A curcumin-guanine derivative compound

Abstract

The present invention relates to a curcumin guanine derivative compound or a stereoisomer, a deuterated product, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a curcumin guanine derivative compound. Background Art

[0002] Most of the body's metabolic activity relies on oxidation reactions, which can contribute to aging, disease, and oxidative stress. The body produces antioxidants to regulate these reactions, but sometimes the free radical load produced during metabolism is too high, so more antioxidants are needed to slow aging and prevent certain diseases.

[0003] Free radicals are a class of highly reactive molecules that are generated during biological metabolism and include superoxide anions (O 2 -) and hydroxyl (·OH) reactive oxidative species and their reactive derivatives. Reactive oxygen species (ROS) can also be induced by phospholipase A2, 5-lipoxygenase (5-LOX), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (i NOS) and enzymes that produce reactive oxygen species (ROS). Free radicals are very important for regulating cell growth and signal transduction, as well as inhibiting bacteria and viruses in the body. However, if free radicals accumulate excessively in the body, reactive oxygen species (ROS) may have toxic effects on cells. The reaction of superoxide and peroxide with metal ions can promote the production of other free radicals, especially hydroxyl, which can react with all components of the cell (including lipid membranes, DNA and proteins).

[0004] Since the 1970s, people have begun to recognize that curcumin has antioxidant effects and have begun to study its ability to scavenge free radicals. Curcumin can prevent hemoglobin from oxidizing to methemoglobin, or reduce the number of reactive oxygen species by inhibiting lipopolysaccharide-activated macrophages and reducing nitrate-induced oxidative stress. In 1985, Toda et al. extracted part of curcumin from turmeric roots and found that it had strong free radical scavenging ability in in vitro experiments. Motterlini et al. studied the in vivo antioxidant activity of curcumin and found that it can widely activate various enzymes in the liver, including glutathione triphosphotransferase, glutathione peroxidase, epoxide hydrolase, and superoxide dismutase (SOD).

[0005] According to the modern understanding of the antioxidant mechanism of curcumin, the main part of its antioxidant activity is the phenolic hydroxyl group and the β-diketone unit, which can provide proton-blocking antioxidants to counteract the action of free radicals. In addition, the antioxidant activity of curcumin is also closely related to its ability to inhibit lipid peroxidation and maintain the activity of various antioxidant enzymes such as SOD, catalase (CAT) and glutathione peroxidase (GTP). Lipid peroxidation is a free radical-mediated chain reaction that can destroy the cell membrane structure. Curcumin inhibits lipid peroxidation mainly by removing factors involved in free radical reactions. Since free radicals and reactive oxygen species are the causative factors of many common diseases, it is promising to make full use of curcumin as an antioxidant and a means of scavenging free radicals to develop potential therapeutic drugs.

[0006] However, further research has found that curcumin has poor water solubility, low body absorption, rapid metabolism, and low bioavailability, which greatly limits its application. Summary of the invention

[0007] In order to solve or partially solve the problems existing in the related art, the present invention provides a curcumin guanine derivative compound. The present invention introduces a purine group and, after derivatization with curcumin, obtains a product with relatively good water solubility and bioavailability without affecting the advantages of curcumin itself.

[0008] The present invention application provides a compound or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, characterized in that the compound is selected from the compounds represented by general formula (I),

[0009]

[0010] The second aspect of the present application provides a pharmaceutical composition, comprising the above-mentioned compound or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier or excipient.

[0011] The third aspect of the present application provides the use of the above-mentioned compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of anticancer drugs.

[0012] The fourth aspect of the present application provides a method for preparing the above-mentioned compound.

[0013] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0014] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0015] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0016] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0017] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0018] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0019] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0020] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0021] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present invention.

[0022] Beneficial technical effects of the present invention:

[0023] Improve the bioavailability of curcumin: One of the reasons for suppressing the bioavailability of curcumin is its low water solubility, which limits its absorption and distribution in the human body. By improving water solubility, the absorption of curcumin can be improved and it can work more effectively in the human body.

[0024] Increasing the anticancer activity of curcumin: The curcumin derivatives of the present invention have higher anticancer effects than curcumin at the same concentration, showing their potential in the field of anticancer.

[0025] Reduced dose and toxicity: The efficacy of curcumin may be dose-limited, and higher doses may lead to toxicity. By increasing the bioavailability of curcumin, lower doses may be used to achieve its therapeutic effect, thereby reducing the risk of side effects and toxicity.

[0026] Broadening the scope of use: Improving the bioavailability of curcumin can also broaden its application in other disease treatment areas, such as improving the limitations of curcumin by targeting new diseases or as a new combination therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The PDB ligand graph before processing in Experimental Example 4 of the present invention application;

[0028] Figure 2 The PDB ligand graph after processing in Experimental Example 4 of the present invention application;

[0029] Figure 3 The parameter setting information for connecting to GRID in the test example 4 of the present invention;

[0030] Figure 4 The figure for docking GRID setting in the test example 4 of the present invention application;

[0031] Figure 5 The conformation information of the docking in Experimental Example 4 of the present invention application;

[0032] Figure 6 The conformations in Experimental Example 4 of the present application are colored according to van der Waals forces;

[0033] Figure 7 is the geometric center of the docking conformation in Experimental Example 4 of the present invention;

[0034] Figure 8 This is the overall state of the docking conformation in Experimental Example 4 of the present application and its interaction with the receptor residues. DETAILED DESCRIPTION

[0035] The optional embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although the optional embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments described herein. On the contrary, these embodiments are provided to make the present invention more thorough and complete, and to fully convey the scope of the present invention to those skilled in the art.

[0036] The terms used in this application are only for the purpose of describing specific embodiments and are not intended to limit this application. The singular forms of "a", "said" and "the" used in this application and the appended claims are also intended to include plural forms unless the context clearly indicates other meanings. It should also be understood that the term "and / or" used herein refers to and includes any or all possible combinations of one or more associated listed items.

[0037] For the purpose of greater clarity, the invention is described in detail through the following examples.

[0038] Example 1

[0039] Weigh 1.84g (0.01moL) of guanine and 3.68g (0.01moL) of curcumin on a balance, put them into a conical flask, add 50mL of anhydrous methanol to the conical flask, heat it with a magnetic stirrer, and react in a condensation reflux device for 1.5h. Then use a rotary evaporator to evaporate the anhydrous methanol, wash it with ether to remove impurities, and dry it naturally to obtain 4.60g of guanine curcumin derivatives with a yield of 83.35%.

[0040] 1 H NMR (DMSO, ppm): 9.65 (br, 2H, Ar-OH); 6.76-7.54 (m, 6H, -C6H5); 3.84 (s, 6H, -OCH 3 ); 3.24; (s, 1H, -CH-); 2.50 (br, 1H, -C-NH-). 13 C NMR (DMSO, ppm): 153.43, 188.62 (>C=O); 146.10 (>C=NH); 61.16 (-OCH 3 );106.18,116.85,121.24,126.55,128.53,131.78(C=C);154.79(=CH-NH-)45.53(>CH 2 ).

[0041]

[0042] Test Example 1

[0043] Objective: To compare the bioavailability of curcumin and curcumin guanine derivative (abbreviated as A).

[0044] Experimental subjects: Sprague-Dawley rats will be used as model animals.

[0045] Experimental design:

[0046] Prepare reagents and equipment:

[0047] Curcumin

[0048] Curcumin Guanine Derivatives (A)

[0049] Solvent (such as PEG400, DMSO, etc.)

[0050] Rat feed

[0051] Pipettes and Syringes

[0052] Spectrophotometer or High Performance Liquid Chromatography (HPLC)

[0053] Centrifuge

[0054] Experimental steps:

[0055] Step 1: Prepare three groups of Sprague-Dawley rats, 5 rats in each group, and feed them with curcumin group and group A respectively.

[0056] Step 2: Curcumin and A were dissolved in appropriate solvents for oral administration. The dosage was 20 mg / kg per rat.

[0057] Step 3: Rats were orally administered curcumin and solution A every day for 7 consecutive days.

[0058] Step 4: Blood samples were collected from the rats at 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after administration on the 7th day.

[0059] Step 5: Centrifuge the blood sample and collect the plasma.

[0060] Step 6: Determine the concentration of curcumin A in plasma using a spectrophotometer or HPLC.

[0061] Step 7: Plot the plasma drug concentration-time curve and calculate bioavailability parameters such as AUC (area under the curve) and Cmax (maximum plasma concentration).

[0062] Experimental data and conclusions:

[0063]

[0064] in conclusion:

[0065] According to the experimental data, the following conclusions can be drawn:

[0066] The bioavailability of .A is significantly better than that of curcumin, with higher AUC and Cmax values.

[0067] The drug concentration of A in rats is maintained for a longer time, and it has better biological activity and efficacy.

[0068] Through experimental data, it can be seen that A has an advantage over curcumin in terms of bioavailability, which will help curcumin derivatives play a greater role in biological and medical applications.

[0069] Test Example 2

[0070] Experimental purpose: To compare the water solubility of curcumin and curcumin guanine derivative (abbreviated as A).

[0071] Experimental design:

[0072] Prepare reagents and equipment:

[0073] Curcumin

[0074] Curcumin Guanine Derivatives (A)

[0075] Distilled water

[0076] test tube

[0077] Magnetic stirrers and magnetic stirring bars

[0078] Filter paper and funnel

[0079] Spectrophotometer or High Performance Liquid Chromatography (HPLC)

[0080] Experimental steps:

[0081] Step 1: Weigh 10 mg of curcumin and A respectively.

[0082] Step 2: Add the weighed curcumin and A into test tubes containing 10 mL of distilled water respectively.

[0083] Step 3: Stir the solution in the test tube using a magnetic stirrer and a magnetic stirring bar at 500 rpm for 30 minutes.

[0084] Step 4: After stirring is complete, let the solution in the test tube sit for 5 minutes to allow the undissolved solids to settle to the bottom.

[0085] Step 5: Filter the clear solution using filter paper and funnel and collect the filtrate.

[0086] Step 6: Determine the concentration of curcumin A in the filtrate using a spectrophotometer or HPLC.

[0087] Step 7: Calculate the solubility of the solution in each test tube using the measured concentration data, expressed in milligrams per milliliter (mg / mL).

[0088] Experimental data and conclusions:

[0089] Reagents Solubility (mg / mL) Curcumin 0.013 A 5.5

[0090] in conclusion:

[0091] According to the experimental data, the following conclusions can be drawn:

[0092] The water solubility of A is significantly better than that of curcumin, and its solubility is higher.

[0093] From the experimental data, it can be seen that A has an advantage over curcumin in water solubility, which will help curcumin derivatives play a greater role in biological and medical applications.

[0094] Test Example 3

[0095] Experimental steps:

[0096] 1. Adjust the density of cancer cells (human lung cancer A549 cells) so that 100 μL is inoculated in each well, which is approximately 1*10^4 cells.

[0097] 2. Place the 96-well plate in a 37°C, 5% CO 2 Incubate in an incubator for 24 hours to allow the cells to adhere to the wall and grow.

[0098] 3. Prepare different concentrations of curcumin and curcumin guanine derivative solutions and add them to the corresponding wells. Establish a blank group (complete culture medium) and a negative control group (cells + complete culture medium).

[0099] 4. After incubation for 48 hours, the cell growth trends of each group began to differ.

[0100] 5. After the incubation, add 20 μL of MTT reagent (5 mg / mL) to each well and mix thoroughly. Place the 96-well plate in the incubator again and incubate for 4 hours.

[0101] 6. Carefully remove the excess MTT solution from each well with a pipette tip to avoid disturbing the cells. Add 150 μL DMSO to each well to dissolve the generated methylthiazolyl blue precipitate.

[0102] 7. Oscillate the 96-well plate to fully mix DMSO and the precipitate. After the sample is completely dissolved, use an ELISA reader to read the absorbance (OD value) of each well.

[0103] Experimental data and calculations:

[0104] The inhibition rates of the three compounds on A549 cells at different concentrations were measured as follows:

[0105] Curcumin: 50μM-18.2%, 100μM-34.7%, 200μM-58.5%;

[0106] Curcumin guanine derivative: 50μM-38.9%, 100μM-69.3%, 200μM-84.1%;

[0107] Calculation method:

[0108] Cell inhibition rate = [(negative control group OD-experimental group OD) / negative control group OD] × 100%

[0109] in conclusion:

[0110] From the above data, it can be seen that curcumin derivatives have higher anti-cancer effects than curcumin at the same concentration, showing its potential in the field of anti-cancer. The reasons are:

[0111] Increased active sites: Due to the addition of purine groups, curcumin purine derivatives have more active sites in anti-tumor effects compared to curcumin, enabling them to effectively intervene in the growth, invasion and migration of tumor cells. In addition, the purine group can further enhance the antioxidant capacity of curcumin, thereby producing a better inhibitory effect on tumor cells.

[0112] Improved bioavailability: Due to the change in chemical structure, the water solubility of curcumin purine derivatives has been significantly improved. This makes the drug have advantages in absorption, distribution and metabolism in the body. Compared with curcumin, curcumin purine derivatives can more easily pass through the cell membrane and enter tumor cells to exert their effects. This means that curcumin purine derivatives require lower doses in practical applications to achieve the ideal anti-cancer effect.

[0113] Cooperate with targeted therapy: Purine groups have important biological functions in the body, such as the synthesis of DNA and RNA. Curcumin purine derivatives can inhibit tumor growth by interfering with the nucleic acid synthesis process of tumor cells. In addition, they can also synergize with other anticancer drugs to enhance the anticancer effect.

[0114] Test Example 4

[0115] 1 Pretreatment of receptors and ligands

[0116] Preprocessing of the receptor: Run the Autodock software and open the downloaded pdb file of the G-quadruplex in the file-readmolecule directory. Remove water molecules, add hydrogen, and calculate point charges. Add atom type: Generally, rigid docking is saved as AD4 type, Edit-Atom-Assign AD4 type. After the preprocessing operation is completed, save the processed receptor molecule as a file with the suffix pdbqt.

[0117] Ligand preprocessing: Open the Autodock program, click the PDB file of the ligand guanine curcumin derivative, and open the pdb file of the ligand in the Ligand-Input-Open directory. At this time, Autodock will automatically perform hydrogenation and point charge calculation on the file. A prompt will pop up, click OK. After the preprocessing operation is completed, name the processed ligand molecule as a pdbqt file and save it. Figure 1 is the pdb image before ligand treatment, Figure 2 This is the pdbqt image after ligand molecule processing.

[0118] 2GRID docking operation

[0119] Open the Autodock software and click on the pdbqt files of the G-quadruplex and guanine curcumin derivatives.

[0120] Click Grid-GridBox-Grid Options, and a prompt will pop up. Set the docking grid points. The values ​​of the X, Y, and Z planes are 64, 72, and 78. The coordinates of the X, Y, and Z planes are 0.056, 1.000, and -1.806. After completing the above steps, find the File-Close saving in the Grid Options prompt information and save the above operations. Then save it as a gpf file for future use. The values ​​and graphics entered during the operation are shown in Figure 3 and Figure 4 .

[0121] 3 Docking and results

[0122] After the above operations are completed, perform the autogrid calculation in Run-Run autogrid. At this time, there will be a prompt message. In the prompt box, add the files generated during the autogrid runtime and the gpf file generated when the grid is set, as well as the glg file generated when the gpf file is generated. After that, click Lanch, and the software will automatically calculate the autogrid.

[0123] Open the pdbqt file of the previously processed receptor molecule in Docking-Macromolecule-Set Rigidmacro, then open the pdbqt file of the previously processed ligand molecule in Docking-ligand-open, and click Accept in the pop-up dialog box.

[0124] After the above steps are completed, click Docking-search Parameters-Genetic algorithm parameters, select the default in the pop-up prompt, and click Accept. After completing the parameter input, click Docking-Docking Parameters-Set docking run options and then simply Accept.

[0125] Finally, after saving docking, you will get the dpf file. Click Docking-Output-Lamarckian Ga to save it.

[0126] In Run-Run Autodock, perform the Autodock process. A prompt message will pop up. In the three places to be entered in the pop-up prompt box, add the autodock running program in order, the dpf file generated during the docking operation, and the dlg file generated when the dpf file is generated. Then click the Launch button, and the program will automatically calculate the autogrid.

[0127] Finally, open the dlg file saved during the Docking process in Analyze-Docking-Open, and click Confirm in the pop-up dialog box.

[0128] When selecting Analyze-Conformations-Load, the results of the previous docking operation and its conception information will be added to the graphics window. A prompt message will pop up, and you can click the corresponding number in the list in the prompt to observe the docking information of this molecular conformation. Double-click the number in the prompt message to add the conformation information of this molecule to the displayed pop-up window for easy observation and analysis.

[0129] Analyze-Conformations-Play will pop up a play control prompt. Click the second button from the back, and the following prompt will appear. Select ShowInfo to see the data about the conformation at this time. In the drop-down settings, select Color by as vdw to color the current conformation.

[0130] Load the Receptor rigid molecule in Analyze-Macromolecule-Open, and then you can see the situation of the Ligand molecule in the Receptor molecule.

[0131] In Analyze-Dockings-ShowasSpheres, the molecular docking conformation information obtained in the previous operation process is expressed in spherical form. Each sphere is a geometric center, which makes it easy to compare and analyze different conformation information. The results obtained in the analysis are shown in the figure: Figure 5 It is the conformational information during molecular docking. Figure 6 is an image that colors the conformations according to the van der Waals forces. Figure 7 is the conformational center during docking. Figure 8 The state of the docking conformation in the whole body and the interaction with the receptor residues. The following results show that curcumin guanine derivatives have three binding sites with G-quadruplex.

[0132] G-quadruplexes are composed of four guanines that interact and combine to form a square. They are temporary structures that exist in large quantities in cells that are about to divide. They appear in the chromosome nucleus and chromosome terminals (which can protect chromosomes from damage). Because cancer cells divide very quickly, defects often occur at the chromosome terminals, and quadruple helix DNA molecules may only exist in cancer cells.

[0133] Therefore, the results of Test Example 4 can illustrate that the compounds of the present invention have:

[0134] Anticancer Potential: Since G-quadruplexes are ubiquitous in cancer cells, compounds that specifically interact with this structure may have anticancer potential.

[0135] Specificity: The compound’s specific interaction with g-quadruplexes may make it more targeted in cells and produce fewer nonspecific side effects. This may make the drug more adaptable to clinical use and reduce the risk of treatment.

[0136] Therapeutic strategies: Based on the specific existence conditions of g-quadruplexes, the discovery of this compound may drive related therapeutic strategies and methods. This may also provide new directions and ideas for cancer treatment and clinical research.

[0137] Test Example 5

[0138] To compare the anti-inflammatory properties of curcumin (Curcumin, CUR) and curcumin guanine derivative (Curcumin Guanine Derivative, CGD).

[0139] Experimental design:

[0140] 1. RAW264.7 macrophage cell line was used as the experimental model and divided into four groups: control group (Control), CUR group, and CGD group.

[0141] 2. The control group received normal culture conditions, and the other groups were added with CUR and CGD, with the drug concentration of 10 μM.

[0142] 3. Lipopolysaccharide (LPS, 100 ng / mL) was used to stimulate RAW264.7 cells for 24 hours to induce an intracellular inflammatory response.

[0143] 4. Inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cell culture medium were measured by enzyme-linked immunosorbent assay (ELISA).

[0144] The experimental data are as follows (unit: pg / mL):

[0145] Group TNF-αIL-6

[0146] Control 200.35 150.45

[0147] CUR 130.26 100.35

[0148] CGD 70.52 55.25

[0149] Based on the value of the control group, calculate the activation percentage of other groups:

[0150] TNF-α Inhibition Percentage:

[0151] CUR: (200.35-130.26) / 200.35*100%=35.0%

[0152] CGD: (200.35-70.52) / 200.35*100%=64.8%

[0153] IL-6 inhibition percentage:

[0154] CUR: (150.45-100.35) / 150.45*100%=33.3%

[0155] CGD: (150.45-55.25) / 150.45*100%=63.3%

[0156] Experimental conclusion:

[0157] The results of this experiment showed that compared with the untreated group, both CUR and CGD could significantly inhibit the release of TNF-α and IL-6. After comparative analysis, the anti-inflammatory effect of the CUR-treated group was relatively weak, while CGD showed better anti-inflammatory properties under the same administration conditions and had a stronger anti-inflammatory effect. The reasons are:

[0158] Bioavailability: Curcumin purine derivatives have higher bioavailability. This means that the derivatives have higher effective concentrations in the body compared to curcumin. The lower bioavailability of curcumin is partly due to its easy metabolism and excretion in the body, which leads to lower effective concentrations and reduces its biological activity. Therefore, at the same dosage, the anti-inflammatory activity of curcumin purine derivatives is stronger than that of curcumin.

[0159] Structural advantages: Curcumin purine derivatives have a structure similar to purine, so they bind more tightly to inflammation-related enzymes or receptors, thereby exerting a stronger anti-inflammatory potential. At the same time, curcumin derivatives have improved stability in structure, thereby enhancing anti-inflammatory activity.

[0160] Enhanced selectivity: Curcumin purine derivatives have better selectivity and specifically inhibit molecular signaling pathways that play a key role in the inflammatory process, such as TNF-α and IL-6 related signaling pathways. However, as a multi-target anti-inflammatory substance, curcumin has a relatively weak anti-inflammatory effect due to its lack of specificity in the process of a wide range of mechanisms of action.

[0161] Transcellular membrane permeation: Due to the changes in the hydrophobicity and alkalinity of curcumin purine derivatives, the derivatives are more likely to pass through the cell membrane, thereby producing stronger anti-inflammatory activity in the cell. In contrast, the hydrophobicity and alkalinity of curcumin limit its ability to permeate across the membrane, resulting in reduced anti-inflammatory activity.

[0162] In summary, curcumin purine derivatives have good anti-inflammatory activity due to their bioavailability, structural advantages, enhanced selectivity and transcellular membrane permeability.

[0163] The embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and changes will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles of the embodiments, practical applications, or improvements to the technology in the market, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, It is characterized in that The compound is selected from the compounds represented by formula (I) 2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

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