WO2021164210A1 - Application d'un dérivé d'acide gallique dans la prévention et le traitement de la maladie de l'athérosclérose - Google Patents

Application d'un dérivé d'acide gallique dans la prévention et le traitement de la maladie de l'athérosclérose Download PDF

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WO2021164210A1
WO2021164210A1 PCT/CN2020/106879 CN2020106879W WO2021164210A1 WO 2021164210 A1 WO2021164210 A1 WO 2021164210A1 CN 2020106879 W CN2020106879 W CN 2020106879W WO 2021164210 A1 WO2021164210 A1 WO 2021164210A1
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gallate
gallic acid
atherosclerosis
cells
acid derivative
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PCT/CN2020/106879
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English (en)
Chinese (zh)
Inventor
邢澍
刘文杰
刘健敏
别利茨基约翰•K
潘学芳
周明扬
李天铎
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齐鲁工业大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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  • the invention belongs to the technical field of crude drugs and medicine, and specifically relates to the application of gallic acid derivatives to prevent and treat atherosclerotic diseases.
  • Atherosclerosis With the rapid development of society, the improvement of living standards and changes in eating habits, in recent years, cardiovascular and cerebrovascular diseases have become a major threat to human health and have become the disease with the highest mortality rate.
  • the main pathological basis of atherosclerosis has been It has become the main cause of death in our country.
  • Atherosclerosis leads to narrowing of the cavities on the inner wall of the blood vessel, and insufficient blood supply to the brain tissue. At the same time, it will be accompanied by plaque shedding, blocking the blood vessel and causing part of the tissue ischemic necrosis.
  • Oxidative stress has direct damage to blood vessel wall cells, causing vascular endothelial damage.
  • the permeability of blood vessels will increase, and low-density lipoprotein will penetrate and accumulate under the skin, and will be oxidized by lipoxygenase and reactive oxygen groups into a large number of oxidized forms.
  • Low-density lipoprotein (ox-LDL) ox-LDL can induce endothelial cells to secrete intercellular adhesion factors and macrophage chemokines, and promote monocytes to differentiate into macrophages through the intima of blood vessels.
  • macrophages swallow a large amount of ox-LDL, which is decomposed into free lipid particles under the action of lysosomes and exists in the cell body, turning the macrophages into heavy and round foam cells.
  • the development direction of atherosclerosis is mainly affected by the network relationship formed by endothelial cells, smooth muscle cells, macrophages and T lymphocytes. Macrophages secrete many growth factors at the same time as they become foamy, which changes the phenotype of vascular smooth muscle cells, proliferates and migrates to the intima. Under the regulation of oxidative stress and autophagy genes, foam cells are prone to apoptotic deposition on the intimal blood vessel wall.
  • a large number of dead foam cells gather to form a lipid mass that adheres to the intimal blood vessel wall to produce collagen and elastic fiber-encapsulated lipids.
  • a large number of vascular smooth muscle cells interspersed between foam cells to produce collagen, elastic fibers and lipopolysaccharides, resulting in an increase in extracellular matrix and the initial formation of local plaques.
  • the present invention provides the application of gallic acid derivatives to prevent and treat atherosclerosis.
  • gallic acid derivatives such as ethyl gallate, etc.
  • the present invention has discovered through research that gallic acid derivatives (such as ethyl gallate, etc.) can inhibit lipid deposition and oxidation.
  • Macrophage foam transformation, macrophage lipid efflux, macrophage and vascular endothelial cell activation and apoptosis which are used to prevent and treat atherosclerosis, so it can be considered to prevent and treat atherosclerosis
  • the effective drug candidates of the company have important clinical application value.
  • the present invention relates to the following technical solutions:
  • prevention and/or treatment refers to any measures applicable to the treatment of atherosclerosis-related diseases, or preventive treatment of such manifestations or symptoms, or avoidance of such manifestations.
  • Disease recurrence such as recurrence after the end of the treatment period or treatment of symptoms of an already onset disease, or interventional prevention or suppression or reduction of the occurrence of such diseases or symptoms in advance.
  • the second aspect of the present invention provides a pharmaceutical composition for preventing and treating atherosclerosis, which is composed of a gallic acid derivative and at least one other pharmaceutical active ingredient and/or at least one other Composition of non-pharmaceutical active ingredients.
  • the pharmaceutical composition of the present invention represents a substance, the gallic acid derivative contained in it has an obvious preventive effect on neonatal atherosclerosis.
  • the above technical scheme opens up new drug uses for gallic acid derivatives, especially ethyl gallate, and also lays an experimental foundation and provides a new perspective for the development of highly effective drugs for preventing and treating atherosclerosis.
  • Figure 1 is a graph showing the results of free radical scavenging experiments in Example 1 of the present invention.
  • Figure 2 is a graph showing the results of an experiment for inhibiting oxidation of ox-LDL in Example 2 of the present invention.
  • Figure 3 is a graph of MTT results in Example 3 of the present invention.
  • Fig. 4 is a diagram of the FACS results of flow cytometry in Example 3 of the present invention.
  • Fig. 5A is a diagram showing the formation of foam cells colored by Oil Red O alone treated with oxidized low-density lipoprotein ox-LDL in Example 4 of the present invention.
  • Fig. 5B is a diagram showing the formation of foam cells colored by oil red O while adding ethyl gallate while ox-LDL treatment in Example 4 of the present invention.
  • Figure 6 is a diagram showing the results of lipid efflux of macrophages in Example 5 of the present invention.
  • Figure 7 is a protein expression band diagram of ABCA1, ABCG1, SR-BI, and Tubulin in RAW264.7 cells in Example 6 of the present invention.
  • Fig. 8A is a representative photograph of atherosclerotic plaque in model animals with different treatments in Example 7 of the present invention.
  • Figure 8B is a statistical diagram of atherosclerotic plaque in Example 7 of the present invention.
  • Fig. 8D is a representative photograph of atherosclerotic plaques in heart slices of the EG 10 mg/kg body weight injection group (EG-L) in Example 7 of the present invention.
  • Figure 8E is a representative photograph of atherosclerotic plaques in heart slices of the EG 20 mg/kg body weight injection group (EG) in Example 7 of the present invention.
  • Figure 8F is a statistical diagram of cardiac atherosclerotic plaques in Example 7 of the present invention.
  • Fig. 9A is a graph showing changes in body weight of mice in Example 8 of the present invention.
  • Figure 9B is a graph of mouse serum indexes in Example 8 of the present invention.
  • Atherosclerosis is caused by multiple pathways, and the treatment mechanism is relatively complicated. Therefore, screening of safer and more effective drugs for the prevention and treatment of atherosclerosis has become a current research hotspot.
  • gallic acid derivatives in the preparation of drugs for the prevention and/or treatment of atherosclerosis is provided.
  • the gallic acid derivative is specifically gallic acid ester, further including but not limited to ethyl gallate, propyl gallate, butyl gallate and heptyl gallate; most preferably Ethyl gallate.
  • the prevention and/or treatment of atherosclerosis is manifested at least as having any one or more of the following uses:
  • the cells include but are not limited to macrophages
  • the macrophage lipid metabolism-related proteins include but are not limited to ABCA1 transporter, ABCG1 transporter and SR-BI protein.
  • gallic acid derivatives in the preparation of drugs for preventing and treating atherosclerosis is disclosed, but also the application of gallic acid derivatives in combination with at least one other active ingredient of the drug can enhance this effect.
  • gallic acid derivatives can also be used in combination with other non-pharmaceutical active ingredients.
  • a pharmaceutical composition for preventing and treating atherosclerosis is provided.
  • the pharmaceutical composition is composed of a gallic acid derivative and at least one other active ingredient of a drug and/or at least one other drug. Active ingredient composition.
  • the pharmaceutical inactive ingredients may be carriers, excipients and diluents commonly used in pharmacy. Moreover, according to the usual methods, it can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, sprays and other oral preparations, external preparations, suppositories, and sterile injection solutions. .
  • non-pharmaceutical active ingredients such as carriers, excipients, and diluents that can be included are well known in the art, and those of ordinary skill in the art can determine that they meet clinical standards.
  • the carrier, excipient and diluent include but are not limited to lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, Starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc Powder, magnesium stearate and mineral oil, etc.
  • the medicament of the present invention can be administered into the body in a known manner.
  • administration is optionally via intravenous, transdermal, intranasal, mucosal or other delivery methods.
  • Such administration can be carried out via a single dose or multiple doses.
  • the actual dose to be administered in the present invention can vary greatly depending on a variety of factors, such as target cells, biological types or their tissues, general conditions of the subject to be treated, and Route of medicine, method of administration, etc.
  • the subject of administration of the pharmaceutical composition can be human and non-human mammals, such as mice, rats, guinea pigs, rabbits, dogs, monkeys, orangutans.
  • the gallic acid derivative is specifically gallic acid ester, further including but not limited to ethyl gallate, propyl gallate, butyl gallate and heptyl gallate; most preferably Ethyl gallate.
  • DPPH determination of free radical elimination prepare 200 ⁇ M DPPH solution, the sample concentration is 2 ⁇ M, 10 ⁇ M, 20 ⁇ M
  • the reagents After the reagents are added, react for 10 minutes at room temperature, adjust to zero with absolute ethanol, measure the absorbance at 517nm, the absorbance of the sample is Ax, the absorbance of the sample group is A0, and the absorbance of the background group is Ax0.
  • Ethyl gallate has a strong scavenging effect on free radicals.
  • the scavenging rate of ethyl gallate on DPPH free radicals at 2 ⁇ M is higher than 75%. With the increase of the concentration to 10 ⁇ M, the scavenging rate is higher than 80%, and the scavenging rate of 20 ⁇ M is close to 100%, which is dose-dependent.
  • LDL Low-density lipoprotein
  • TBARS Low-density lipoprotein
  • Ethyl gallate concentration 2 ⁇ M, 10 ⁇ M, 20 ⁇ M, 4h, 8h, 12h, 24h when LDL reacts with divalent copper ion and ethyl gallate respectively, add EDTA to stop the reaction, determine the content of TBARS in LDL, Determine the degree of oxidation of LDL.
  • the degree of oxidation of LDL in the DMSO control group was significantly higher than that of the ethyl gallate treatment group at 4h, 8h, 12h, or 24h.
  • the degree of oxidation of the DMSO group increased more.
  • 2 ⁇ M of ethyl gallate increased by 35nM
  • 10 ⁇ M of ethyl gallate increased by 20nM
  • 20 ⁇ M of ethyl gallate increased by 11nM.
  • Ethyl gallate has a significant inhibitory effect on the oxidation of low-density lipoprotein caused by copper ions (simulating factors such as free radicals in the body), and it is dose-dependent.
  • Method 1 MTT method to determine cell viability (viability): cell culture, macrophage RAW264.7, medium RPMI1640+10% FBS. Plant the cell density at 10,000 per well in a 96-well plate, put the seeded 96-well plate in the incubator until the cell monolayer covers the bottom of the well, add the sample to be tested (ox-LDL stimulation group, add ox-LDL to The final concentration is 100 ⁇ g/mL), with 3 replicate holes in each group. Incubate in 5% carbon dioxide at 37°C for 48 hours and observe the changes in cell morphology under a microscope.
  • Method 2 Flow cytometry FACS fluorescence double staining to determine cell apoptosis: cell culture, macrophage RAW264.7, medium RPMI1640+10% FBS, planting cell density of 100000-500000 per well in a 12-well plate. In the box, until the cells are completely attached to the wall and the cells are in good condition, add different concentrations of ethyl gallate and incubate for 24 hours. The blank control uses the same concentration of DMSO. After 24h, oxidized low-density lipoprotein (ox-LDL) with a final concentration of 100 ⁇ g was added to each well and stimulated for 24h.
  • ox-LDL oxidized low-density lipoprotein
  • the cells were digested and resuspended, centrifuged at 300g for 5 min, and the supernatant was discarded. Wash the cells once with cell staining solution, discard the supernatant after centrifugation, and add 500 ⁇ L diluted Annexin V Binding Buffer working solution to resuspend the cells. Add 5 ⁇ L of Annexin V-FITC and 5 ⁇ L of pyridine iodide (PI) staining solution to the cell resuspension. After mixing, avoid light for 15-20min. After the reaction is completed, the sample is placed on ice and used for flow cytometry detection within 1 hour.
  • PI pyridine iodide
  • ethyl gallate has no toxic side effects on cells at concentrations of 10 ⁇ M, 20 ⁇ M, and 40 ⁇ M.
  • Oxidized low-density lipoprotein ox-LDL has a significant inhibitory effect on cell growth.
  • adding different concentrations of ethyl gallate EG during ox-LDL treatment weakened the inhibitory effect of cells, indicating that EG can reduce the damage effect of ox-LDL on cells.
  • Q1 is the area of dead cells
  • the proportion of the blank group was 0.05%
  • the ox-LDL action group was 0.2%
  • the OX-LDL+EG combined action group was 0.16%
  • Q2 is the area of late cell apoptosis
  • the proportion of the blank group was 3.75%
  • the ox-LDL action group was 5.01%
  • the EG+ox-LDL co-action group was 2.57%, indicating that EG significantly alleviated the serious cell damage caused by ox-LDL.
  • Q3 is the cell's early and mid-stage apoptotic area, The proportion of the blank group was 6.32%.
  • Ethyl gallate itself has no toxic side effects on cells at concentrations of 10 ⁇ M, 20 ⁇ M, and 40 ⁇ M. Oxidized low-density lipoprotein ox-LDL causes macrophage damage, apoptosis, and affects the normal growth of cells. Ethyl gallate treatment can significantly increase cell viability and inhibit cell apoptosis caused by ox-LDL, thereby alleviating and Prevent atherosclerosis.
  • Oil Red O is a non-polar dye that can make oils appear red.
  • Cell culture RAW264.7, RPMI1640+10% FBS, planting cell density of 100000-500000 in 6-well plates, culture until the cells grow stably. Change to serum-free RPMI1640 culture, and add the test substance to stimulate the cells at the same time.
  • the blank control is DMSO+ox-LDL
  • the experimental group is EG+OX-LDL, stimulated for 24h. Add ox-LDL with a final concentration of 30 ⁇ g/ml to each well for 24h.
  • Ethyl gallate was significantly higher than the blank treatment group under the effects of 5 ⁇ M and 20 ⁇ M, and it was dose-dependent with the increase of concentration.
  • Cell culture RAW264.7, RPMI1640+10% FBS plant the cells in a 6-well plate, culture until the cells cover the bottom of the 6-well plate, and add the test substance to stimulate for 36 hours.
  • Cells were lysed with RIPA+1% PMSF for 15 minutes, placed on ice for 30 minutes, 10,000 rpm, 5°C, and protein was extracted for 10 minutes.
  • Transfer membrane 60V, 120min, antibody ABCA1, ABCG1, SR-BI, internal reference is ⁇ -Tubulin.
  • ethyl gallate EG treatment can significantly up-regulate the expression of ABCA1, ABCG1 and SR-BI proteins related to lipid transport and efflux in macrophages, thereby promoting lipid efflux and inhibiting macrophages Foaming, preventing atherosclerosis.
  • ApoE knockout mice 20 weeks old, injected with 0.9% saline, EG 10mg/kg mouse body weight (labeled EG-L), EG 20mg/kg mouse body weight (labeled EG), intraperitoneal injection of 0.1ml per day, Continuous injection for 30 days.
  • the intact arteries of the mice were taken, and the plaques were dissected and analyzed; 10 ⁇ M sections of the heart were used to observe the plaques.
  • the plaque area in the untreated group (saline injection, Saline group) was about 10%, while the plaque area in the different EG concentration treatment group was generally less than 5%. And showing a dose-dependent trend, the effect is remarkable.
  • the plaques in the heart can also be seen in the heart slices.
  • the plaque area of the blank group was significantly higher than that of the EG treatment group with different concentrations. It is concluded that EG can effectively reduce the plaque growth of AopE knockout mice, and EG has a certain effect on delaying the process of atherosclerosis.
  • the invention relates to inhibitors by intraperitoneal injection of mice, compared with the same volume injection group with normal saline, and observes the organs through the death rate, body weight change, anatomy observation and determination of different indexes reflecting liver injury in the serum to reflect the toxicity.
  • the medicament ethyl gallate of the present invention was administered by intraperitoneal injection at doses of 10 mg/kg and 20 mg/kg of mouse body weight, and no animal death was seen immediately after administration and 1 to 90 days after administration. There was no significant change in animal body weight on the 14th, 28th, 42nd and 56th days after administration compared with the control group. The animals were dissected on the 64th day after administration, and no pathological changes related to the drug were found in various organs. Measure the content of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) in animal serum that reflect liver injury. The different doses of drug treatment groups are compared with normal saline injection There was no significant difference between the groups.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • LDH lactate dehydrogenase

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Abstract

La présente invention concerne une application d'un dérivé d'acide gallique dans la prévention et le traitement de la maladie de l'athérosclérose, se rapportant au domaine technique des médicaments biologiques. Au moyen de la recherche, il a été découvert que le dérivé d'acide gallique, en particulier le gallate d'éthyle, peut présenter la fonction de prévenir et de traiter l'athérosclérose en inhibant le dépôt et l'oxydation des lipides, la transformation spumeuse des macrophages, l'efflux des lipides des macrophages, et l'activation et l'apoptose des cellules endothéliales intravasculaires et des macrophages. La présente invention développe une nouvelle utilisation pharmaceutique du dérivé d'acide gallique, en particulier concernant le gallate d'éthyle, pose également une fondation expérimentale concernant le développement d'un médicament pertinent dans la prévention et le traitement efficaces de l'athérosclérose, et fournit un nouveau champ visuel.
PCT/CN2020/106879 2020-02-19 2020-08-04 Application d'un dérivé d'acide gallique dans la prévention et le traitement de la maladie de l'athérosclérose WO2021164210A1 (fr)

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