the anti-hepatic fibrosis medicines that grinds mainly by suppress or the reaction that reduces inflammation, anti-oxidation stress, inhibition liver fibrosis process in the hepatic stellate cell activator, the propagation that play a major role or promote its apoptosis, protection hepatocyte, promote the short fibrosis factor active of liver regeneration, inhibition or neutralization and suppress extracellular matrix synthetic or promote link such as its degraded.In recent decades, though anti-hepatic fibrosis medicines research has obtained certain progress, but present many medicines still are in clinical preceding or clinical experimental stage, as TGF beta 1 antagonists, hepatocyte growth factor, S-ademetionine, pirfenidone etc., but still there is not the treatment that a kind of chemicals is approved for human hepatic fibrosis at present.
Except that hepatic fibrosis, fibrosis also can betide multiple histoorgans such as lung, kidney, the heart.Amount of literature data studies show that, ECM produces cell, play an important role in organ or tissue's fibrosis as matter fibroblast, lung fibroblast, heart fibroblast etc. between liver sternzellen, mesangial cell, kidney, they have become the target of prevention and treatment organ or tissue fibering, suppress the celliferous activation of ECM, propagation or promote that its apoptosis is the Fibrotic important means of control.
Chinese patent application numbers 200910199252.0 provides the preparation method of a class sulfo-matrine chemical compound and pharmaceutically acceptable salt class thereof, the cytokine that also provides this compounds can suppress to participate in inflammatory process produces and nuclear factor NF κ B transcriptional activity, can be used for preparing treatment cytokine and nuclear factor NF κ B participation such as the relevant diseases associated with inflammation such as chronic inflammatory disease and the medicine of pathological process.
Summary of the invention
The present invention is on the prior art basis, further discloses 13-methylamino-18-sulfo-matrine chemical compound (I) and pharmaceutically acceptable salt class thereof the purposes in the preparation anti-fibrosis medicine.
Chemical compound provided by the invention (I), its structural formula is seen Fig. 1.
Above-claimed cpd pharmaceutically acceptable salt class is acetate, hydrochlorate, sulfate, disulfate, hydrobromate, oxalates, citrate, mesylate etc.
The present invention experimental results show that from cell experiment and whole animal 13-methylamino-18-sulfo-matrine chemical compound (I) has anti-fibrosis effect: methylamino-18-sulfo-matrine chemical compound (I) is synthetic inhibited to rats'liver sternzellen, mesangial cell, lung fibroblast, heart fibroblast proliferation and collagen from cytologic experiment proof 13-; By zoopery explanation 13-methylamino-18-sulfo-matrine chemical compound (I) acute liver damage that mouse carbon tetrachloride and D-Gal cause had protective effect; Confirm that with rat bile duct ligation (BDL) Liver Fibrosis Model and thioacetamide (TAA) Liver Fibrosis Model 13-methylamino-18-sulfo-matrine chemical compound (I) can significantly alleviate the formation of hepatocellular degeneration, necrosis and fibrous tissue, and anti-fibrosis effect is better than the Matrine Injection of matrine and clinical use, and on too many levels, produce pharmacologically active, can suppress hepatic stellate cell propagation and activation, matter makes the transition between inhibition fibrosis liver epithelial cell.Pulmonary Fibrosis in Rats due to the bleomycin had the effect that reduces lung tissue of rats hydroxyproline content and rats death rate.Presentation of results 13-methylamino-18-sulfo-matrine chemical compound (I) has definite anti-fibrosis effect, therefore can be used to preparation prevention and treatment hepatic fibrosis or other histoorgan fibrosis medicines.
Description of drawings
The compounds of this invention (I) 13-methylamino-18-sulfo-matrine structure is seen Fig. 1; Fig. 2 is seen in the formation that the visible chemical compound of pathologic finding (I) can significantly alleviate hepatocellular degeneration, necrosis and fibrous tissue in bile duct ligation (BDL) Liver Fibrosis Model in the rat liver fibrosis model; In thioacetamide (TAA) Liver Fibrosis Model, chemical compound (I) (25,50mg/kg) can significantly reduce Serum ALT, AST level (p＜0.01) and the liver hydroxyproline content (p＜0.01) that TAA raises, and be better than matrine group or kurarinone group (P＜0.05), the results are shown in Figure 3; Immunohistochemical staining TAA fibrosis model group, the result shows that chemical compound (I) reduces extracellular matrix and produces, and the treatment hepatic fibrosis is by matter (epithelial-to-mesenchymal transition transition between the epithelial cell that suppresses hepatocyte and HSC, EMT) work, see Fig. 4.
The specific embodiment:
Below in conjunction with embodiment the present invention is further described, but the specific embodiment of the present invention is not limited to following examples.
Embodiment 1:13-methylamino-18-sulfo-matrine chemical compound (I) produces cell proliferation and the synthetic effect test method of collagen to ECM:
Cell proliferation test: the every hole of 96 porocyte culture plates adds 1 * 104 rats'liver sternzellen HSC-T6, mesangial cell, lung fibroblast, heart fibroblast, in 37 ℃ of CO2 incubators, hatch 24h, add 100 μ l then and contain the DMEM culture fluid of different pharmaceutical concentration and 10% new-born calf serum (NCS) or do not have the medicine culture fluid, continue to add Thiazolyl blue (MTT) microplate reader mensuration 570nm trap value behind the cultivation 48h.
The synthetic mensuration of collagen: adopt 3H-proline isotope method.Cell concentration is adjusted into 2.5 * 105/ml, and every hole adds 100 μ l on 96 orifice plates, cultivates 24h and makes it to form monolayer, to eliminate the cell growth to the synthetic influence of collagen.Add the ascorbic medicine contain 50 μ g.ml-1 and 10%NCS or transforminggrowthfactor-(TGF β 1) then and cultivate 48h again, add every hole [3H]-proline 18.5kBq simultaneously.Cell with trypsinization after, be collected on the glass fiber filter paper, measure cell 3H-proline value of mixing (cpm) with liquid scintillation instrument.
The result shows, 13-methylamino-18-sulfo-matrine chemical compound (I) (5～40 μ mol.L-1) significantly concentration dependence ground inhibition ECM produces cell hepatic stellate cell HSC-T6, mesangial cell, lung fibroblast, heart fibroblast proliferation and collagen synthetic (table 1,2).
Table 1 13-methylamino-18-sulfo-matrine chemical compound (I) produces the influence of cell proliferation to ECM
Compare with matched group,
*P＜0.05,
*P＜0.01
Table 2 13-methylamino-18-sulfo-matrine chemical compound (I) produces the synthetic influence of cell collagen to ECM
Compare with matched group,
*P＜0.05,
*P＜0.01
Embodiment 2: the acute liver damage model
90 of ICR mices, male and female half and half, weight 20 ± 2g.Be divided into 9 groups at random, 10 every group.The 1st group is the normal control group, and 2-5 group lumbar injection 0.5% carbon tetrachloride-olive oil 10/kg makes carbon tetrachloride acute liver damage model, and 6-9 group lumbar injection D-Gal 800mg/kg makes D-Gal acute liver damage model.2,6 groups is model control group, and 3,7 groups of bifendate 200mg/kg gastric infusions are as positive controls.Irritate stomach for 4,8 groups and give 13-methylamino-18-sulfo-matrine chemical compound (I) 50mg/kg, irritate stomach for 5,9 groups and give kurarinone 50mg/kg as the experiment contrast group as experimental group.Above-mentionedly respectively organize the modeling after 3 days of Give medicine, get blood and liver after 48 hours, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) kit measurement (bio-engineering research institute is built up in Nanjing), liver is done pathologic finding according to a conventional method.
Table 3 13-methylamino-18-sulfo-matrine chemical compound (I) is to the influence of acute liver damage Serum ALT and AST
Table 3 result as seen, 13-methylamino-18-sulfo-matrine chemical compound (I) significantly reduces Serum ALT and the AST that hepatic injury that carbon tetrachloride and aminogalactose cause raises, and acts on quite with bifendate, is better than kurarinone.Light microscopy checking, 13-methylamino-18-sulfo-matrine chemical compound (I) obviously alleviates hepatocellular degeneration necrosis and inflammatory infiltration.13-methylamino-18-sulfo-matrine chemical compound (I) is described, and hepatic injury has protective effect to chmice acute.
Embodiment 3: the rat liver fibrosis model
(1) bile duct ligation (BDL) Liver Fibrosis Model
60 of male SD rats, body weight 150g～200g, the cleaning level, zoopery center, Chinese Academy of Sciences Shanghai provides, and is divided into 6 groups at random, 10 every group.After the anesthesia of lumbar injection chloral hydrate solution, the ligation common bile duct prepares common bile duct ligation Liver Fibrosis Model.If sham operated rats, model control group, 13-methylamino-18-sulfo-matrine chemical compound (I) (25,50mg/kg), matrine matched group (50mg/kg), Matrine Injection positive controls (50mg/kg).Postoperative 2d Guan Wei Give medicine is put to death rat behind the modeling 3w.Postcava puncture blood drawing, detect serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) with the fully automatic blood biochemistry analyzer, alkali hydrolysis method detects the hepatic tissue hydroxyproline, hepatic tissue section adopts HE dyeing, sirius red and masson collagen staining respectively, 4 visuals field of every section picked at random, behind image analysis system measurement positive staining, the percentage ratio of area of collagen and the automatic calculating and the gross area is taken the mean as the objective indicator of judging degree of hepatic fibrosis.Read sheet by the senior doctor of Pathology Deparment, carry out liver fibrosis classification.The rat quantity that enters experiment statistics at last is as follows: 10 of negative control group, 8 of model control group (dead in 2 modeling processes), chemical compound (I) 25mg/kg organizes 8 (1 administration 2d death, dead in 1 modeling process), 9 of chemical compound (I) 50mg/kg groups (dead behind 1 administration 5d).8 of matrine groups (1 administration 3d death, dead in 1 modeling process), or 9 of kurarinone groups (1 administration 2d death).
The result shows that the normal rat of ALT of model control group rat and AST level obviously raises, the normal rat of hepatic tissue hydroxyproline content obviously raise (P＜0.01).(25,50mg/kg), ALT, AST level are obviously improved (P＜0.01) than model group to chemical compound (I), and the hepatic tissue hydroxyproline content obviously reduces (P＜0.01), and are better than matrine group or kurarinone group (P＜0.05).Hepatic tissue section HE dyeing, sirius red and masson collagen staining, chemical compound (I) 25,50mg/kgsirus and masson collagen staining area reduce by 42% than model group, are better than matrine group (31.4%), kurarinone group (40.2%) with dosage.The visible chemical compound of pathologic finding (I) can significantly alleviate the formation of hepatocellular degeneration, necrosis and fibrous tissue and (show 4-5, Fig. 2).
Table 4 BDL Liver Fibrosis Model rat is respectively organized serological index and hepatic tissue hydroxyproline content
Annotate: * P＜0.01 vs model;
#P＜0.05 vs matrine, kurarinone
Table 5 BDL Liver Fibrosis Model rat fibrosis relatively
(2) thioacetamide (TAA) Liver Fibrosis Model
The SD rat gives thioacetamide, and (thioacetamide, TAA) solution is pressed 0.2g/kg dosage lumbar injection.Inject weekly 3 times, per two days 1 time, inject 8w continuously, the inductive rat liver fibrosis model of preparation TAA.Random packet, establish model control group, MASM (25,50mg/kg), matrine matched group (50mg/kg), Matrine Injection positive controls (50mg/kg).The normal control group is established in experiment simultaneously.Every group 10.Inject 6w difference Guan Wei Give medicine every day in TAA.Put to death all rats on the 2nd day behind the Mo Give medicine, postcava puncture blood drawing preparation serum detects alanine aminotransferase (ALT), aspartate aminotransferase indexs such as (AST) with the fully automatic blood biochemistry analyzer.Get the same area hepatic tissue and do pathological section, pathological change is observed in HE dyeing; Masson ' s trichrome and Sirius Red dyeing is measured ECM content and to the degree of hepatic fibrosis classification, the image analyzer semi-quantitative analysis; Alkali hydrolysis method detects the hepatic tissue hydroxyproline content.
The result shows, compares with model group, chemical compound (I) (25,50mg/kg) Serum ALT, AST level (p＜0.01) and the liver hydroxyproline content (p＜0.01) that TAA raises be can significantly reduce, and matrine group or kurarinone group (P＜0.05) are better than.The formation that chemical compound (I) can significantly alleviate hepatocellular degeneration, necrosis and fibrous tissue is observed in hepatic tissue section HE dyeing.Siriusred and masson collagen staining, chemical compound (I) 25,50mg/kg sirus and masson collagen staining area reduce by 45% and 61% than model group, are better than matrine thin (42%), kurarinone group (48%) with dosage.(the results are shown in Table 6,7, Fig. 3)
Table 6 TAA Liver Fibrosis Model rat is respectively organized serological index and hepatic tissue hydroxyproline content
Annotate: * P＜0.01 vs model;
#P＜0.05 vs matrine, kurarinone
Table 7 BDL Liver Fibrosis Model rat fibrosis relatively
(3) inhibitory action that matter between TAA fibrosis liver epithelial cell is made the transition
The expression of immunohistochemical staining TAA fibrosis model group and chemical compound (I) 50mg/Kg treatment group liver α-SMA, Vimentin, E-cadherin, TGF-β 1 and HNF4 α.The result shows that the downward modulation of α-SMA and TGF-β 1 is followed in the Vimentin protein level downward modulation of hepatic fibrosis zone, and hepatic parenchymal cells and nonparenchymal cell film E-cadherin up-regulated, hepatocyte HNF4 alpha expression also raises.Show that chemical compound (I) reduces extracellular matrix and produces, the treatment hepatic fibrosis is that (epithelial-to-mesenchymal transition, (Fig. 4) EMT) works transition by matter between the epithelial cell that suppresses hepatocyte and HSC.
The expression of immunohistochemical staining TAA fibrosis model group and chemical compound (I) 50/Kg treatment group liver α-SMA, Vimentin, E-cadherin, TGF-β 1 and HNF4 α.
The The above results explanation, 13-methylamino-18-sulfo-matrine chemical compound (I) has significant treatment fibrosis effect.
Embodiment 4: the Pulmonary Fibrosis in Rats model
The SD rat adopts the method for disposable instillation 5% Pingyangmycin (5mg/Kg) in the trachea to prepare the Pulmonary Fibrosis in Rats model.Random packet is established model control group, chemical compound (I) 50mg/kg group, prednisone group (20mg/kg).The normal control group is established in experiment simultaneously.Every group 10.Difference Guan Wei Give medicine every day behind Pingyangmycin administration 24h.The Give medicine is put to death rat after 14 days and 28 days, detects the lung tissue hydroxyproline content, gets the [inferior lobe and does pathologic finding.
The result shows that 13-methylamino-18-sulfo-matrine chemical compound (I) group and prednisone group can significantly reduce hydroxyproline content (table 8) in the lung tissue homogenate.Pathologic finding shows, 13-methylamino-18-sulfo-matrine chemical compound (I) pulmonary fibrosis degree thin and prednisone group rat all alleviates than rat model, have only slight fibrosis to form the slight broadening of alveolar septum, a spot of inflammatory cell infiltration (table 9) mostly.Presentation of results, 13-methylamino-18-sulfo-matrine chemical compound (I) has significant pulmonary fibrosis resistant effect.
Table 9 the 14th and 28 days rat alveolitises and fibrosis classification
13-methylamino of the present invention-18-sulfo-matrine chemical compound (I) has remarkable inhibition extracellular matrix and produces cell proliferation and the synthetic effect of collagen; Have definite anti-fibrosis effect, in addition, The compounds of this invention also has low toxin, therefore can be used to preparation prevention and treatment hepatic fibrosis or other histoorgan fibrosis medicines.
Claims (2)
1.13-methylamino-18-sulfo-matrine chemical compound (I), its structural formula are as shown in the figure, the purposes in preparation anti-hepatic fibrosis or other histoorgan fibrosis medicines.
2.13-the purposes in preparation anti-hepatic fibrosis or other histoorgan fibrosis medicines such as methylamino-18-sulfo-matrine chemical compound (I) pharmaceutically acceptable salt class acetate, hydrochlorate, sulfate, disulfate, hydrobromate, oxalates, citrate, mesylate.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103933038A (en) * | 2014-04-28 | 2014-07-23 | 中国人民解放军第二军医大学 | Application of matrine compounds in preparing anti-hepatic fibrosis and anti-liver cancer medicaments |
| CN105769862A (en) * | 2016-04-11 | 2016-07-20 | 中国人民解放军第二军医大学 | Application of matrine derivative 13-methylamino-18-sulpho-matrine to anti-radiation injuries |
| CN106619628A (en) * | 2017-01-20 | 2017-05-10 | 上海长海医院 | Application of matrine derivatives in preparation of medicines for preventing or treating postmenopausal osteoporosis |
| CN106974928A (en) * | 2016-01-19 | 2017-07-25 | 上海国宝企业发展中心 | The purposes of cordycepin and preparation in preventing and treating organ fibrosis medicine and health-oriented products |
| CN108904570A (en) * | 2018-07-23 | 2018-11-30 | 遵义医学院附属医院 | A kind of acute liver damage inducer and its application |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103933038A (en) * | 2014-04-28 | 2014-07-23 | 中国人民解放军第二军医大学 | Application of matrine compounds in preparing anti-hepatic fibrosis and anti-liver cancer medicaments |
| CN103933038B (en) * | 2014-04-28 | 2016-08-17 | 中国人民解放军第二军医大学 | One group of matrine compound is for preparing the application of anti-hepatic fibrosis and medicines resistant to liver cancer |
| CN106974928A (en) * | 2016-01-19 | 2017-07-25 | 上海国宝企业发展中心 | The purposes of cordycepin and preparation in preventing and treating organ fibrosis medicine and health-oriented products |
| CN105769862A (en) * | 2016-04-11 | 2016-07-20 | 中国人民解放军第二军医大学 | Application of matrine derivative 13-methylamino-18-sulpho-matrine to anti-radiation injuries |
| CN106619628A (en) * | 2017-01-20 | 2017-05-10 | 上海长海医院 | Application of matrine derivatives in preparation of medicines for preventing or treating postmenopausal osteoporosis |
| CN106619628B (en) * | 2017-01-20 | 2019-11-15 | 上海长海医院 | Application of the matrine derivative in preparation prevention or treatment Postmenopausal Osteoporosis drug |
| CN108904570A (en) * | 2018-07-23 | 2018-11-30 | 遵义医学院附属医院 | A kind of acute liver damage inducer and its application |
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Application publication date: 20111130 |