阅读说明：本技术 苯乙醇苷类化合物在制备抗肝纤维化药物中的应用 (Application of phenylethanoid glycosides compounds in preparation of anti-hepatic fibrosis drugs ) 是由 沈婷 胡卫成 纪丽莲 于 2020-05-25 设计创作，主要内容包括：本发明涉及药物技术领域,尤其是涉及苯乙醇苷类化合物在制备抗肝纤维化药物中的应用。苯乙醇苷类化合物在制备抗肝纤维化药物中的应用,其中,所述苯乙醇苷类化合物包括化合物1-12中的任一种或多种。本发明通过体外抗纤维化实验,首次提出并证实了上述苯乙醇苷类化合物对TGFβ1刺激的大鼠肝星状细胞HSC-T6细胞增殖具有一定的抑制作用,从而实现抗肝纤维化的作用。(The invention relates to the technical field of medicines, in particular to application of phenylethanoid glycosides compounds in preparation of anti-hepatic fibrosis medicines. The application of the phenylethanoid glycosides compounds in preparing anti-hepatic fibrosis drugs, wherein the phenylethanoid glycosides compounds comprise any one or more of compounds 1-12. The invention firstly provides and proves that the phenethyl alcohol glycoside compound has certain inhibition effect on rat hepatic stellate cell HSC-T6 cell proliferation stimulated by TGF beta 1 through an in-vitro anti-fibrosis experiment, thereby realizing the anti-hepatic fibrosis effect.)

1. The application of phenylethanoid glycosides compounds in preparing anti-hepatic fibrosis drugs, wherein the phenylethanoid glycosides compounds comprise any one or more of compounds 1-12;

the structural formulas of the compounds 1 to 12 are respectively as follows:

2. the use according to claim 1, wherein the phenylethanoid glycosides compounds act as NF- κ B signaling pathway inhibitors.

3. The use according to claim 1, wherein said phenylethanoid glycosides compounds inhibit proliferation of hepatic stellate cell HSC-T6 cells.

4. The use according to claim 3, wherein the proliferation of the hepatic stellate cell HSC-T6 cells is induced by TGF β 1.

5. The use according to claim 1, wherein the phenylethanoid glycosides compounds are extracted from plants of the genus incarvillea;

preferably, the incarvillea plant includes any one of rhizomes of Artocarpus heterophyllus, rhizomes of Artocarpus heterophyllus and rhizomes of Artocarpus Tinctoria.

6. An anti-liver fibrosis pharmaceutical composition, comprising any one or more of compounds 1-12, and/or a pharmaceutically acceptable salt of any one or more of said compounds 1-12;

the structural formulas of the compounds 1 to 12 are respectively as follows:

7. the anti-hepatic fibrosis pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable salt comprises any one or more of a sulfate, a phosphate and a hydrochloride.

8. The anti-hepatic fibrosis pharmaceutical composition of claim 6, further comprising a pharmaceutically acceptable excipient.

9. The anti-hepatic fibrosis pharmaceutical composition of claim 8, wherein the pharmaceutical composition is in a form for gastrointestinal administration or in a form for parenteral administration.

Technical Field

The invention relates to the technical field of medicines, in particular to application of phenylethanoid glycosides compounds in preparation of anti-hepatic fibrosis medicines.

Background

Hepatic fibrosis (hepatic fibrosis) is a pathological process caused by viral hepatitis, alcoholic liver, fatty liver, drug-toxicity liver disease, liver damage of systemic diseases and the like, is an intermediate link from the development of chronic liver disease to liver cirrhosis, and is a great problem which puzzles the medical field on how to effectively control the hepatic fibrosis. The 3-year survival rate of patients with late-stage cirrhosis is only 16%, and the 6 th death of people who die directly from cirrhosis worldwide is the 6 th death of people. The correct selection of anti-hepatic fibrosis drugs can not only inhibit or reverse hepatic fibrosis, but also lay the foundation for further treatment, so that the search of drugs for effectively reversing hepatic fibrosis becomes one of the key points of research in the medical field.

Hepatic fibrosis refers to the excessive deposition of diffuse extracellular matrix (ECM) in the liver. Hepatic Stellate Cells (HSCs) are the major source of excess ECM during hepatic fibrosis, activated HSCs proliferate abundantly, undergo phenotypic changes and secrete excessive ECM deposition into the liver is critical for hepatic fibrosis. Oxygen free Radicals (ROS) released by hepatocytes after injury can induce HSC to activate proliferation and stimulate collagen gene expression, and hepatocytes after apoptosis can promote collagen secretion by HSCs. Inhibition of conversion of resting HSCs into activated HSCs is an important strategy for treating liver fibrosis.

At present, the treatment of hepatic fibrosis mainly comprises blocking the cause of hepatic fibrosis, and anti-hepatic fibrosis drugs such as colchicine, penicillamine and the like have large toxic and side effects and are not easy to popularize clinically. The natural medicine has the advantages of diversity of structure and biological activity, and the like, and provides unique chemical structure and pharmacological activity for designing ideal new medicines.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The first purpose of the invention is to provide the application of the phenylethanoid glycosides compounds in preparing anti-hepatic fibrosis drugs.

The second purpose of the invention is to provide a pharmaceutical composition for resisting hepatic fibrosis.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

the application of phenylethanoid glycosides compounds in preparing anti-hepatic fibrosis drugs, wherein the phenylethanoid glycosides compounds comprise any one or more of compounds 1-12;

the structural formulas of the compounds 1 to 12 are respectively as follows:

hepatic fibrosis is a complex pathological process which is commonly participated in by a plurality of cytokines and a plurality of PI3K-Akt cell signaling pathways, and a TGF beta 1-Smad pathway, a Rho-ROCK pathway, a MAPK pathway and the like are known at present. Transforming growth factor-beta (TGF-beta) is the most critical cytokine in hepatic fibrosis, and can inhibit proliferation of liver cells, stimulate HSC activation, promote ECM production, and regulate apoptosis of liver cells. Research shows that NF-kB can influence the damage repair of liver inflammatory reaction by regulating the increase or decrease of the expression of inflammatory factors and anti-inflammatory factors, thereby influencing the development of liver fibrosis. In the resting state, NF-. kappa.B exists cytosolically in the form of a p50/p65 heterodimer bound to the inhibitory protein Iκ B α. The activation process is to phosphorylate inhibitory protein IkB-alpha to change its conformation and then to be detached from NF-kB, so that NF-kB is activated, the activated NF-kB enters into nucleus, contacts with DNA and starts or inhibits the transcription of related genes. The activated NF-kB can promote the release of cytokines such as TNF-alpha, MIP-2, ICAM-1 and the like, promote inflammatory reaction and activate HSC. When hepatic fibrosis occurs, various inflammatory factors activate NF-kB to aggravate and damage liver tissues, initiate lipid peroxidation, promote hepatocyte apoptosis and HSC activation and proliferation, and block NF-kB signals to relieve hepatic fibrosis and hepatic stellate cell apoptosis.

The invention firstly provides and proves that the phenethyl alcohol glycoside compound has certain inhibition effect on rat hepatic stellate cell HSC-T6 cell proliferation stimulated by TGF beta 1 through an in-vitro anti-fibrosis experiment, thereby realizing the anti-hepatic fibrosis effect. A computer target analysis platform and a molecular docking technology are utilized to find out the possible anti-hepatic fibrosis target NF-kB (PDB code:4G3D) of the phenylethanoid glycoside compound, the target is an important kinase for activating NF-kB, and the inhibition of the target can weaken the conduction of NF-kB downstream signals. The luciferase gene further proves that the phenylethanoid glycosides compounds can inhibit NF-kB expression.

In a specific embodiment of the invention, the phenylethanoid glycosides compounds are used as NF-kB signal pathway inhibitors.

In a specific embodiment of the invention, the phenylethanoid glycosides compounds inhibit proliferation of hepatic stellate cell HSC-T6 cells.

In a specific embodiment of the invention, the proliferation of the hepatic stellate cell HSC-T6 cells is induced by TGF β 1.

In a specific embodiment of the invention, the phenylethanoid glycoside compound is applied to preparation of an anti-oxidative stress medicament.

In a specific embodiment of the invention, the phenylethanoid glycosides compounds are extracted from plants of the genus incarvillea. Wherein the caraway plant comprises any one of the rhizome of Artocarpus heterophyllus, the rhizome of Artocarpus bipinnata and the rhizome of Artocarpus Tinctoria. The extraction method comprises the following steps: extracting with water, performing macroporous adsorbent resin column chromatography, and performing gradient elution separation. The structure was verified by means of nuclear magnetic resonance and LC-MS techniques.

The invention also provides an anti-hepatic fibrosis pharmaceutical composition, which comprises any one or more of the compounds 1-12, and/or pharmaceutically acceptable salts of any one or more of the compounds 1-12.

In a specific embodiment of the invention, the pharmaceutically acceptable salt comprises any one or more of a sulfate, a phosphate and a hydrochloride. Can be adjusted according to actual requirements.

In a specific embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

Wherein, the auxiliary materials can be selected from one or more of the following materials: solvents, solubilizers, flavoring agents, preservatives, lubricants, wetting agents, emulsifiers, disintegrants, fillers, tonicity adjusting agents, pH adjusting agents, permeation enhancers, stabilizers, glidants, suspending agents, coating materials, fragrances, anti-adhesives, integration agents, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, encapsulation agents, humectants, absorbents, diluents, and release retardants, and the like.

In a specific embodiment of the present invention, the pharmaceutical composition is in a form for gastrointestinal administration or in a form for parenteral administration, preferably in a form for gastrointestinal administration.

The gastrointestinal administration dosage form is a dosage form that the pharmaceutical composition enters the gastrointestinal tract after being orally taken and can take effect through absorption, and the dosage form comprises tablets, granules, capsules, solutions, suspensions and the like.

Parenteral dosage forms are dosage forms other than oral administration by the route of administration, including injectable dosage forms, dermal dosage forms, respiratory dosage forms, and the like. Wherein, the injection administration forms such as injection, including intravenous injection, intradermal injection and the like; administration forms for respiratory tract such as spray, etc.

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

(1) in the invention, the phenylethanoid glycosides compound is firstly proposed and proved to have a certain inhibition effect on rat hepatic stellate cell HSC-T6 cell proliferation stimulated by TGF beta 1 through an in-vitro anti-fibrosis experiment, so that the anti-hepatic fibrosis effect is realized;

(2) according to the invention, researches verify that the phenylethanoid glycosides compounds can inhibit NF-kB expression, inhibit proliferation of hepatic stellate cell HSC-T6 cells and resist oxidative stress; evaluating the interaction strength of the target and the active molecules by adopting a molecular docking method, and analyzing the structure-activity relationship by combining the matching degree of the ligand and the pharmacophore model; the anti-hepatic fibrosis action mechanism of the phenylethanoid glycoside compound is deeply researched by adopting a molecular biology method, and a new thought is provided for the development and preparation of anti-hepatic fibrosis drugs.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.

FIG. 1 is a graph showing the effect of phenylethanoid glycosides provided herein on TGF β 1-stimulated proliferation of HSC-T6 cells;

FIG. 2 shows the predicted target results using the SEAWARE target analysis platform according to the present invention;

FIG. 3 shows the docking results of the phenylethanoid glycosides compounds of the present invention with target 4G 3D;

FIG. 4 shows the result of NF- κ B nuclear transfer detected by luciferase gene of phenylethanoid glycosides compounds provided by the invention.

Detailed Description

The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings and the detailed description, but those skilled in the art will understand that the following described embodiments are some, not all, of the embodiments of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. 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. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.