CN115381807A

CN115381807A - Application of guaiacol chlorobebutryate in liver protection activity

Info

Publication number: CN115381807A
Application number: CN202210143502.4A
Authority: CN
Inventors: 施欢贤; 谢允东; 张丽华; 周静
Original assignee: Shaanxi University of Chinese Medicine
Current assignee: Shaanxi University of Chinese Medicine
Priority date: 2022-02-16
Filing date: 2022-02-16
Publication date: 2022-11-25

Abstract

The invention discloses application of guaiacol chlorobebutyrate with liver protection activity, belonging to the technical field of biological medicines. The invention discloses a guaiacol clofibrate compound which is an ester condensed by guaiacol and clofibrate. Therefore, the compound is expected to become a new medicine with liver protection activity.

Description

Application of guaiacol chlorobebutryate in liver protection activity

Technical Field

The invention belongs to the technical field of biological medicines, and particularly relates to application of guaiacol chlorobebutyrate with liver protection activity.

Background

The drug-induced liver injury refers to liver injury induced by various prescription or non-prescription western medicines, traditional Chinese medicines or health products and the like and metabolites thereof. Clinically, the hepatitis can be divided into hepatocellular hepatitis, cholestatic hepatitis and mixed hepatitis according to pathological types. The drug-induced liver injury can be asymptomatic liver dysfunction or acute and chronic liver injury clinically, and is manifested by nonspecific symptoms such as nausea, hypodynamia, abdominal pain and the like, or specific liver injury symptoms such as jaundice, ascites, hepatic encephalopathy and the like. Research shows that the number of drugs causing liver injury is large, and currently, more than 1000 drugs are used, which become important issues of drug safety. Epidemiological research finds that the incidence rate of drug-induced liver injury accounts for 10% -15% of adverse drug reactions, and people who die from drug-induced liver injury are in the fifth world. Therefore, the method has important significance for preventing and treating drug-induced liver injury.

The guaiacol clofibrate is an ester compound formed by condensing natural phenolic compounds guaiacol and clofibrate, the application of the compound in treatment of hyperlipidemia is disclosed previously, and related reports on the aspect of liver protection of the compound are never made.

Disclosure of Invention

In order to overcome the drawbacks of the prior art described above, it is an object of the present invention to provide a use of guaiacol chlorobebutyrate for its hepatoprotective activity.

In order to achieve the purpose, the invention adopts the following technical scheme to realize the purpose:

the invention discloses an application of guaiacol chlorobebutyrate in preparation of a medicine for treating liver diseases.

The invention discloses application of guaiacol clofibrate in preparation of a drug for treating drug-induced liver injury.

Preferably, the medicament has the effects of protecting liver activity and improving liver function indexes.

Preferably, the medicament is a medicament with antioxidant and anti-inflammatory activities.

Further preferably, the drug is a drug that reduces the levels of AST, ALT and TNF- α.

Preferably, the medicament is used for reducing the MDA content and increasing the SOD content.

The invention also discloses a medicine with liver protection activity, which is prepared from the guaiacol chlorine beumarate and pharmaceutically acceptable auxiliary materials, wherein the structure of the guaiacol chlorine beumarate is as follows:

preferably, the adjuvant comprises one or more of diluents, excipients, fillers, binders, humectants, disintegrants, absorption enhancers, surfactants, adsorption carriers, and lubricants.

Preferably, the drug is capable of being introduced into body tissues by oral, injection, osmotic, absorption, and physically or chemically mediated methods; or mixed or coated with other substances and introduced into body.

Compared with the prior art, the invention has the following beneficial effects:

the invention firstly researches the liver protection activity of the guaiacol clofibrate, finds that the guaiacol clofibrate has obvious liver protection activity, obviously improves the liver function index, and simultaneously has antioxidant and anti-inflammatory activity and improves liver injury. The experimental result shows that firstly, the guaiacol clofibrate can obviously reduce the AST and ALT content, and the AST and ALT reducing effect is stronger along with the increase of the dosage; secondly, the guaiacol clofibrate can obviously increase SOD and reduce MDA content, and the higher the dosage is, the stronger the SOD increasing and MDA reducing effects are, which shows that the guaiacol clofibrate has obvious antioxidation in a liver injury model; thirdly, the guaiacol clofibrate can obviously reduce the content of TNF-alpha, and the higher the dosage is, the stronger the TNF-alpha reducing effect is, which indicates that the guaiacol clofibrate has obvious anti-inflammatory effect in a liver injury model. Therefore, the compound is expected to become a new medicine with liver protection activity.

Drawings

FIG. 1 is a graph of the effect of the compound guaiacol clofibrate on aspartate Aminotransferase (AST) in a liver injury model;

FIG. 2 is a graph of the effect of the compound guaiacol clofibrate on the liver injury model alanine Aminotransferase (ALT);

FIG. 3 is a graph showing the effect of the compound guaiacol chlorobebutyrate on liver injury model superoxide dismutase (SOD);

FIG. 4 is a graph of the effect of the compound guaiacol chlorobebutyrate on the lipid peroxidation product, propanedione (MDA), in a model of liver injury;

FIG. 5 is a graph showing the effect of guaiacol chlorobebutyrate on tumor necrosis factor (TNF-. Alpha.) in a model of liver injury.

Detailed Description

In order to make those skilled in the art better understand the technical solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

It should be noted that the terms "first," "second," and the like in the description and claims of the present invention and in the drawings described above are used for distinguishing between similar elements and not necessarily for describing a particular sequential or chronological order. It is to be understood that the data so used is interchangeable under appropriate circumstances such that the embodiments of the invention described herein are capable of operation in sequences other than those illustrated or described herein. Moreover, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.

The invention is described in further detail below with reference to the accompanying drawings:

example 1 Synthesis of guaiacol chlorobebutyrate

Clofibrate butyric acid (3.00g, 13.97mmol), guaiacol (1.73g, 13.94mmol), EDCI (4.00g, 20.91mmol) and DMAP (0.34g, 2.79mmol) were dissolved in DMF (80 mL) solvent, stirred at room temperature overnight and the progress of the reaction was checked by TLC. After the reaction was completed, 50mL of distilled water was added, 80mL of ethyl acetate was added to the system, and 1M HCl solution (30 mL. Times.3), saturated sodium carbonate solution (30 mL. Times.3) and saturated sodium chloride were sequentially dissolved in the above-mentioned solventThe solution (30 mL × 3) was washed, dried over anhydrous sodium sulfate, filtered, rotary-distilled under reduced pressure, and separated and purified by column chromatography (petroleum ether: ethyl acetate = 35). The nuclear magnetic data are as follows: ¹ H NMC(400MHz,CDCl3)δ:7.17～7.20(m,2H,ArH),6.92～6.99(m,6H,ArH),3.77(s,3H,CH3O-),3.77(s,6H,-C(CH3)2-). ¹³ C NMR(100MHz,CDCl3)δ172.22,154.07,151.11,139.51,129.11,127.33,127.27,122.42,120.87,120.84,112.49,79.53,55.78,25.52.

the structural formula is as follows:

example 2 pharmacological Activity study of guaiacol chlorobebutyrate

The hepatoprotective activity of guaiacol chlorobebutyrate is realized by improving the model of mouse liver injury induced by acetaminophen

1. Experimental materials and instruments

Materials: acetaminophen (shanghai' an nigaku reagent limited), guaiacol chlorobebutyrate (prepared as described above).

The instrument comprises: model H1850 ultrarefrigerated centrifuge (hunan instrument centrifuge instruments ltd); an ELX808 full-wavelength plate reader (BioTek corporation, usa); DH43L type electric heating constant temperature incubator (Tianjin Tester apparatus Co., ltd.).

Animals: KM mouse (20.0 + -2.0 g)

2. Experimental methods

Mice were fed adaptively for 3d, and were randomly divided into a normal group, a model group, a positive drug group, a guaiacol chlorobebutyrate low-dose group, i.e., a CF-Y (L) group, a guaiacol chlorobebutyrate medium-dose group, i.e., a CF-Y (M) group, and a guaiacol chlorobebutyrate high-dose group, i.e., a CF-Y (H) group, each group consisting of 8 mice: (1) normal group, gavage with 0.5% CMC-Na solution; (2) model group, gavage with 0.5% CMC-Na solution; (3) a positive drug group, wherein 200mg/kg Glutathione (GSH) is administrated by intragastric administration; (4) CF-Y (L) group, 50mg/kg CF-Y is administered by intragastric administration; (5) CF-Y (M) group, 100mg/kg CF-Y is administered by intragastric administration; (6) CF-Y (L) group, 200mg/kg CF-Y was gavaged. Except for the normal group and the model group which are respectively administrated by intragastric administration with 0.05 percent of CMC-Na solution, the rest groups are respectively administrated by intragastric administration once a day for 7 days continuously, after the 7 th day administration for 6 hours, normal group is administrated by intraperitoneal injection with physiological saline with equal dose, the rest groups are administrated by paracetamol solution with 300mg/kg, eyeballs are all picked after 24 hours to take blood, the collected whole blood is kept still for 2 hours on an ice bath, and then the blood plasma is obtained by centrifuging for 15 minutes at 4000 r/min. Then the superoxide dismutase, the malondialdehyde and the tumor necrosis factor alpha in the blood plasma are measured according to the kit, and the glutamic-oxalacetic transaminase and the glutamic-pyruvic transaminase are measured by a biochemical analyzer.

3. Results of the experiment

The plasma levels of glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase in each group of mice are shown in Table 1 and FIGS. 1 and 2.

TABLE 1 AST and ALT content (n = 8) in each group of mice

Note: # indicates P <0.01 compared to Normal group; * Denotes P <0.01 compared to Model set.

As can be seen from the analysis of Table 1 and FIGS. 1 and 2, the compound CF-Y can significantly reduce the AST and ALT content, and as the CF-Y dose is increased, the AST and ALT reducing effect is stronger, and the CF-Y has obvious liver protection effect.

The superoxide dismutase and malondialdehyde levels in the plasma of each group of mice are shown in table 2 and fig. 3 and 4.

TABLE 2 SOD and MDA contents in the plasma of mice of each group (n = 8)

Note: # indicates P <0.01 compared to Normal group; * Represents P <0.05 compared to the Model set, represents P <0.01 compared to the Model set.

As can be seen from the analysis of Table 2, and FIGS. 3 and 4, the compound CF-Y can significantly increase SOD and reduce MDA content, and the higher the dose of the compound CF-Y is, the stronger the SOD increasing and MDA reducing effects are, and the compound CF-Y has obvious antioxidation in a liver injury model.

The plasma TNF-. Alpha.content of each group of mice is shown in Table 3 and FIG. 5.

TABLE 3 TNF-. Alpha.content in plasma of mice of each group (n = 8)

Note: # indicates P <0.01 compared to Normal group; * Represents P <0.05 compared to the Model group, and represents P <0.01 compared to the Model group.

As can be seen from the analysis of Table 3 and FIG. 5, the compound CF-Y can significantly reduce the content of TNF-alpha, and the higher the compound CF-Y dose is, the stronger the TNF-alpha reducing effect is, and the compound CF-Y has obvious anti-inflammatory effect in a liver injury model.

In conclusion, the research on the anti-liver injury activity shows that the compound CF-Y provided by the invention has multiple activities of remarkably reducing AST and ALT, resisting oxidation, resisting inflammation and the like, can obviously improve liver injury and plays a role in protecting the liver.

The above-mentioned contents are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modification made on the basis of the technical idea of the present invention falls within the protection scope of the claims of the present invention.

Claims

1. Use of guaiacol chlorobebutyrate in preparation of medicine for treating liver diseases is provided.

2. Use of guaiacol chlorobebutyrate in preparation of medicine for treating drug induced liver injury is provided.

3. The use according to claim 1 or 2, wherein the medicament is a medicament having a hepatoprotective activity, improving an index of liver function.

4. The use of claim 1 or 2, wherein the medicament is a medicament having antioxidant, anti-inflammatory activity.

5. The use of claim 4, wherein said agent is an agent that reduces AST, ALT, and TNF- α levels.

6. The use of claim 4, wherein the medicament is a medicament that reduces the MDA level and increases the SOD level.

7. The medicine with the liver protection activity is characterized by being prepared from guaiacol chlorine beumate and pharmaceutically acceptable auxiliary materials, wherein the structure of the guaiacol chlorine beumate is as follows:

8. the drug having hepatoprotective activity of claim 7, wherein the excipient comprises one or more of a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption enhancer, a surfactant, an adsorptive carrier, and a lubricant.

9. The agent having hepatoprotective activity of claim 7, wherein the agent is capable of being introduced into body tissues by oral, injection, osmotic, absorption, and physically or chemically mediated methods; or mixed or coated with other materials and introduced into body.