Star polymer for promoting lung function repair and preparation method thereof

Abstract

The invention provides a star polymer for promoting lung function repair and a preparation method thereof. The preparation method comprises the following steps: carrying out epoxy group modification on hydroxyl chalcone to obtain epoxidized chalcone, grafting the epoxidized chalcone to an amino group on a side arm of a star-shaped copolymer mother nucleus by using an introduced epoxy group, and grafting a polyethylene glycol chain segment on the side arm of the star-shaped copolymer mother nucleus to increase the water solubility; the defects that the chalcone compound is high in melting point and difficult to dissolve in water are improved in a targeted manner. Besides, the core of the star-shaped copolymer comprises a cystamine structure, and is easy to generate reduction reaction in a living body, so that the degradation and absorption of the star-shaped polymer in the living body are promoted, and finally the effects of improving the anti-inflammatory activity of the star-shaped polymer and promoting lung function repair are achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and specifically relates to an epoxy chalcone compound and a preparation method thereof, as well as a corresponding star-shaped polymer and a preparation method and application thereof. Background Art

[0002] Many diseases such as rheumatoid arthritis and lung injury are related to inflammation. Inflammation is a defensive response of the body to injury and harmful stimuli, but excessive inflammation can cause secondary tissue damage and dysfunction. Among them, the inflammatory process is related to the overexpression of pro-inflammatory factors and oxidative stress, which further exacerbates the inflammatory response. At present, anti-inflammatory treatment is considered to be an effective treatment method for inflammatory diseases. However, conventional clinical anti-inflammatory treatment methods usually include antibiotic and systemic steroid treatments. The treatment methods used are single, only for preventing bacterial infection, and cannot directly cure inflammation. In addition, most antibiotic drugs have side effects, including causing cardiovascular diseases and liver and kidney toxicity. Therefore, it is crucial to develop new and effective inflammation regulation strategies.

[0003] Compared with traditional treatment regimens, a promising new approach is to synthesize bioactive polymers and use them as substances to regulate the inflammatory environment. Currently, a variety of polymer-based nanoparticles and nanovesicles have been developed and have played an active role in anti-inflammatory treatment. For example, the literature doi:10.1021 / acsnano.8b01152; doi:10.1002 / adfm.201501712; doi:S2452199X20302176 developed poly(citrate-silicon), polycitrate-polyethyleneimine, and polycitrate-based bone nanocomposites, which were functionalized by chemical grafting or reaction of citrate with polymers, thereby activating mitochondria to effectively stimulate cell proliferation and regulating the inflammatory response through their antioxidant ability.

[0004] However, most of the reported polymers have problems such as low bioactivity, poor persistence, and complex synthesis. Therefore, it is still very necessary to develop a new bioactive polymer nanosystem with simple synthesis, strong anti-inflammatory activity, and good biocompatibility to treat inflammatory diseases. In addition, from the perspective of better developing polymers for regulating the inflammatory environment and improving the controllability of degradation, using natural bioactive molecules as monomers to synthesize living polymers with controllable activity is also a current new strategy.

[0005] There are many natural small molecules with biological activity, such as polyphenols, flavonoids, paclitaxel, camptothecin, etc. Among them, flavonoids are a class of secondary metabolites widely distributed in higher plants. The general molecular structure formula is a series of C6Ar-C3-C6Ar compounds in which two benzene rings are connected by three carbons. Current research has found that a variety of flavonoids have multiple biological effects such as anti-cancer, antioxidant, anti-inflammatory, antibacterial, antiviral, neurite growth-stimulating effects, and prevention of cardiovascular diseases. Due to the diverse structures of flavonoids, they can bind to different receptors respectively, have a wide range of target effects, show obvious biological activity and low toxicity, and can be used as ideal molecular templates. However, the molecular structure characteristics of flavonoids determine that they have a high melting point (at least above 50°C) and are insoluble in water. Directly using them as medicine has limitations such as low solubility, low absorption rate, and low bioavailability. Summary of the Invention

[0006] The purpose of the present invention is to overcome the above deficiencies and propose an epoxidized chalcone compound and its preparation method, as well as a corresponding star polymer and its preparation method and application.

[0007] To achieve the above technical objectives, the technical solutions adopted by the present invention are as follows:

[0008] In the first aspect, an epoxidized chalcone compound has the following structure:

[0009]

[0010] Preferably, the structure of the epoxidized chalcone compound includes:

[0011] Or

[0012] In the second aspect, the preparation method of the above-mentioned epoxidized chalcone compound includes: reacting hydroxy chalcone with epichlorohydrin to obtain it;

[0013] Furthermore, the molar ratio of hydroxy chalcone to epichlorohydrin is 1:(1 - 2);

[0014] Furthermore, when hydroxy chalcone reacts with epichlorohydrin, a quaternary ammonium salt is used as a catalyst; preferably, the quaternary ammonium salt is benzyltriethylammonium chloride;

[0015] Preferably, the dosage of the catalyst is 0.5 - 5 wt% of the total weight of the reactants;

[0016] Preferably, the hydroxy chalcone is selected from any one or two of 2'-hydroxy chalcone or 4'-hydroxy chalcone;

[0017] Further, the specific steps of the preparation method include:

[0018] S1. Mix the reactant hydroxy chalcone with epichlorohydrin and a quaternary ammonium salt catalyst evenly and then carry out the reaction;

[0019] S2. Dropwise add an aqueous solution of NaOH to the reaction system;

[0020] S3. After the reaction is completed, carry out suction filtration and liquid-liquid extraction on the crude product, take the organic phase, carry out drying and vacuum distillation to obtain the epoxidized chalcone compound.

[0021] Preferably, in step S1, the reaction temperature is 80 - 120 °C and the reaction time is 1 - 4 hours;

[0022] Preferably, in step S2, the concentration of the aqueous solution of NaOH is 20 - 50 wt%;

[0023] Preferably, in step S2, the reaction temperature is 80 - 120 °C and the reaction time is 1 - 4 hours;

[0024] Preferably, in steps S1 and S2, nitrogen or an inert gas is continuously introduced into the reaction system for protection;

[0025] Preferably, in step S3, the product after vacuum distillation is further subjected to vacuum drying, and the drying temperature is from room temperature to 60 °C.

[0026] In a third aspect, a star polymer includes a cystamine core and linear side arms, the linear side arms are sequentially connected to the cystamine core, and the number of linear side arms per molecule is ≥ 4;

[0027] Among them, the linear side arms include: non-grafted linear side arms, linear side arms grafted with polyethylene glycol segments, and linear side arms grafted with chalcone;

[0028] Among them, the chemical structure of the cystamine core is:

[0029] The chemical structure of the non-grafted linear side arms includes: Or Any one or two of them;

[0030] The chemical structure of the linear side arms grafted with polyethylene glycol segments is: Among them, n ≥ 1;

[0031] The chemical structure of the linear side arms grafted with chalcone includes: Or Any one or two of them;

[0032] Fourth aspect, the preparation method of the star polymer described above includes: grafting a polyethylene glycol segment and an epoxidized chalcone compound onto the linear side arms of a star polymer core;

[0033] Among them, the star polymer core is selected from: G0, G1 or G2 generation PAMAM star polymers with cystamine as the core;

[0034] The method of grafting a polyethylene glycol segment onto the linear side arms of a star polymer core includes: reacting methoxy carboxyl polyethylene glycol with the amino group of the linear side arms of the star polymer core;

[0035] Preferably, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) is used as a catalyst during the reaction;

[0036] Preferably, the temperature of the reaction process is from room temperature to 60 °C;

[0037] Preferably, the molar ratio of the carboxyl group in methoxy carboxyl polyethylene glycol to the amino group in the star polymer core is (1 - 2):4;

[0038] The method of grafting an epoxidized chalcone compound onto the linear side arms of a star polymer core further includes: reacting an epoxidized chalcone compound with the amino group of the linear side arms of the star polymer core;

[0039] Preferably, the temperature of the reaction process is from room temperature to 60 °C;

[0040] Preferably, the molar ratio of the epoxy group in the epoxidized chalcone compound to the amino group in the star polymer core is (0.5 - 2):1;

[0041] More preferably, the molar ratio of the epoxy group in the epoxidized chalcone compound to the amino group in the star polymer core is (0.5 - 1.5):1.

[0042] Fifth aspect, the application of the epoxidized chalcone compound and / or star polymer described above in the preparation of a drug for promoting lung function repair.

[0043] The beneficial effects of the present invention are as follows: Epoxidized chalcone compounds are obtained by modifying hydroxy chalcone with epoxy groups. The introduced epoxy groups are used to graft it onto the amino groups on the side arms of the star copolymer core, and at the same time, polyethylene glycol segments are grafted onto the side arms of the star copolymer core to increase the water solubility of the star copolymer, thereby improving the absorption rate and utilization rate of the chalcone-capped star copolymer in vivo. In addition, the core of the star copolymer contains a cystamine structure, which is prone to reduction reactions in vivo, thereby promoting the degradation and absorption of the star polymer in vivo, and achieving the effects of improving the anti-inflammatory activity of the star polymer and promoting the repair of lung function. Such chalcone-capped star copolymers have application value in the medical field. Description of the Drawings

[0044] Figure 1 Effects of the star polymers or mixtures prepared in Examples 2-4 and Comparative Example 1 on the proliferation ability of BEAS-2B cells.

[0045] Figure 2 Test results of the star polymers or mixtures prepared in Examples 2-4 and Comparative Example 1 on the scratch assay of BEAS-2B cells.

[0046] Figure 3 Effects of the star polymers or mixtures prepared in Examples 2-4 and Comparative Example 1 on the migration ability of BEAS-2B cells.

[0047] Figure 4 Effects of the star polymers or mixtures prepared in Examples 2-4 and Comparative Example 1 on the transepithelial electrical resistance of BEAS-2B cells. Detailed Embodiments

[0048] Combined with the embodiments of the present invention, the technical solutions in the embodiments will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention. It should be noted that the terms used here are only for describing specific embodiments, rather than intending to limit the exemplary embodiments according to the present invention. As used here, unless otherwise clearly specified in the context, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0049] If the specific experimental conditions are not specified in the embodiments, they shall be in accordance with the conventional conditions in the art or the conditions recommended by the reagent company; the materials, reagents, etc. used in the embodiments, unless otherwise specified, can be obtained through commercial channels.

[0050] Example 1

[0051] Epoxidation of 4'-hydroxychalcone: In a three-necked flask equipped with a stirrer, a condenser for reflux, and a nitrogen inlet device, 89.7 g of 4'-hydroxychalcone, 5.0 g of benzyltriethylammonium chloride, and 55.5 g of epichlorohydrin were successively added. Under continuous nitrogen protection in the reaction system, the flask was heated to 100 °C and reacted for 3 h. Subsequently, 40 mL of a 40% (w / w) aqueous NaOH solution was added dropwise to the system, and the reaction was continued at 100 °C for 1 h. After the reaction, filtration was carried out, and the filtrate was extracted with distilled water and separated three times. The organic layer was taken and dried over anhydrous sodium sulfate. Subsequently, filtration was carried out, and the filtrate was concentrated under reduced pressure to remove the solvent. The product was dried at 50 °C in a vacuum oven to obtain 4'-hydroxychalcone glycidyl ether with a yield of 89%.

[0052] The reaction equation for preparing 4'-hydroxychalcone glycidyl ether in Example 1 is as follows

[0053]

[0054] The structure of the product 4'-hydroxychalcone glycidyl ether was confirmed as follows

[0055] 1H Nuclear Magnetic Resonance 1 H NMR(CDCl3,400MHz):δ2.89 - 3.17(3H,2.95(dd,J = 8.06,4.18Hz),3.06(dd,J = 7.68,4.18Hz),3.08(dddd,J = 8.06,7.68,5.14,5.14Hz)),4.56 - 4.67(2H,4.61(d,J = 5.14Hz),4.61(d,J = 5.14Hz)),6.72(1H,d,J = 15.68Hz),7.07(2H,ddd,J = 8.30,1.23,0.46Hz),7.36 - 7.64(8H,7.43(dddd,J = 7.90,7.23,1.99,0.46Hz),7.44(tt,J = 7.23,1.31Hz),7.45(dddd,J = 7.90,1.60,1.31,0.46Hz),7.51(d,J = 15.68Hz),7.58(ddd,J = 8.30,1.81,0.46Hz)).

[0056] 13C Nuclear Magnetic Resonance 1313C NMR (CDCl3, 100 MHz): δ 44.64 (1C, s), 50.35 (1C, s), 69.51 (1C, s), 114.34 (2C, s), 121.17 (1C, s), 128.02 (1C, s), 128.07 (2C, s), 128.31 (2C, s), 130.65 (2C, s), 134.22 (1C, s), 134.90 (1C, s), 144.66 (1C, s), 156.48 (1C, s), 188.36 (1C, s).

[0057] Example 2

[0058] Polyethylene glycol grafted star polymer: Weigh 7.61 g of the generation G1 PAMAM star polymer with a cystamine core (Weihai Chenyuan, molecular formula C 64 H 132 N 26 O 12 S2) into a three-necked flask, add 12.5 g of methoxy carboxyl polyethylene glycol with a molecular weight of 1000, 0.1 g of catalyst 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 0.5 mL of triethylamine, react at 40 °C for 2 hours, and remove the solvent by vacuum distillation to obtain the star polymer grafted with polyethylene glycol.

[0059] Synthesis of chalcone-capped star polymer: Add 5.61 g of 4'-hydroxy chalcone glycidyl ether at 40 °C, use 5 mL of ethyl acetate as the solvent, stir and react at 40 °C for 1 hour, and remove the solvent by vacuum distillation after the reaction is completed to obtain the chalcone-capped star polymer.

[0060] Example 3

[0061] Polyethylene glycol grafted star polymer: The same as in Example 2.

[0062] Synthesis of chalcone-capped star polymer: Add 11.21 g of 4'-hydroxy chalcone glycidyl ether at 40 °C, use 10 mL of ethyl acetate as the solvent, stir and react at 40 °C for 1 hour, and remove the solvent by vacuum distillation after the reaction is completed to obtain the chalcone-capped star polymer.

[0063] Example 4

[0064] Polyethylene glycol grafted star polymer: The same as in Example 2.

[0065] Synthesis of chalcone-terminated star polymer: 16.82 g of 4'-hydroxychalcone glycidyl ether was added at 40°C, 15 mL of ethyl acetate was used as solvent, and the reaction was stirred at 40°C for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a chalcone-terminated star polymer.

[0066] Comparative Example 1

[0067] 16.82 g of 4'-hydroxychalcone glycidyl ether, 7.61 g of G1 generation PAMAM star polymer with cystamine core and 12.5 g of methoxycarboxyl polyethylene glycol with a molecular weight of 1000 were physically mixed for 30 minutes under mechanical stirring and set aside.

[0068] Comparative Example 2

[0069] Synthesis of chalcone-terminated star polymer: The same as Example 4, but no polyethylene glycol segment was used to graft the star polymer.

[0070] In vitro experiments

[0071] Human bronchial epithelial BEAS-2B cells were treated with lipopolysaccharide (LPS) to establish a cell injury model. Human bronchial epithelial cells (BEAS-2B) were purchased from the China Center for Type Culture Collection (CCTCC).

[0072] The 5-ethynyl-2'-deoxyuridine (EdU) staining method was used to test the effects of the star polymers or mixtures prepared in Examples 2-4 and Comparative Example 1 on cell proliferation caused by inflammatory damage. BEAS-2B cells were cultured at 4×10 5 Cells / well were evenly inoculated in a 6-well plate and placed in an incubator. The cells were treated into the following groups: a blank group, a control group, an example 2 group, an example 3 group, an example 4 group, and a comparative example 1 group. Examples 2, 3, 4, and comparative example 1 group used DMSO to prepare a 10 μM chalcone-terminated star polymer or blend, which was pretreated for 2 hours and then treated with LPS for 24 hours. After adding 1 mL of paraformaldehyde to each well for 15 minutes of fixation, the fixative was discarded. 1 mL of PBS buffer was added to each well for decolorization and rinsing on a shaker twice, each time for 3 minutes. Finally, the nuclei were stained. After staining, the slides were removed from the six-well plate, and the cell surface was contacted with a glass slide dripped with an anti-fluorescence quencher. The slides were sealed and observed and photographed using a laser confocal microscope. The photos were analyzed and quantitatively compared using Image J software. The test results are listed in Figure 1 .

[0073] The scratch assay was used to test the effect of chalcone-capped star polymers on the migration ability of BEAS-2B cells. The specific steps of the scratch assay were to draw two vertical lines on the back of each well of a six-well plate with a marker pen. BEAS-2B cells in the logarithmic growth phase were seeded into the six-well plate at a density of 5×10 5 cells / well and incubated overnight in a cell culture incubator; when the cell confluence reached 80%, a 200 μL pipette tip was inserted into a pipette gun and used to replicate along the drawn lines. At the same time, the star polymers or blends capped with chalcone prepared with DMSO at a concentration of 10 μM in Examples 2, 3, 4 and Comparative Example 1 were added for pretreatment for 2 h and then placed in the incubator. After that, LPS was added and photographs were taken under a microscope at 0, 12, and 24 h. The photographs were analyzed and quantitatively compared using Image J software, and the test results are listed in Figure 2 , Figure 3 .

[0074] The effect of chalcone-capped star polymers on pulmonary epithelial cell barrier dysfunction was evaluated by measuring the trans-epithelial electric resistance (TEER) value. The specific operation was to seed BEAS-2B cells into a Transwell chamber, and the cell resistance values in the upper and lower chambers of the Transwell were read using an electric resistance meter, thereby reflecting the integrity of the pulmonary epithelial cell structure and the cell permeability and filtration conditions. The test results are listed in Figure 4 .

[0075] Animal experiments

[0076] Sixty-four SPF-grade mice (Guangzhou Cyagen Biosciences Inc.) were randomly divided into 8 groups, namely a blank group, an LPS model group, experimental groups (Examples 1-4), and control groups (Comparative Examples 1 and 2). Two hours before modeling, the mice were intragastrically administered 4'-hydroxychalcone glycidyl ether of Example 1, chalcone-capped star polymers of Examples 2, 3, 4 and Comparative Example 2, and the mixture of Comparative Example 1 at a dose of 10 mg / kg according to the groups. Then, the mice were subjected to aerosol inhalation of LPS for 30 minutes. The total amount and concentration of LPS for aerosol inhalation were 12 mL of 2.5 g / mL LPS. After the aerosol inhalation was completed, the mice were returned to the cage. After 48 hours, the mice were sacrificed, and lung tissue samples and bronchoalveolar lavage fluid were collected for further testing.

[0077] The relevant tests for animal experiments include: the wet / dry weight ratio (W / D) of mouse lung tissue, the extraction of mouse bronchoalveolar lavage fluid, collection of cell precipitates in the lavage fluid, and then using an animal blood analyzer to detect the types and numbers of inflammatory cells in the lavage fluid, as well as using a TNF-α ELISA kit to detect the level of inflammatory factor TNF-α in mouse serum. The above test data are expressed as mean ± standard deviation. The test results are listed in Table 1.

[0078] Table 1

[0079]

[0080] After Figure 1 the EdU staining experiment, it was found that after treating BEAS-2B cells with 20 μg / mL LPS for 24 h, the number of EdU-labeled positive cells decreased significantly; while under the condition of adding 10 μM of the mixture of 4'-hydroxychalcone glycidyl ether of Example 1, the chalcone-capped star polymers of Examples 2, 3, 4 and Comparative Example 2, and 10 mg / kg of Comparative Example 1, the number of EdU-labeled positive cells increased. According to the comparative analysis of the test results of Examples 2-4, it was found that as the dosage of 4'-hydroxychalcone glycidyl ether as the capping agent increased, the corresponding number of EdU-labeled positive cells increased, indicating that there is a certain dose relationship between 4'-hydroxychalcone glycidyl ether and the cell proliferation rate. Comparative Example 1 did not use 4'-hydroxychalcone glycidyl ether to cap the star polymer, and directly physically mixed 4'-hydroxychalcone glycidyl ether with G1-generation PAMAM star polymer and methoxycarboxyl polyethylene glycol. Comparative Example 2 did not use polyoxyethylene chain segment grafted star polymer. The products prepared in Comparative Examples 1 and 2 still had the effect of improving the proliferation rate of BEAS-2B cells, but compared with Example 4 with the same dosage of chalcone-based compound, the promotion effect of Comparative Examples 1 and 2 on the proliferation rate of BEAS-2B cells was poor.

[0081] After Figure 2 、 3 the scratch experiment, it was found that compared with the control group, LPS significantly inhibited the healing of cell scratch wounds and the migration ability of cells decreased significantly. However, under the condition of adding 10 μM of the mixture of 4'-hydroxychalcone glycidyl ether of Example 1, the chalcone-capped star polymers of Examples 2, 3, 4 and Comparative Example 2, and 10 mg / kg of Comparative Example 1, the scratch wound healing of BEAS-2B cells accelerated and the migration ability was significantly enhanced. Compared with Example 4 with the same dosage of chalcone-based compound, the promotion of the migration ability of BEAS-2B cells by the mixture of Comparative Example 1 and the star polymer without polyethylene glycol grafted in Comparative Example 2 decreased.

[0082] After Figure 4Results of the transepithelial electrical resistance test showed that after 24 hours of adding 20 μg / mL LPS, the resistance value of BEAS-2B cells decreased by 25 - 30%. However, under the conditions of adding the 4'-hydroxychalcone glycidyl ether of Example 1, the chalcone-capped star polymers of Examples 2, 3, 4 and Comparative Example 2, and 10 μM of the mixture of Comparative Example 1 at 10 mg / kg, the decrease in the resistance value of LPS-induced BEAS-2B cells could be significantly inhibited, avoiding the destruction of the barrier function of lung epithelial cells. Compared with Example 4 with the same dosage of chalcone-based compounds, the ability of the mixture of Comparative Example 1 and the chalcone-capped star polymer of Comparative Example 2 without using polyethylene glycol-grafted star polymer to maintain the barrier function of BEAS-2B cells decreased.

[0083] Through the data analysis in Table 1, the wet weight / dry weight ratio (W / D) of lung tissue, as an index to measure the severity of pulmonary edema, was significantly increased in the LPS model group of mice compared with the blank group, indicating severe pulmonary edema. However, the 4'-hydroxychalcone glycidyl ether of Example 1, the chalcone-capped star polymers of Examples 2, 3, 4, the mixture of Comparative Example 1, and the chalcone-capped star polymer of Comparative Example 2 could all reduce the W / D value of mice, that is, it indicated that the chalcone-capped star polymer could improve pulmonary edema in mice. The improvement effect of the 4'-hydroxychalcone glycidyl ether prepared in Example 1 on pulmonary edema in mice was relatively not obvious, which might be related to the poor hydrophilicity of the chalcone-based compound itself. At the same time, compared with Example 4 with the same dosage of chalcone-based compounds, Comparative Example 1 without capping reaction and Comparative Example 2 without introducing polyethylene glycol segments had a worse effect on reducing the W / D value of mice.

[0084] By analyzing the contents of inflammatory cells neutrophils, lymphocytes, and monocytes in mice, the inflammation and pulmonary tracheal filtration conditions of mice were evaluated. Among them, the numbers of inflammatory cells neutrophils, lymphocytes, and monocytes detected in the LPS model group of mice increased significantly, while the 4'-hydroxychalcone glycidyl ether of Example 1, the chalcone-capped star polymers of Examples 2, 3, 4, the mixture of Comparative Example 1, and the chalcone-capped star polymer of Comparative Example 2 could reduce the above-mentioned inflammatory cell numbers in the experimental group of mice, improve the permeability of the pulmonary trachea, and reduce inflammatory damage. The improvement effect of the 4'-hydroxychalcone glycidyl ether prepared in Example 1 on reducing the number of inflammatory cells in mice was relatively not obvious, which might be related to the poor hydrophilicity of the chalcone-based compound itself. At the same time, compared with Example 4 with the same dosage of chalcone-based compounds, Comparative Example 1 without capping reaction and Comparative Example 2 without introducing polyethylene glycol segments had a worse effect on reducing the number of inflammatory cells in mice.

[0085] The ELISA method was used to detect the level of inflammatory factor TNF-α in the serum of mice in the LSP model group, and it was found that the TNF-α level was increased by about 1.7 times compared with the blank group. However, in the experimental groups of mice using 4'-hydroxychalcone glycidyl ether of Example 1, chalcone-capped star polymers of Examples 2, 3, and 4, the mixture of Comparative Example 1, and chalcone-capped star polymers of Comparative Example 2, the TNF-α level in the serum was significantly reduced, showing anti-inflammatory activity. The 4'-hydroxychalcone glycidyl ether prepared in Example 1 had relatively insignificant effect on reducing the TNF-α level in the serum of mice, which might be related to the poor hydrophilicity of the chalcone-based compound itself. At the same time, compared with Example 4 with the same dosage of chalcone-based compound, Comparative Example 1 without the capping reaction and Comparative Example 2 without introducing the polyethylene glycol segment had worse effects on reducing the TNF-α level in the serum of mice.

[0086] Finally, it should be noted that the above are only the preferred embodiments of the present invention and are not used to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or perform equivalent substitutions on some of them. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention. Although the specific implementation manners of the present invention have been described above, it is not a limitation to the protection scope of the present invention. Those skilled in the art should understand that based on the technical solutions of the present invention, various modifications or deformations that can be made without creative labor by those skilled in the art are still within the protection scope of the present invention.

Claims

1. An epoxy chalcone compound, characterized in that, The structure of the compound is as follows:

2. The preparation method of the epoxy chalcone compound according to claim 1, characterized in that, It is obtained by reacting hydroxy chalcone with epichlorohydrin.

3. The preparation method of the epoxy chalcone compound according to claim 2, characterized in that, The molar ratio of hydroxy chalcone to epichlorohydrin is 1:(1 - 2); and / or, a quaternary ammonium salt is used as a catalyst when hydroxy chalcone reacts with epichlorohydrin; and / or, the dosage of the catalyst is 0.5 - 5 wt% of the total weight of the reactants; And / or, the hydroxy chalcone is selected from: 2 ’ -hydroxy chalcone or 4 ’ -hydroxy chalcone, either one or both of them.

4. The preparation method of the epoxy chalcone compound according to claim 2, wherein The specific steps of the preparation method include: S1. Mix the reactants hydroxy chalcone, epichlorohydrin, and the quaternary ammonium salt catalyst evenly and then carry out the reaction; S2. Dropwise add an aqueous solution of NaOH to the reaction system; S3. After the reaction is completed, filter the crude product by suction, carry out liquid - liquid extraction, take the organic phase, dry it, and perform vacuum distillation to obtain the epoxidized chalcone compound.

5. The preparation method of the epoxy chalcone compound according to claim 4, wherein In step S1, the reaction temperature is 80 - 120 °C and the reaction time is 1 - 4 hours; and / or, in step S2, the concentration of the aqueous solution of NaOH is 20 - 50 wt%; and / or, in step S2, the reaction temperature is 80 - 120 °C and the reaction time is 1 - 4 hours; and / or, in steps S1 and S2, nitrogen or an inert gas is continuously introduced into the reaction system for protection; and / or, in step S3, the product after vacuum distillation is further dried under vacuum, and the drying temperature is from room temperature to 60 °C.

6. A star polymer, characterized in that, The star - shaped polymer includes a cystamine core and linear side arms. The linear side arms are sequentially connected to the cystamine core, and the number of linear side arms per molecule is ≥4; The linear side arms include: non - grafted linear side arms, linear side arms grafted with polyethylene glycol segments, and linear side arms grafted with chalcone; Among them, the chemical structure of the cystamine core is: The chemical structure of the linear side arm without grafting includes: Or Any one or both of them; The chemical structure of the linear side arm grafted with polyethylene glycol segments is as follows: where n ≥ 1; The chemical structure of the linear side arm of the grafted chalcone includes: or Any one or two of them.

7. The preparation method of the star polymer according to claim 6, wherein, Graft the polyethylene glycol segment and the epoxidized chalcone compound onto the linear side arms of the star - shaped polymer parent nucleus; Among them, the star - shaped polymer parent nucleus is selected from: G0 - generation, G1 - generation, or G2 - generation PAMAM star - shaped polymers with cystamine as the core.

8. The method for preparing the star polymer according to claim 7, characterized in that, The method for grafting the polyethylene glycol segment onto the linear side arms of the star - shaped polymer parent nucleus includes: reacting methoxy - carboxyl polyethylene glycol with the amino group of the linear side arms of the star - shaped polymer parent nucleus; and / or, 2-(7 - azabenzotriazol - 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) is used as a catalyst during the reaction; and / or, the temperature during the reaction is from room temperature to 60 °C; and / or, the molar ratio of the carboxyl group in methoxy - carboxyl polyethylene glycol to the amino group in the star - shaped polymer parent nucleus is (1 - 2):

4.

9. The preparation method of the star polymer according to claim 7, wherein, The method for grafting the epoxidized chalcone compound onto the linear side arms of the star - shaped polymer parent nucleus includes: reacting the epoxidized chalcone compound with the amino group of the linear side arms of the star - shaped polymer parent nucleus; and / or, the temperature during the reaction is from room temperature to 60 °C; and / or, the molar ratio of the epoxy group in the epoxidized chalcone compound to the amino group in the star - shaped polymer parent nucleus is (0.5 - 2):

1.

10. A use, characterized in that, Use of the epoxidized chalcone compound as claimed in claim 1 and / or the star - shaped polymer as claimed in claim 6 in the preparation of a drug for promoting lung function repair.

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