CN116036058A - Application of 4-O-methyl psoralea chalcone in preparation of medicines for treating or preventing thrombosis - Google Patents
Application of 4-O-methyl psoralea chalcone in preparation of medicines for treating or preventing thrombosis Download PDFInfo
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- 241001446509 Psoralea Species 0.000 title claims abstract description 32
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 title claims abstract description 28
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 235000005513 chalcones Nutrition 0.000 title claims abstract description 27
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 7
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- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
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- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
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- Health & Medical Sciences (AREA)
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- Chemical & Material Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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Abstract
The invention relates to a new application of 4-O-methyl psoralea chalcone, in particular to an application of 4-O-methyl psoralea chalcone in preparing a medicine for treating or preventing thrombosis. The present invention found that 4-O-methyl psoralea chalcone inhibited thrombosis by blocking 14-3-3ζ interaction with integrin β3, ic50=9.9 μm. The 4-O-methyl psoralea chalcone can effectively inhibit thrombosis on animal level, and the administration concentration is effective in 10mg/kg-100mg/kg, and has obvious dose dependence. Meanwhile, the 4-O-methyl psoralea chalcone is found to have no obvious bleeding tendency. The 4-O-methyl psoralea chalcone has very positive effects on preparing medicines for treating and/or preventing thrombosis.
Description
Technical Field
The invention relates to a new application of 4-O-methyl psoralea chalcone, in particular to an application of 4-O-methyl psoralea chalcone in preparing a medicine for treating or preventing thrombosis.
Background
According to studies on global disease burden, cardiovascular disease (CVD) has been shown to have the highest mortality among all non-infectious diseases, while thrombosis is one of the important causes of high mortality cardiovascular disease. Platelets play an important role in the pathogenesis of these diseases, and antiplatelet therapy is an important means of controlling thrombosis. However, anti-platelet drugs such as aspirin and clopidogrel increase the risk of bleeding, and may induce hemorrhagic cerebral stroke and increase the risk of therapeutic resistance, and thus, although anti-platelet therapy has been greatly successful, the medical demand for novel anti-platelet drugs has not been satisfied.
The bi-directional signaling mechanism of integrin beta 3 is important for thrombosis and hemostasis. The interaction of the integrin beta 3 and the adapter 14-3-3ζ is interfered spatially or temporally, so that the outlide-in signal path of the integrin can be blocked, the Inside-out signal path of the integrin is not influenced, and the purposes of inhibiting the expansion of platelets and the formation of thrombus are achieved, and bleeding is not caused because the adhesion of the platelets to an endothelial injury part is not influenced. Inhibition of this target is a safe and effective antithrombotic strategy.
Chalcone compounds are widely used in medicinal plants in nature, and the basic skeleton of the chalcone compounds is 1, 3-diphenylpropenone, so that the psoralea compounds have high flexibility, can be combined with different receptors, and show wide biological activity, such as: anti-inflammatory, anti-tumor, antibacterial, etc. 4-O-methyl psoralea chalcone as one of the psoralea compounds has been reported to have an effect of inhibiting the activity of SARS-CoV papain-like protease (PLpro), ic50=10.1 μm.
Although the biological activity of the psoralea compounds and 4-O-methyl psoralea chalcone is widely studied, the antithrombotic activity of the 4-O-methyl psoralea chalcone is not reported.
Disclosure of Invention
The invention aims to: the invention aims to provide a novel medical application of 4-O-methyl psoralea chalcone according to the current situation of the background technology so as to widen the application range of the 4-O-methyl psoralea chalcone.
The technical scheme is as follows: the invention discovers that 4-O-methyl psoralea chalcone inhibits thrombosis
Further, protein 14-3-3ζ may be blocked from interacting with integrin β3 at a semi-inhibitory concentration of 9.9 μm.
Further, as an active ingredient for inhibiting thrombosis by blocking the interaction of 14-3-3ζ with integrin beta 3.
The invention provides application of 4-O-methyl psoralea chalcone in preparing a medicine for treating and/or preventing thrombosis.
Further, the pharmaceutical dosage form is an oral administration dosage form.
Further, the oral administration form is an emulsion.
Because thrombosis is one of the important causes of cardiovascular diseases with high mortality rate, most antithrombotic drugs have bleeding side effects, and bleeding causes cerebral hemorrhage at great risk, so the search for the possibility of removing thrombus without bleeding risk is a technical problem to be solved in the field.
The present invention found that 4-O-methyl psoralea chalcone inhibited thrombosis by blocking 14-3-3ζ interaction with integrin β3, ic50=9.9 μm. The 4-O-methyl psoralea chalcone can effectively inhibit thrombosis on animal level, and the administration concentration is effective in 10mg/kg-100mg/kg, and has obvious dose dependence. Meanwhile, the 4-O-methyl psoralea chalcone is found to have no obvious bleeding tendency. The 4-O-methyl psoralea chalcone has very positive effects on preparing medicines for treating and/or preventing thrombosis.
Drawings
FIG. 1 is a graph showing the results of a semi-inhibitory concentration assay for the interaction of 4-O-methyl psoralea chalcone blocking protein 14-3-3ζ with integrin beta 3;
FIG. 2 is a graph showing the measurement of carrageenan-induced thrombosis and thrombus length in mice inhibited by 4-O-methyl psoralea chalcone;
FIG. 3 is a statistical plot of 4-O-methyl psoralea chalcone inhibiting carrageenan-induced tail thrombosis and thrombus length in mice;
FIG. 4 is a graph of FeCl inhibition by 4-O-methyl psoralea chalcone 3 Inducing carotid thrombosis and blood flow cut-off time observation results of the mice;
FIG. 5 is a 4-O-methyl bone supplementLipochalcone inhibition of FeCl 3 Inducing carotid thrombosis and blood flow cut-off time statistics of the mice;
FIG. 6 is a graph of FeCl inhibition by 4-O-methyl psoralea chalcone 3 Inducing carotid thrombosis and blood flow velocity statistics of the mice;
FIG. 7 is a statistical result of the effect of 4-O-methyl psoralea fruit chalcone on blood clotting function and on blood bleeding time in the tail of mice;
Detailed Description
Example 1
The compounds of the invention inhibit the interaction of protein 14-3-3ζ with the KEATSTF domain of integrin beta 3.
The experimental method comprises the following steps: competitive binding inhibition experiments using a microphoresis instrument (MST). 200ul of 200uM recombinant 14-3-3 zeta protein was incubated with 200ul of 100nM of the synthetic polypeptide FITC-KEATSTF in the dark for 10min, the protein and polypeptide were diluted with buffer ((0.01M HEPES pH 7.4,0.15M NaCl,0.005% (v/v) Surfactant P20) the compound was diluted in a gradient with a maximum concentration of 70uM, 10-16 gradients were set up and 10ul volumes were mixed with equal volumes of the mixture diluted in the gradient, and the mixture was blown and mixed well.
Experimental results: as shown in fig. 1, the compound dose-dependent blocking protein 14-3-3ζ interacted with the integrin beta 3KEATSTF region at a half maximal inhibitory concentration of 9.9uM. The compounds of the present invention are capable of interacting with the integrin beta 3keats tf region of the highly potent inhibitor protein 14-3-3ζ.
Example 2
The compounds of the present invention inhibit carrageenan-induced thrombosis in the tail of mice.
The experimental method comprises the following steps: carrageenan induced thrombosis model experiments. The tested animals are ICR male mice, and are fed in separate cages before experiments in clean animal experiments of animal centers of university of Chinese medical science. The mice to be tested are divided into 6 groups of model group, clopidogrel group and aspirin group, and the number of the mice is 8 in each group. The administration doses are respectively model group of olive oil containing 5% DMSO, clopidogrel group of 10mg/kg and aspirin group of 100mg/kg, the high, medium and low doses of the compound are respectively 100mg/kg,33mg/kg and 10mg/kg, the compound is dissolved by DMSO, and the olive oil is diluted to prepare emulsion containing 5% DMSO. The administration time is that of the administration in advance, the administration mode is that of the administration by gastric lavage, 50mg/kg carrageenan solution is injected into the abdominal cavity after 1 hour of gastric lavage, and the mice are placed in the environment of 15 ℃ for low temperature feeding for 24 hours. After successful molding, the thrombus length at the tail of the mice was measured. Raw data were analyzed using GraphPad Prism 6.0 software. The measured values are expressed as mean ± standard error of the mean of each set of independent experiments. The inter-group analysis employed one-factor analysis of variance, with p <0.05 considered statistically significant.
Experimental results: the compounds of the present invention inhibit carrageenan-induced thrombosis in the tail of mice. Wherein, as shown in FIGS. 2-3, the average thrombus length of the model group was 4.91.+ -. 0.55cm, indicating that the carrageenan-induced mouse tail thrombus model was successfully constructed. Clopidogrel as a positive drug and aspirin with average thrombus length of 2.31+ -0.77 cm and 2.93+ -0.93 cm respectively. The average thrombus length of the high-dose group, the middle-dose group and the low-dose group of the compound is 2.79+/-0.93 cm, 3.24+/-0.38 cm and 3.85+/-0.73 cm respectively. The compounds significantly reduced the length of thrombus compared to the model group, indicating that the compounds have an inhibitory effect on thrombus formation and have a significant metering dependence.
Example 3
The compound of the invention inhibits FeCl 3 Inducing carotid thrombosis in mice.
The experimental method comprises the following steps: feCl 3 And (3) inducing a carotid artery thrombosis model experiment of the mice. The tested animals are ICR male mice, and are fed in separate cages before experiments in clean animal experiments of animal centers of university of Chinese medical science. The mice to be tested are divided into a model group and a clopidogrel group, and 5 groups of the compounds with high, medium and low dosages and the like are adopted, and 6 mice in each group are treated. The administration dose is model group of olive oil containing 5% DMSO and clopidogrel group of 100mg/k respectivelyg, the high, medium and low doses of the compound are respectively 100mg/kg,33mg/kg and 10mg/kg, the compound is dissolved by DMSO, and the compound is diluted by olive oil to prepare an emulsion containing 5% DMSO. The administration time is the administration in advance, the administration mode is the stomach irrigation, and the mould is made after 2 hours of stomach irrigation. The molding method comprises anesthetizing a test mouse with 10% chloral hydrate, incising neck skin of the mouse along the longitudinal line of the cervical midline with sterilizing equipment, separating muscle tissue with surgical forceps, exposing trachea, separating lateral carotid artery about 3cm, separating carotid artery from surrounding tissue with plastic film, protecting surrounding vascular tissue, and sucking 7.5% FeCl 3 A small filter paper sheet of the solution is clung to the carotid artery, and after applying the paper sheet for 2min, the blood vessel is imaged under a moorFLPI-2 laser speckle blood flow imager. One angiogram was taken every minute, each mouse was sacrificed thirty minutes after taking, blood flow per minute was analyzed with mfpi 2 software while counting the time of disappearance of blood flow, and raw data was analyzed using GraphPad Prism 6.0 software. The measured values are expressed as mean ± standard error of the mean of each set of independent experiments. The inter-group analysis adopts single factor analysis of variance, p<0.05 is considered statistically significant.
Experimental results: the compound can inhibit FeCl 3 Inducing carotid thrombosis in mice. As shown in figures 4-5, the average time of blood flow disappearance of the model group is 6.17+/-1.17 min, the average time of blood flow disappearance of the clopidogrel positive drug group is 21.17+/-3.55 min, and the average time of blood flow disappearance of the compound high, medium and low dose groups is 100mg/kg 14.33+/-2.81 min,33mg/kg 10.83+/-1.72 min and 10mg/kg 9.83+/-1.72 min. The positive drug and the compound can significantly extend the time to disappearance of blood flow compared to the model group, the compound having a pronounced dose dependence. As shown in fig. 6, the compounds significantly reduced the blood flow reduction rate compared to the model group.
Example 4
The compounds of the present invention have no significant risk of bleeding.
The experimental method comprises the following steps: tail breaking experiment. The tested animals are ICR male mice, and are fed in separate cages before experiments in clean animal experiments of animal centers of university of Chinese medical science. The mice to be tested are divided into a model group and a clopidogrel group, and 5 groups of the compounds with high, medium and low dosages and the like are adopted, wherein 8 mice are arranged in each group. The administration dosage is model group of olive oil containing 5% DMSO, clopidogrel group is 100mg/kg, the high, medium and low dosages of the compound are 100mg/kg,33mg/kg and 10mg/kg respectively, the compound is dissolved by DMSO, and the olive oil is diluted to prepare emulsion containing 5% DMSO. The administration time is the administration in advance, and the administration mode is gastric lavage. 1h after administration, placing the mice on a fixer to prevent the tail of the mice from being disturbed, preparing a culture dish filled with normal saline, performing tail breaking treatment at the position of 2mm of the tail tip of the mice, placing the tail breaking position in the culture dish, starting timing from the outflow of blood until stopping blood flow, counting time, and analyzing the original data by using GraphPad Prism 6.0 software. The measured values are expressed as mean ± standard error of the mean of each set of independent experiments. The inter-group analysis employed one-factor analysis of variance, with p <0.05 considered statistically significant.
Experimental results: the compounds of the present invention have no significant risk of bleeding. As shown in fig. 7, the average bleeding time of the tail of the mice in the model group is 161s, the average bleeding time of the clopidogrel group is 611.5s, and the average bleeding time of the high, medium and low dose groups of the compound of the invention is 170.4s,190.4s and 161.5s respectively. Clopidogrel has a significant risk of bleeding compared to the model group, while the compound group has no significant difference in bleeding time from the model group, indicating that the compound has no effect on the clotting function of mice, and no significant risk of bleeding.
Claims (3)
1.4-O-methyl psoralea chalcone in the preparation of medicaments for treating or preventing thrombosis,
the chemical structural formula of the 4-O-methyl psoralea chalcone is as follows:
2. the use of claim 1, wherein the pharmaceutical dosage form is an oral dosage form.
3. The use according to claim 2, wherein the oral administration form is an emulsion.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310168056.7A CN116036058A (en) | 2023-02-27 | 2023-02-27 | Application of 4-O-methyl psoralea chalcone in preparation of medicines for treating or preventing thrombosis |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310168056.7A CN116036058A (en) | 2023-02-27 | 2023-02-27 | Application of 4-O-methyl psoralea chalcone in preparation of medicines for treating or preventing thrombosis |
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| CN116036058A true CN116036058A (en) | 2023-05-02 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105982881A (en) * | 2015-02-09 | 2016-10-05 | 上海中医药大学 | Application of bavachalcone and analogues thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105982881A (en) * | 2015-02-09 | 2016-10-05 | 上海中医药大学 | Application of bavachalcone and analogues thereof |
Non-Patent Citations (1)
| Title |
|---|
| GUANG XIN等: "Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release", FREE RADICAL BIOLOGY AND MEDICINE, vol. 108, 8 February 2017 (2017-02-08), pages 256 * |
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