CN114224893B - Application of quinazoline derivative in preparation of drugs for preventing and treating arsenic-induced liver injury - Google Patents
Application of quinazoline derivative in preparation of drugs for preventing and treating arsenic-induced liver injury Download PDFInfo
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- CN114224893B CN114224893B CN202210084671.5A CN202210084671A CN114224893B CN 114224893 B CN114224893 B CN 114224893B CN 202210084671 A CN202210084671 A CN 202210084671A CN 114224893 B CN114224893 B CN 114224893B
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides application of quinazoline derivatives in preparing medicaments for preventing and treating liver injury caused by arsenic, wherein the quinazoline derivatives have a structural formula shown in a formula I. The invention belongs to the technical field of medicines, and provides application of quinazoline derivatives in preparing medicines for preventing and treating arsenic-induced liver injury, wherein the quinazoline derivatives are used for intervening an arsenic-poisoning cell model and a mice infected with arsenic from in-vivo and in-vitro levels to discuss the prevention and protection effects of the quinazoline derivatives on the arsenic-induced liver injury.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of quinazoline derivatives in preparation of medicines for preventing and treating liver injury caused by arsenic.
Background
Arsenic (As) acts As a naturally occurring environmental poison and carcinogen, and is readily available to humans and animals through food, water and occupational contamination, resulting in multiple organ system damage. Currently, over 2 hundred million people worldwide face the problem of exceeding arsenic content in drinking water, leading to a large number of arsenic poisoning phenomena, especially in later developing countries. In Guizhou province and Shaanxi province in China, more local arsenic poisoning phenomenon caused by coal pollution exists.
Liver is used as main metabolism and detoxication organ of arsenic, and can be retained in high concentration in its metabolism process, so that liver diseases with different degrees, such as abnormal liver function, hepatomegaly, liver fibrosis, liver cirrhosis and even cancerous changes, become one of the main causes of arsenic death. The prior researches find that: oxidative stress and lipid peroxidation are causative factors of liver injury caused by arsenic, and arsenic can generate a large amount of free radicals and non-free radical products in liver metabolism to cause lipid peroxidation of liver cell membranes, so that cell membrane and organelle structures are damaged, and the membrane fluidity is abnormal; a large amount of intracellular enzymes (ALT, AST) are released into the blood, and free radical scavenging enzymes (SOD, GPX) are exhausted, so that the damage to the liver cells is further aggravated, the activity level of Glutathione (GSH) is reduced, and the level of Malondialdehyde (MDA) is increased, thereby causing abnormal liver function and fat metabolism disorder.
Quinazoline compounds (quinzoles) are a class of nitrogen-containing heterocyclic compounds that are commonly found in nature. The quinazoline ring structure is the skeleton of various alkaloids, quinazoline compounds with different structures can have different effects, and medicines such as dactyltinib, gefitinib, doxazosin and the like have excellent effects of resisting tumors, resisting hypertension and the like respectively by taking quinazoline as a pharmacophore. The quinazoline compounds have the advantages of low toxicity, high efficiency, unique action mode, easy transformation and the like, and become one of research hotspots in the fields of pharmaceutical chemistry and pharmacology.
The quinazoline compounds play an important role in the fields of anti-tumor, antihypertensive, antimalarial, antibacterial, anti-inflammatory, antituberculosis, insecticidal, weeding and the like, and have not been reported in the aspect of preventing and treating liver injury.
Disclosure of Invention
In order to enrich the prior art and expand the application range of quinazoline compounds, the invention provides the application of quinazoline derivatives in preparing medicaments for preventing and treating arsenic-induced liver injury on the basis of obtaining quinazoline derivatives shown in a formula I by early research, construction and screening, and performing intervention of quinazoline derivatives on an arsenic-poisoning cell model and a mice infected with arsenic from in vivo and in vitro levels, discussing the prevention and protection effects of quinazoline derivatives on arsenic-induced liver injury.
The purpose of the present invention will be further explained by the following detailed description.
The invention provides application of quinazoline derivatives in preparing medicaments for preventing and treating liver injury caused by arsenic, wherein the quinazoline derivatives have a structural formula shown in a formula I:
in the invention, the code of the quinazoline derivative is KZL-047, and in the drawings of part of the specification, the quinazoline derivative is further simplified into KZL.
Preferably, the arsenic is sodium arsenite.
More preferably, the liver injury comprises: abnormal liver function, hepatomegaly, liver fibrosis, liver cirrhosis, and liver cancer.
Compared with the prior art, the invention has the beneficial effects that: the invention proves the efficacy of quinazoline derivatives (KZL-047) shown in the formula I in the aspect of preventing and treating liver injury caused by arsenic from in vivo and in vitro levels, and provides the application of the quinazoline derivatives in preparing medicaments for preventing and treating liver injury caused by arsenic. According to the invention, through constructing an arsenic poisoning cell model and intervening with KZL-047, the invention discovers that KZL-047 can relieve the activity of inhibiting the growth of liver cells mediated by sodium arsenite and can relieve the apoptosis of L-02 cells induced by sodium arsenite. According to the invention, through constructing an arsenic poisoning mouse model and intervening with KZL-047, the KZL-047 is found to be capable of preventing and treating SA-caused mouse liver injury.
Drawings
FIG. 1 is a graph showing the effect of KZL-047 at various concentrations on L-02 cell growth.
FIG. 2 is a graph showing the effect of different concentrations of KZL-047 on the proliferation of SA-treated L-02 cells. Wherein 2-A is a graph of the result of detecting that SA has an inhibitory effect on the in vitro growth of L-02 cells through an MTT test, and has concentration dependence; 2-B is a morphological examination of L-02 cells observed under a microscope as SA concentration increases; 2-C is a graph of the effect of cell proliferation on the continuous treatment of the L-02 cells for 48h with KZL-047 of different concentrations after the L-02 cells are treated for 24h with SA of 20 mu mol/L as a contamination concentration; 2-D is a morphological detection diagram of the treatment of L-02 cells with KZL-047 of different concentrations for 48h after selecting SA of 20. Mu. Mol/L as the contamination concentration for 24 h.
FIG. 3 is a graph showing the effect of 20. Mu. Mol/L SA and KZL-047 at various concentrations on L-02 apoptosis. Wherein, 3-A is a graph of apoptosis level detection results after treatment with SA and KZL-047 of different concentrations; 3-B is a flow cytometry plot of apoptosis induced by 20. Mu. Mol/L SA and apoptosis alleviation by KZL-047 at various concentrations.
Detailed Description
The invention will be described in further detail with reference to the drawings and examples.
In the invention, the experimental materials are conventional commercial products or can be obtained by the conventional technical means in the field, the detection method is carried out according to the general method or the instruction of a kit in the field, and the DMEM high-sugar culture medium added with fetal bovine serum is adopted as the culture solution of the L-02 cells.
The normal human liver cell line (L-02) used in this experiment was purchased from the cell bank of the national academy of sciences, shanghai, china; sodium Arsenite (SA) as a standard, purchased from Sigma, usa; tetramethylazosin (MTT) powder and dimethyl sulfoxide (DMSO), available from beijing solebao corporation; DMEM high sugar medium, available from HyClone corporation, usa; fetal Bovine Serum (FBS), purchased from holly company; 96-well plates, available from Nest, USA. SPF-class male mice of Kunming species 140, 8-10 weeks old, weighing 25-30g, supplied by the Liaoning laboratory animal resource center, animal license number (license number: SCXK (Liao) 2020-0001).
EXAMPLE MTT assay to examine the effect of KZL-047 on L-02 cell proliferation
Taking L-02 cells with good three-generation state, and regulating cell concentration to 5×10 3 Well/well and inoculated in 96-well plate, 200. Mu.L of cell culture solution was added to each well, and after incubation in an incubator at 37℃for 24 hours, KZL-047 was added at different concentrations (DMSO, 1.25, 2.50, 5.0, 10.0, 20.0. Mu. Mol/L) respectively, 5 multiplex wells per concentration. After continuous treatment in an incubator at 37℃for 48 hours, photographs were taken under an inverted fluorescence microscope. Then, 20. Mu.L MTT is added into each well, incubation is carried out for 4 hours at 37 ℃, centrifugation is carried out for 30 minutes at normal temperature of 3000rpm/min, liquid in a 96-well plate is sucked out by using absorbent paper, 150. Mu.L DMSO is added, vibration is carried out for 15 minutes at room temperature, absorbance (OD) is detected by using an enzyme-labeled instrument under 490nm excitation light, the detection result is shown as figure 1, the average value of three independent experiments is expressed as +/-SD, compared with a control group, * P<0.05， ** P<0.01. the low-concentration KZL-047 can obviously promote the proliferation of L-02 cells after 48 hours of action (P<0.05 High (high) ofConcentration promotion was reduced, so subsequent experiments were performed with 5.0. Mu. Mol/L and 10.0. Mu. Mol/L.
Example effect of KZL-047 on SA leading to inhibition of L-02 cell proliferation and apoptosis
After SA was continuously treated with DMSO at different concentrations (10.0, 20.0, 40.0, 80.0 and 160. Mu. Mol/L) for 24 hours according to the method of example one, absorbance (OD) was measured with a microplate reader under 490nm excitation light, and the measurement results were shown in FIG. 2-A as the average.+ -. SD of three independent experiments, compared with the control group, * P<0.05， ** P<0.01， *** P<0.001. l-02 cells were treated with SA at different concentrations for 24h, IC 50 The value is 25.80+/-2.34 mu mol/L, and the result shows that the activity of the L-02 cells is reduced along with the increase of the SA concentration, which indicates that the SA can inhibit the proliferation of the L-02 cells in a concentration-dependent manner, and 20 mu mol/L is selected as the subsequent contamination and modeling concentration. The cell morphology was observed by photographing in an inverted fluorescence microscope, and as a result, as shown in FIG. 2-B, the cell morphology was rounded by shuttles, and the number was reduced. The follow-up experimental design was divided into 4 groups, a blank group (DMSO), a model group (20. Mu. Mol/L SA), and a KZL-047 intervention group (20. Mu. Mol/L SA treated +5. Mu. Mol/L KZL, 20. Mu. Mol/LSA treated +10. Mu. Mol/L KZL), the culture broth was removed after SA treatment for 24 hours, and the KZL-047 intervention group was further added with a cell culture broth containing the corresponding concentration of KZL-047 for 48 hours, and the results were shown in FIG. 2-C. In comparison with the control group, * P<0.05， ** P<0.01; in contrast to the set of models, a P<0.05， aa P<0.01. the results show that: when SA concentration was 20. Mu. Mol/L, molding was successful, cell growth was significantly inhibited compared with the control group (P<0.05 A) is provided; after increasing the KZL-047 of 5. Mu. Mol/L and 10. Mu. Mol/L, the cell growth was still inhibited to some extent as compared with the control group (P<0.05 But the degree of inhibition of cell growth was significantly lower than in the model group (P)<0.05). These results indicate that low concentrations of KZL-047 significantly reduce the inhibition of normal hepatocyte proliferation by SA. As shown in FIG. 2-D, it is evident that after 24 hours of treatment of hepatocytes with 20. Mu. Mol/L SA, the cell morphology started to change from smooth to irregular, with blurred boundaries, with enlarged cell gaps, but withAfter treatment with KZL-047 of 5. Mu. Mol/L and 10. Mu. Mol/L for 48h, the cell morphology was gradually recovered, the boundaries became clear, and the rounded cells were reduced. These data indicate that KZL-047 can relieve the growth inhibition of normal liver cells after 20 mu mol/L SA treatment at a lower concentration, and shows a certain recovery effect.
The third generation of L-02 cells was expressed as 3X 10 5 Inoculating the culture medium/mL into a 6-hole plate, adding 20 mu mol/L SA, performing modeling culture for 24 hours, sucking out the original culture solution, adding KZL-047 with different concentrations, and performing culture for 48 hours, wherein three parallel experiments are respectively arranged. The cells were collected, washed twice with PBS, and the cell concentration was adjusted to 1X 10 with 1X binding buffer 6 mu.L of FITC and 5. Mu.L of PI were added to the cells per mL. Gently mixed, incubated at room temperature for 15min in the absence of light, cells were collected, stained with FITC and PI, and immediately examined for apoptosis by flow cytometry, the results are shown in FIG. 3-B. Flow cytometry examined the potential effect of KZL-047 on alleviating SA-induced apoptosis of L-02 cells, as shown in FIG. 3-A. As a result of the study, the apoptosis rate of human hepatocytes L-02 induced by SA of 20. Mu. Mol/L was 13.56% (P <0.01 compared with the control group), and the apoptosis rates of L-02 cells were reduced to 8.59% (P) by treating the cells with KZL-047 of 5. Mu. Mol/L and 10. Mu. Mol/L, respectively<0.05 And 3.81% (P)<0.01 Gradually approaching the case of untreated normal hepatocytes. In contrast to the blank set of the cells, * P<0.05， ** P<0.01; in contrast to the set of models, a P<0.05， aa P<0.01. expressed as mean ± SD of three independent experiments. The result shows that KZL-047 can obviously reduce SA-induced normal hepatocyte apoptosis.
Animal experiment investigation of example three KZL-047
Grouping and administration: adaptively feeding for 1 week (room temperature is 20-24 ℃, humidity is 50-60 percent, day and night circulation and free drinking water) before formal experiments, randomly dividing 140 SPF-level male Kunming mice into two groups for prevention and treatment, setting a blank group (physiological saline) in each group, setting a model group (5 mg/kg SA), setting a positive control group (11.375 mg/kg dicyclo alcohol and 182mg/kg glutathione) and setting a total of 7 groups (25, 50 and 100 mg/kg) of KZL low, medium and high dosage groups; in the prevention group, the blank group is filled with equal volume of physiological saline, the model group is filled with 5mg/kg of SA solution, and the other 5 groups are respectively filled with corresponding doses of medicine +5mg/kg of SA solution, and the filling is carried out for 4 weeks continuously for 1 time a day; in the treatment groups, except the blank group, the other groups were subjected to molding treatment in accordance with 5 mg/kg.d SA solution for 4 consecutive weeks, and from the fifth week onward, the model group was perfused with gastric physiological saline, and the other 5 groups were given the corresponding drugs for 4 consecutive weeks.
The measuring and observing method comprises the following steps: after the last administration, all mice are fasted and not forbidden for 8 hours; the blood sample of the mice is collected by an eyeball method, the mixture is stood for half an hour at room temperature, the supernatant is collected by centrifugation at 3 000r/min for 15min, biochemical indexes such as ALT, AST, TBIL and the like are measured, the obtained data are subjected to statistical treatment, the statistical treatment is expressed as mean number +/-standard deviation, the difference significance is judged by T test, and the results are shown in tables 1 and 2 respectively.
No mortality or clinical abnormalities were observed in all experimental mice. In the prophylaxis and treatment groups, SA-treated mice consumed less food than the blank and quinazoline-treated mice.
TABLE 1 variation of ALT, AST, TBIL Activity in serum from prophylaxis groups of mice
Note that: in comparison with the blank set of the cells, ** p is less than 0.01; in comparison with the set of models, aa P＜0.01。
TABLE 2 variation of ALT, AST, TBIL Activity in serum from mice of treatment group
Note that: in comparison with the blank set of the cells, ** p is less than 0.01; in comparison with the set of models, aa P＜0.01。
as can be seen from the prophylaxis group results (table 1) and the treatment group results (table 2), the ALT, AST, TBIL activity of the model group was significantly increased after SA treatment for the experimental hours, and there was a significant difference (P < 0.01) compared to the blank group, indicating that the modeling was successful. In the prophylaxis group, the activity of the mice ALT, AST, TBIL in the model group was significantly increased (P < 0.01) compared to the blank group, and there was no significant difference (P > 0.05) between the positive control group and the KZL-047 dose group, whereas the activity of the mice ALT, AST, TBIL in the positive control group and the KZL-047 dose group was decreased (P < 0.01) compared to the model group, and there was no significant difference (P > 0.05) between the positive control group and the KZL-047 dose group compared to the positive control group. In the treated group (see Table 2), the trend of change in the activity of mouse serum ALT, AST, TBIL was consistent with that of the prophylactic group and was dose dependent, i.e., the activity decreased with increasing KZL-047 dose. The quinazoline derivative prepared by the invention has good effect of preventing and treating liver injury, and the effect is equivalent to the activity of positive drugs.
The foregoing is a further detailed description of the invention in connection with the preferred embodiments, and it is not intended that the invention be limited to the specific embodiments described. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.
Claims (3)
1. The application of quinazoline derivatives in preparing medicaments for preventing and treating liver injury caused by arsenic is characterized in that: the quinazoline derivative has a structural formula shown in a formula I:
2. use of a quinazoline derivative according to claim 1 in the manufacture of a medicament for the treatment of liver injury, wherein: the arsenic is sodium arsenite.
3. Use of quinazoline derivatives according to claims 1 and 2 in the manufacture of a medicament for the prevention and treatment of liver damage, characterised in that: the liver injury includes: abnormal liver function, hepatomegaly, liver fibrosis, liver cirrhosis, and liver cancer.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004059454A (en) * | 2002-07-25 | 2004-02-26 | Japan Energy Corp | QUINAZOLONE DERIVATIVE AND NF-kappaB ACTIVATION INHIBITOR |
| CN103191145A (en) * | 2013-03-27 | 2013-07-10 | 南京理工大学 | Application of adenosine and derivatives thereof in prevention and treatment of medicament-induced liver injury |
| CN109045035A (en) * | 2018-07-19 | 2018-12-21 | 广西科技大学 | Application of 7- (2,2- dimethyl -3- crotonoyl the amido)-octahydro benzene quinoline acetic acid esters in preparation treatment liver disease drug |
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| WO2003103581A2 (en) * | 2002-06-05 | 2003-12-18 | Genentech, Inc. | Compositions and methods for liver growth and liver protection |
| WO2016033296A1 (en) * | 2014-08-28 | 2016-03-03 | Codexis, Inc. | N-substituted 4-aminoquinazoline derivatives and methods of use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004059454A (en) * | 2002-07-25 | 2004-02-26 | Japan Energy Corp | QUINAZOLONE DERIVATIVE AND NF-kappaB ACTIVATION INHIBITOR |
| CN103191145A (en) * | 2013-03-27 | 2013-07-10 | 南京理工大学 | Application of adenosine and derivatives thereof in prevention and treatment of medicament-induced liver injury |
| CN109045035A (en) * | 2018-07-19 | 2018-12-21 | 广西科技大学 | Application of 7- (2,2- dimethyl -3- crotonoyl the amido)-octahydro benzene quinoline acetic acid esters in preparation treatment liver disease drug |
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Address after: 550004 No. 3491, Baijin Avenue, shawen ecological science and Technology Industrial Park, high tech Zone, Guiyang, Guizhou Patentee after: Guizhou Natural Products Research Center Address before: 550004 No. 3491, Baijin Avenue, shawen ecological science and Technology Industrial Park, high tech Zone, Guiyang, Guizhou Patentee before: KEY LABORATORY OF NATURAL PRODUCT CHEMISTRY OF GUIZHOU ACADEMY OF SCIENCES (KEY LABORATORY OF NATURAL PRODUCT CHEMISTRY, GUIZHOU MEDICAL University) |