CN118593506A - Application of compound a or derivative thereof in preparing medicine for preventing and treating liver fibrosis diseases - Google Patents
Application of compound a or derivative thereof in preparing medicine for preventing and treating liver fibrosis diseases Download PDFInfo
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Abstract
The invention relates to the technical field of liver fibrosis medicines, and particularly discloses application of a compound a or a derivative thereof in preparation of medicines for preventing and treating liver fibrosis diseases. 2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol (compound a) is capable of significantly inhibiting lactate dehydrogenase activity and inhibiting hepatic fibrosis gene expression induced by TGF-beta. The compound a can inhibit lactic dehydrogenase to weaken hepatic stellate cell activation, and finally achieve the aim of treating hepatic fibrosis. The compound a has potential application value in preparing lactate dehydrogenase inhibitor and liver fibrosis disease prevention and treatment medicines, has great clinical significance, provides a new target point for treating liver fibrosis diseases, and provides more medicine choices for patients suffering from liver fibrosis diseases.
Description
Technical Field
The invention belongs to the technical field of liver fibrosis medicines, and particularly relates to application of a compound a or a derivative thereof in preparation of medicines for preventing and treating liver fibrosis diseases.
Background
Liver fibrosis is a pathological process, and refers to a disease of abnormal hyperplasia of connective tissue in liver caused by liver toxic substances or various pathogenic factors such as viral hepatitis, and seriously endangers human health. Any liver injury has liver fibrosis process in the liver repairing and healing process, and if injury factors cannot be removed for a long time, the fibrosis process can develop into liver cirrhosis and even liver cancer after long-term persistence. At present, few medicines for treating liver fibrosis are clinically used, and no efficient medicine and method for reversing fibrosis are found yet.
Existing studies indicate that hepatic stellate cells are stimulated and activated by exogenous molecules of different nature to undergo fibrosis. Activation of hepatic stellate cells is an important precondition for fibrosis occurrence, so that new drugs for targeted inhibition of hepatic stellate cell activation can be found, and the method has important significance for finding and treating hepatic fibrosis diseases. Studies show that after hepatic stellate cells are activated, metabolism in the cells can change, a large amount of energy is required to be consumed, and inhibition of glycolysis and glutamine deprivation has the effect of inhibiting hepatic stellate cell activation; liver injury results in increased expression of Lactate Dehydrogenase (LDH), which in turn catalyzes the conversion of pyruvate to lactate, which inhibits the action of sodium oxamate, a known lactate dehydrogenase inhibitor, against liver fibrosis. Inhibition of hepatic stellate cell activation by inhibition of lactate dehydrogenase as an anti-fibrotic target may be of great importance for improving liver fibrosis.
2- [2-Amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol (2- [2-amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol) is an organic compound having the formula C 18H17N3O4 and is useful as a BMI1 inhibitor for the treatment of gastrointestinal stromal tumors. However, the prior art does not disclose any report that 2- [2-amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol or its derivatives can alleviate liver fibrosis by inhibiting lactate dehydrogenase.
Disclosure of Invention
In view of the above problems, the present invention provides an application of a compound a or a derivative thereof in preparing a medicament for preventing and treating liver fibrosis diseases.
In order to solve the technical problems, the invention adopts the following technical scheme:
In a first aspect, the invention provides an application of a compound a or a derivative thereof in preparing a medicament for preventing and treating hepatic fibrosis diseases, wherein the compound a is 2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol, and the structural formula of the compound a is shown as formula 1:
Compared with the prior art, the application of the compound a or the derivative thereof in preparing the medicine for preventing and treating the hepatic fibrosis diseases provided by the invention has the advantages that 2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidine-4-yl ] -5-methoxyphenol (compound a, CAS registry number 877810-03-2) can obviously inhibit the activity of lactate dehydrogenase and inhibit hepatic stellate cell fibrosis gene expression induced by TGF-beta. The invention proves that the 2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidine-4-yl ] -5-methoxyphenol has potential application value in preparing lactate dehydrogenase inhibitors and medicines for preventing and treating hepatic fibrosis diseases, has great clinical significance, provides a new pharmaceutical thought and a new treatment means for relieving the hepatic fibrosis diseases, and simultaneously provides more medicine choices for patients suffering from the hepatic fibrosis diseases.
Preferably, the drug targets lactate dehydrogenase.
A large number of experiments show that the lactic dehydrogenase can be used for screening an action target point of an anti-hepatic fibrosis disease drug, and 2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidine-4-yl ] -5-methoxyphenol is a potential and effective lactic dehydrogenase inhibitor, and can weaken hepatic stellate cell activation by inhibiting the lactic dehydrogenase, so that the purpose of treating hepatic fibrosis is finally achieved, and the lactic dehydrogenase can be used for researching an action mechanism of the hepatic fibrosis disease and developing a tool drug for the hepatic fibrosis disease.
In a second aspect, the present invention provides a pharmaceutical composition for preventing and treating liver fibrosis diseases, comprising the above 2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol or its derivatives.
In a third aspect, the present invention provides a pharmaceutical preparation for preventing and treating liver fibrosis diseases, wherein the active ingredient of the pharmaceutical preparation is the pharmaceutical composition.
Preferably, the pharmaceutical preparation further comprises pharmaceutically acceptable excipients.
Further preferably, the auxiliary material comprises at least one of excipient, disintegrant, lubricant, binder or solvent.
Preferably, the pharmaceutical preparation is a tablet, pill, capsule, granule, caplet, suspension, drop pill, oral liquid, injection, aerosol, suppository or subcutaneous administration.
The medicine composition for preventing and treating liver fibrosis diseases may be prepared into medicine preparation for oral administration or non-oral administration. The amount administered may vary depending on the dosage form, frequency of administration, mode of administration, course of disease, individual differences of patients, and health conditions.
Drawings
FIG. 1 is a graph showing immunofluorescence of alpha-SMA in the control group, CCl 4 group and CCl 4 + sodium oxamate group of example 1 of the present invention;
FIG. 2 is a bar graph of fluorescence quantitative PCR tests for Col 1. Alpha.1 in the control, CCl 4 and CCl 4 + sodium oxamate groups of example 1 of the present invention;
FIG. 3 is a bar graph of fluorescence quantitative PCR tests for Col 3. Alpha.1 in the control, CCl 4 and CCl 4 + sodium oxamate groups of example 1 of the present invention;
FIG. 4 is a bar graph of fluorescent quantitative PCR tests for alpha-SMA in the control, CCl 4 and CCl 4 + sodium oxamate groups of example 1 of the present invention;
FIG. 5 is a graph showing immunofluorescence of alpha-SMA from the control, TGF-beta + sodium oxamate and TGF-beta + sodium oxamate + lactate groups of example 2 of the present invention;
FIG. 6 is a bar graph of fluorescence quantitative PCR tests of Col1α1 in the control group, TGF- β group, TGF- β+ sodium oxalate group, and TGF- β+ sodium oxalate+lactate group of example 2 of the present invention;
FIG. 7 is a bar graph of fluorescence quantitative PCR tests of Col3α1 in the control group, TGF- β group, TGF- β+ sodium oxalate group, and TGF- β+ sodium oxalate+lactate group in example 2 of the present invention;
FIG. 8 is a bar graph of fluorescent quantitative PCR tests for HK-II in the control, TGF-beta + sodium oxamate and TGF-beta + sodium oxamate + lactate groups of example 2 of the present invention;
FIG. 9 is a bar graph of fluorescent quantitative PCR testing of PKM2 in the control, TGF-beta + sodium oxamate and TGF-beta + sodium oxamate + lactate groups of example 2 of the present invention;
FIG. 10 is a bar graph of fluorescent quantitative PCR tests for GLS2 in the control, TGF-beta + sodium oxamate and TGF-beta + sodium oxamate + lactate groups of example 2 of the present invention;
FIG. 11 is a bar graph of fluorescent quantitative PCR tests of GLDH1 in the control group, TGF-beta group, TGF-beta+ sodium oxalate group and TGF-beta+ sodium oxalate+lactate group of example 2 of the present invention;
FIG. 12 is a bar graph of fluorescent quantitative PCR testing of SLC1A5 in the control, TGF-beta + sodium oxamate and TGF-beta + sodium oxamate + lactate groups of example 2 of the present invention;
FIG. 13 is a graph showing changes in lactate concentration in cell homogenates of a control group, a TGF-beta group, a TGF-beta+ sodium oxalate group, and a TGF-beta+ sodium oxalate+lactate group in example 2 of the present invention;
FIG. 14 is a graph showing NAD +/NADH change in cell homogenates of the control group, TGF-beta group, TGF-beta+ sodium oxalate group and TGF-beta+ sodium oxalate+lactate group in example 2 of the present invention;
FIG. 15 is a graph showing the change in LDHA in the cell homogenates of the control group, TGF-beta group, TGF-beta+ sodium oxalate group and TGF-beta+ sodium oxalate+lactate group in example 2 of the present invention;
FIG. 16 is a graph showing the change in ATP yield in cell homogenates of the control group, TGF-beta group, TGF-beta+ sodium oxalate group and TGF-beta+ sodium oxalate+lactate group in example 2 of the present invention;
FIG. 17 is a graph showing changes in the activity of mitochondrial complex I in the control group, TGF-beta group, TGF-beta+ sodium oxalate group and TGF-beta+ sodium oxalate+lactate group according to example 2 of the present invention;
FIG. 18 is a graph showing changes in the activity of mitochondrial complex II in the control group, TGF-beta group, TGF-beta+ sodium oxalate group and TGF-beta+ sodium oxalate+lactate group according to example 2 of the present invention;
FIG. 19 is a mitochondrial membrane potential map of the control, TGF-beta + sodium oxamate and TGF-beta + sodium oxamate + lactate groups of example 2 of the invention;
FIG. 20 is a graph showing immunofluorescence of LDHA in the control group, TGF-beta group, TGF-beta+ sodium oxalate group, and TGF-beta+ sodium oxalate+lactate group according to example 3 of the present invention;
FIG. 21 is a graph showing immunoblots of proteins from a control group, TGF-beta group, TGF-beta+ sodium oxalate group, and TGF-beta+ sodium oxalate+lactate group in example 3 of the present invention;
FIG. 22 is a bar graph showing cytoplasmic LDHA/beta-actin expression in the control, TGF-beta + sodium oxamate, and TGF-beta + sodium oxamate + lactate groups of example 3 of the present invention;
FIG. 23 is a bar graph showing the expression of nuclear LDHA/Histone H in the control, TGF-beta + sodium oxamate and TGF-beta + sodium oxamate + lactate groups of example 3 of the present invention;
FIG. 24 is a graph showing changes in intracellular LDH in the control, TGF-beta + sodium oxamate and TGF-beta + sodium oxamate + lactate groups of example 3 of the present invention;
FIG. 25 is a graph showing changes in the concentration of lactic acid in the nucleus of a control group, TGF-beta group, TGF-beta+ sodium oxalate group and TGF-beta+ sodium oxalate+lactate group in example 3 of the present invention;
FIG. 26 is a graph showing changes in the concentration of lactic acid in the nucleus of a cell after knocking down LDHA in the cell in example 3 of the present invention;
FIG. 27 is a graph showing the change in LDH in cell homogenates in the control group and the experimental groups of compounds a to h according to example 4 of the present invention; in the figure, -represents no addition, + represents addition;
FIG. 28 is a bar graph of fluorescence quantitative PCR tests for Col 1. Alpha.1 in the control, TGF-beta and TGF-beta+ compound a groups of example 4 of the present invention;
FIG. 29 is a bar graph of fluorescence quantitative PCR tests for Col 3. Alpha.1 in the control, TGF-beta and TGF-beta+ compound a groups of example 4 of the present invention;
FIG. 30 is a bar graph of fluorescent quantitative PCR testing of alpha-SMA in the control, TGF-beta and TGF-beta+ compound a groups of example 4 of the present invention;
In FIGS. 2 to 4, # represents a significant difference (P < 0.05) from the control group; * Indicating significant differences (P < 0.05) compared to cci 4 group;
in FIGS. 6 to 18 and 22 to 30, # represents a significant difference (P < 0.05) from the control group; * Indicating a significant difference (P < 0.05) compared to the TGF-beta group.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The specific conditions are not noted in the invention, and the method is carried out according to the conventional conditions or the conditions suggested by manufacturers; the reagents or apparatus used were conventional products available commercially without the manufacturer's attention. In the embodiments of the present invention, the percentages are all by volume unless otherwise specified.
Male C57BL/6J mice, 6-8 weeks old, were purchased from Liaoning Changsheng Biotechnology Co. Mice are fed in an independently ventilated mechanism cage (IVC) system, so that the mice can drink and ingest freely and fully, and the light and dark cycles are carried out for 12 hours, and the room temperature is limited to 21-25 ℃. Following the principle of completely random grouping in the behavioural experiments, mice were transferred to the behavioural laboratory one day in advance to adapt to the environment, and the experiment remained quiet and odorless throughout the course of the experiment. Animal experiments were approved by the university of Hebei's animal ethics committee and followed the guidelines for laboratory animal care and use of Hebei's university.
In order to better illustrate the present invention, the following examples are provided for further illustration.
Example 1 animal behavioural test
After one week of prior adaptation, the mice were randomized into control, model and dosing groups. The model group adopts CCl 4 to induce liver injury of mice, and the volume concentration of the olive oil with the volume concentration of CCl 4 of 10% is injected into the abdominal cavity, the injection amount is 2mL/kg, and the model group is recorded as CCl 4 group; the administration group adopts CCl 4 to induce liver injury of mice, and then orally administrates sodium oxamate every day, wherein the dosage is 750mg/kg, and is recorded as CCl 4 +sodium oxamate group; the control group was not treated. Mice were sacrificed 48h after cci 4 injection, blood and liver were collected rapidly and stored at-80 ℃ for further analysis.
Immunofluorescence test: liver tissue was fixed and then sectioned to a thickness of 6 μm and permeabilized with PBS containing 0.2% Triton X-100 at room temperature for 5min; after blocking for 1h with PBS containing 10% FBS, adding primary antibody alpha-SMA (volume ratio of primary antibody to PBS is 1:200, cell signaling technique) and incubating overnight in a humidified chamber at 4deg.C; the sections were then washed and after incubation with fluorescein-labeled secondary antibody (from zemoeimeric) for 1h, nuclei were counterstained with 4', 6-diamine-2-phenylindole Dihydrochloride (DAPI). Fluorescence was observed and captured using a disk scanning unit confocal imaging system (available from olympus), the results of which are shown in fig. 1.
Fluorescent quantitative PCR test: the liver tissue total RNA was extracted from the control group, model group and administration group using a one-step total RNA extraction kit (purchased from Promega), and the results are shown in FIGS. 2 to 4. Total RNA was reverse transcribed into cDNA using TaqMan reverse transcription kit (available from Semer Fielder) according to the instructions. The relative quantification of mRNA expression was performed using a PCR kit (QIAGEN from Germany) and a CFX96 Touch Real-Time system. The control group uses actin beta (beta-actin) as an internal reference. Primers were synthesized by the Biotechnology company and the sequences of the type 1 collagen alpha1 strand (collagen TYPE I ALPHA1CHAIN GENE, col1 alpha 1), type 3 collagen alpha1 strand (collagen TYPE III ALPHA chain, col3 alpha 1), alpha-smooth muscle actin (alpha-smooth muscle actin, alpha-SMA) and beta-actin primers are shown in Table 1.
TABLE 1 primer sequences for Col 1. Alpha.1, col 3. Alpha.1, alpha-SMA and beta-actin
From FIGS. 1 to 4, it can be seen that CCl 4 stimulation can cause fibrosis of the liver of the mice, and the liver fibrosis degree can be effectively improved after the treatment of sodium oxamate serving as a lactate dehydrogenase inhibitor.
EXAMPLE 2 Primary hepatic stellate cell assay
Primary Hepatic Stellate Cell (HSC) extraction experiments were performed on normal mice. Firstly, pouring Hanks liquid containing 100mg/mL penicillin, streptomycin and 0.5% EGTA; 10% collagenase IV solution was prepared, 10% penicillin and streptomycin were added, and CaCl 2 was added to a final concentration of 0.2mM, and the mice were continuously perfused. The liver was carefully removed and digested at 37 ℃ for 45min; the digested liver tissue was filtered, and hepatic stellate cells were isolated by gradient centrifugation.
The control group was not treated; the experimental groups were divided into three groups, and the three groups were stimulated by adding 10. Mu.g/mL TGF-. Beta.to the culture medium of hepatic stellate cells, respectively, one group was treated with sodium oxamate (to a final concentration of 20 mM), and one group was treated with sodium oxamate (to a final concentration of 20 mM) and exogenous lactic acid (to a final concentration of 10 mM) simultaneously. The three experimental groups were designated as TGF-beta group, TGF-beta+sodium oxalate group and TGF-beta+sodium oxalate+lactate group, respectively.
Immunofluorescence test: after 24h treatment with the corresponding reagent, the control and experimental groups (3 groups) were washed with PBS and fixed in 4% paraformaldehyde for 20min; PBS containing 0.2% Triton X-100 was allowed to permeate for 5min; the cells were blocked with PBS containing 10% FBS for 1h, and alpha-SMA and LDHA (the volume ratio of primary antibody to PBS solution was 1:1000, available from Wohan Sanying Biotechnology Co., ltd.) were labeled with primary antibody overnight. The sections were then incubated with fluorescein-labeled secondary antibodies (available from zemoeimeric) for 1h. Nuclei were counterstained with DAPI staining for 10min. The image was taken by ImageXpress Micro confocal microscope (available from the Megu molecular apparatus) and the results are shown in FIG. 5.
Fluorescent quantitative PCR test: the total RNA of the cells of the control group and the experimental group (group 3) were extracted by using a one-step total RNA extraction kit (purchased from Prograham) respectively, and the results are shown in FIGS. 6 to 12. Primer sequences for Col 1. Alpha.1 and Col 3. Alpha.1 are shown in Table 1, primer sequences for hexokinase 2 (HK-II), pyruvate kinase isozyme 2 (PKM 2), glutaminase 2 (GLS 2), glutamate dehydrogenase 1 (GLDH 1) and neutral amino acid transporter B (SLC 1A 5) are shown in Table 2.
TABLE 2 primer sequences for HK-II, PKM2, GLS2, GLDH1 and SLC1A5
The NAD +/NADH, LDHA, ATP production and lactate concentration in the cell homogenates of the control and experimental groups (group 3) were measured using a commercial kit (purchased from Nanjing's institute of biological engineering) and the results are shown in FIGS. 13-16.
Mitochondrial complex activity assay: the activity of mitochondrial complexes I (Complex I) and II (Complex II) was determined using a commercial kit (available from Beijing Soy Biotechnology Co., ltd.). The cells of the control group and the experimental group (3 groups) were collected to extract the supernatant, and then the supernatant was again isolated, and the pellet and crushed cells were collected to examine the activity of the mitochondrial complex, and the results are shown in FIGS. 17 to 18.
Mitochondrial membrane potential detection: HSCs of control and experimental groups (group 3) were seeded in 6-well plates, stained with 5,5', 6' -tetrachloro-1, 1', 3' -tetraethyl pirimicarb-cyanoiodide (JC-1) after 24h treatment with the corresponding reagents, and incubated at 37 ℃ for 30min. The HSCs were then washed twice with JC-1 staining buffer, and stained using ImageXpress Confocal (available from Megu molecular apparatus) and the results are shown in FIG. 19.
As can be seen from fig. 5-7, sodium oxamate is effective against liver fibrosis, but the addition of lactic acid weakens the effect of sodium oxamate. From FIGS. 8 to 13, it can be seen that TGF-beta stimulation increases expression of genes related to glycolysis of primary hepatic stellate cells, genes related to glutamine metabolism, and lactate content, indicating that primary hepatic stellate cell activation is involved in metabolic recombination during liver fibrosis, TGF-beta stimulation increases lactate content to also demonstrate a change in glycolysis, while sodium oxalate has a restorative effect on glycolysis. As can be seen from FIG. 14, TGF-beta stimulation decreases NAD +/NADH, and sodium oxamate decreases the magnitude of the decrease in NAD +/NADH. From FIGS. 16-19, it can be seen that TGF-beta stimulation increases the activity of mitochondrial complexes I and II, while sodium oxamate inhibits the increase in mitochondrial complex activity, with more pronounced inhibition of mitochondrial complex I activity.
EXAMPLE 3 Primary hepatic stellate cell Nuclear assay
Immunofluorescence test: after 24h treatment with the corresponding reagent, the control and experimental groups (3 groups) were washed with PBS and fixed in 4% paraformaldehyde for 20min; PBS containing 0.2% Triton X-100 was allowed to permeate for 5min; the cells were blocked with PBS containing 10% FBS for 1h, and alpha-SMA and LDHA (the volume ratio of primary antibody to PBS solution was 1:1000, available from Wohan Sanying Biotechnology Co., ltd.) were labeled with primary antibody overnight. The sections were then incubated with fluorescein-labeled secondary antibodies (available from zemoeimeric) for 1h. Nuclei were counterstained with DAPI staining for 10min. The image was taken by ImageXpress Micro confocal microscope (available from the Megu molecular apparatus) and the results are shown in FIG. 20.
Protein immunoblotting: extracting nucleoprotein and total protein of hepatic stellate cells in a control group and an experimental group (3 groups), extracting the nucleoprotein by using a Biyun-Tian cell plasma protein and nucleoprotein extraction kit, cleaning adherent cells by using PBS, scraping cell supernatant by using a cell scraper, centrifugally collecting and discarding, adding 200 mu L of cell plasma protein extraction reagent A, carrying out ice bath for 15min after vortex, adding 10 mu L of cell plasma protein extraction reagent B for 1min, and centrifuging for 5min at 12000 r/min-16000 r/min to obtain the cell plasma protein; after adding 50. Mu.L of a nucleoprotein extraction reagent to the pellet, vortexing and then ice-bathing, repeating this step for 30min and centrifuging again to obtain the supernatant. then adding loading buffer, and boiling at 100deg.C for 10min; proteins were separated on a 10% SDS-PAGE gel and transferred to PVDF membrane (from Merck) and after 3min of blocking with 5% skimmed milk at room temperature, washed in TBST and incubated overnight at 4℃with primary antibody. The volume ratio of primary antibody to TBST solution was 1:1000, primary antibodies were LDHA (purchased from Proteintech, 19987-1-AP), histone H3 (purchased from Proteintech, 1768-1-AP), acetyl-H3 (purchased from CELL SIGNALING Technology, D5E 4), acetyl-H4 (purchased from Affinity Biosciences Pty Ltd, AF 3355), HDAC3 (purchased from Affinity Biosciences, DF 6280), HDAC4 (purchased from Affinity Biosciences, AF 6349), HDAC5 (purchased from Affinity Biosciences, AF 5348), C-Myc (purchased from CELL SIGNALING Technology, D84C 12) and anti-beta-actin (purchased from CELL SIGNALING Technology, 4970S). The next day, goat anti-rabbit IgG (purchased from Abcam, ab 181662) labeled with horseradish peroxidase (HRP) was used as the secondary antibody at a volume ratio of 1:1000 to TBST solution. Results were visualized using Clarity TM WESTERN ECL Substrate in a Bio-Rad chemistry TM XRS system (available from BioRad Laboratories) and are shown in FIG. 21. The results are shown in FIGS. 22 to 23, with the beta-actin or Histone H as the standard (the nucleus is Histone H3, the cytoplasm is beta-actin) and the control group as 1, and the results as fold changes.
The nuclear LDH and lactate concentrations of the control and experimental groups (group 3) were measured using a commercial kit (purchased from the institute of bioengineering, build-up in south kyo) and the results are shown in fig. 24 to 25.
From fig. 20 to 25, it can be seen that TGF- β stimulation results in an increase in LDHA in primary hepatic stellate cell nuclei, accelerating LDHA nuclear transfer, while sodium oxamate inhibits nuclear translocation of LDHA.
The cell was knockdown with respect to LDHA (designated TGF-beta + LDHA SIRNA group and TGF-beta + LDHA SIRNA + lactate group), and the lactic acid content in the nucleus was again examined, and the results are shown in FIG. 26. From the figure, it can be seen that the lactic acid content of the group knocked down LDHA is significantly reduced, indicating that LDHA promotes the production of lactic acid in the nucleus.
Example 4 verification test
And respectively dissolving the compounds a-h in DMSO to prepare a solution with the concentration of 10mM, and respectively replacing sodium oxalate with the solutions of the compounds a-h to treat hepatic stellate cells of normal mice.
The compound a is 2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol; the compound b is 2- [ 2-amino-5- (2-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol (which can be regarded as a derivative of the compound a), and has a structural formula shown in formula 2:
The control group was not treated; the experimental groups were divided into two groups, and the two groups were stimulated by adding 10. Mu.g/mL TGF-. Beta.s to the culture medium of hepatic stellate cells, respectively, and one group was treated with solutions of compounds a to h, respectively (to give final concentrations of compounds a to h of 10. Mu.M, respectively). The 2 experimental groups of compound a were designated as TGF-beta group and TGF-beta+ compound a group, respectively.
The LDH content of the cell homogenates of the control group and the experimental groups of compounds a-h were measured using a commercial kit (purchased from Nanjing institute of biological engineering) and the results are shown in FIG. 27. As can be seen from fig. 27, compound a (2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol) and its derivative compound b (2- [ 2-amino-5- (2-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol) are capable of effectively inhibiting LDH activity.
Fluorescent quantitative PCR test: the total RNA of the cells of the control group and the experimental group (group 3) were extracted by using a one-step total RNA extraction kit (purchased from Prograham) and the results are shown in FIGS. 28 to 30. Primer sequences for Col 1. Alpha.1, col 3. Alpha.1 and alpha-SMA are shown in Table 1.
As can be seen from fig. 27 to 30, compound a (2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol) is capable of effectively inhibiting LDH activity and can inhibit the decrease in expression of fibrosis genes induced by TGF- β, indicating that 2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol is a candidate drug that can inhibit hepatic stellate cell activation by inhibiting lactate dehydrogenase, ultimately achieving the treatment of hepatic fibrosis.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.
Claims (7)
1. An application of a compound a or a derivative thereof in preparing a medicament for preventing and treating hepatic fibrosis diseases, wherein the compound a is 2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol, and the structural formula of the compound a is shown as formula 1:
2. Use of compound a or a derivative thereof according to claim 1 for the manufacture of a medicament for the prevention and treatment of liver fibrosis diseases, wherein the medicament targets lactate dehydrogenase.
3. A pharmaceutical composition for preventing and treating liver fibrosis diseases, comprising 2- [ 2-amino-5- (3-methoxyphenoxy) pyrimidin-4-yl ] -5-methoxyphenol or a derivative thereof.
4. A pharmaceutical preparation for preventing and treating liver fibrosis diseases, characterized in that the active component of the pharmaceutical preparation is the pharmaceutical composition for preventing and treating liver fibrosis diseases according to claim 3.
5. The pharmaceutical formulation for preventing and treating liver fibrosis diseases of claim 4, further comprising pharmaceutically acceptable excipients.
6. The pharmaceutical formulation for preventing and treating liver fibrosis diseases of claim 5, wherein the excipients include at least one of excipient, disintegrant, lubricant, binder or solvent.
7. A pharmaceutical formulation for preventing and treating liver fibrosis according to any one of claims 4 to 6, wherein the pharmaceutical formulation is a tablet, pill, capsule, granule, caplet, suspension, drop pill, oral liquid, injection, aerosol, suppository or subcutaneous administration.
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