Furan-substituted flavonoid compound as well as preparation method and application thereof
By synthesizing furan-substituted flavonoids, the problems of poor solubility and high synthesis difficulty of existing flavonoids have been solved, achieving high solubility and high bioactivity of the compounds, with anti-cancer potential, and reducing synthesis costs.
Patent Information
- Application Number
- CN202511333606.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-18
- Publication Date
- 2025-11-07
AI Technical Summary
Existing flavonoids have complex structures, poor solubility, low utilization of physiological activity, and demanding chemical synthesis processes, which increases the difficulty and cost of synthesis.
We designed and synthesized furan-substituted flavonoids by reacting flavonoids with azoles under specific conditions to prepare novel furan-substituted flavonoids. We adopted a simplified synthetic route to avoid harsh conditions such as high temperature and high pressure.
It improves the solubility and bioactivity of the compound, provides a stronger anticancer effect, reduces the cost and difficulty of synthesis, and has potential applications in cancer treatment.
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Figure CN120904181A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of organic drug synthesis, in particular to a kind of furan-substituted flavonoid compounds and preparation method and application thereof. BACKGROUND
[0002] Flavonoids (also known as flavonoids) are an important class of natural organic compounds, with broad-spectrum physiological and pharmacological activities, low toxicity, strong biological activity, and are an important component of traditional Chinese medicine, widely exist in fruits, vegetables, pasture, medicinal plants.
[0003] However, the structure of natural flavonoids is complex, the solubility is poor, and the physiological activity utilization rate is not high, which limits its wide clinical application. Therefore, scientific researchers focus on the structural modification of flavonoids, on the one hand to enhance the solubility and improve the bioavailability, and on the other hand to develop new flavonoids with stronger activity and smaller side effects.
[0004] The existing flavonoids have harsh reaction conditions, and usually require specific temperature, pressure, catalyst and other reaction conditions in the process of chemical synthesis, which has high requirements for equipment and operation, increases the difficulty and cost of synthesis. SUMMARY
[0005] The technical problem to be solved by the present application is to provide a novel furan-substituted flavonoid compound and a preparation method and application thereof.
[0006] To solve the above technical problems, according to one aspect of the present application, a furan-substituted flavonoid compound is provided, which comprises a compound of general formula I or its geometric isomer or its pharmaceutically acceptable salt.
[0007] In general formula I, R1 is hydrogen, alkyl or hydroxyl; R2 is hydrogen or hydroxyl; R3 is hydrogen or hydroxyl; Azole is an azole group; n = 2, 3, 4…
[0008] Further, the Azole is selected from 1-substituted 1,2,4-triazole, 2-methyl imidazole, 4-nitro imidazole, 2-methyl-5-nitro imidazole, benzimidazole, 6-nitro benzimidazole, 2-methyl-5-nitro benzimidazole, 2-methyl benzimidazole, 5,6-dimethyl benzimidazole, 2-mercapto benzimidazole group, 1,2,4-triazole, 5-methyl tetrazole.
[0009] According to another aspect of the present application, a preparation method of the above-mentioned furan-substituted flavonoid compound is provided, comprising: Step one, flavonoids, potassium carbonate, and dibromo-substituted alkane are stirred in acetonitrile at 60℃ to obtain intermediate II, ; Step two, after mixing and reacting the azole compound, inorganic base reagent and organic solvent, adding intermediate II, refluxing and stirring until the reaction is completed, a furan-substituted flavone compound represented by general formula I is obtained, .
[0010] Further, in step two, the molar ratio of intermediate II: azole compound: inorganic base reagent is 1: (1-1.4): (1-2.0).
[0011] Further, in step two, the reaction temperature of the azole compound, inorganic base reagent and organic solvent is 50°C.
[0012] Further, in step two, after adding intermediate II, the refluxing reaction temperature is 60-80°C.
[0013] Further, the organic solvent is acetone, acetonitrile or ethanol.
[0014] Further, the inorganic base reagent is potassium carbonate or sodium carbonate.
[0015] According to another aspect of the present application, there is provided a use of the furan-substituted flavone compound as described above in the preparation of a medicament for preventing or treating cancer.
[0016] According to another aspect of the present application, there is provided a pharmaceutical composition comprising the furan-substituted flavone compound as described above and at least one pharmaceutically acceptable excipient, adjuvant or carrier.
[0017] The present application combines flavone drugs with azoles and furans to design and synthesize a class of furan-substituted flavone compounds with novel structures. The synthesized furan flavone compounds are detected by CCK-8 experiments to detect the proliferation inhibition effect on A549 cells, and they all show certain inhibition effect on A549 cells, and the inhibition rate of the best active compound can reach 54.77%. Therefore, the compounds are expected to provide more efficient candidate drugs for cancer treatment, and help to solve the clinical treatment problems.
[0018] In addition, the preparation method of the furan-substituted flavone compound provided by the present application has a short synthesis route, and does not require catalysts, high temperature, high pressure, anhydrous and anaerobic harsh conditions in the preparation process. The preparation method is simple, the raw materials are easy to obtain, and the cost is low. BRIEF DESCRIPTION OF DRAWINGS
[0019] Figure 1 The relative cell viability of compound I-2 obtained by the embodiment of the present application in HEK293 cells is shown. DETAILED DESCRIPTION
[0020] A typical embodiment of the present application is to use the drug splicing principle, splicing flavone drugs with azole, furan, design and synthesis of a novel structure of furan-substituted flavonoids, which contains the compounds described in general formula I or its geometric isomers or its pharmaceutically acceptable salt;
[0021] In the formula, R1 is hydrogen, alkyl or hydroxyl; R2 is hydrogen or hydroxyl; R3 is hydrogen or hydroxyl; Azole is azole group; n = 2, 3, 4…
[0022] In a preferred embodiment, the pharmaceutically acceptable salt is hydrochloride, nitrate or acetate.
[0023] In a preferred embodiment, the Azole is selected from 1-substituted 1,2,4-triazole, 2-methyl imidazole, 4-nitro imidazole, 2-methyl-5-nitro imidazole, benzimidazole, 6-nitro benzimidazole, 2-methyl-5-nitro benzimidazole, 2-methyl benzimidazole, 5,6-dimethyl benzimidazole, 2-mercapto benzimidazole group, 1,2,4-triazole, 5-methyl tetrazole.
[0024] The heterocyclic compound with furan group has a variety of pharmacological activities due to its favorable chemical structure, can inhibit specific enzymes or interfere with DNA replication, has multiple anticancer mechanisms. Therefore, we can enhance the anticancer biological activity of flavone parent compounds by introducing furan heterocycle to improve the drugability of natural flavones.
[0025] Another typical embodiment of the present application provides a preparation method of the above-mentioned furan-substituted flavonoids, comprising: Step one, flavonoids III, potassium carbonate, dibromo-substituted alkane in acetonitrile control temperature 60℃, fully stirred to obtain intermediate II, ; In flavonoids III and intermediate II, R1 is hydrogen, alkyl or hydroxyl; R2 is hydrogen or hydroxyl; R3 is hydrogen or hydroxyl; Azole is azole group; n = 2, 3, 4…
[0026] Step two, mix azole compounds, inorganic base reagent and organic solvent and fully react, then add intermediate II, reflux and stir until the reaction is completed, to obtain furan-substituted flavonoids represented by general formula I, .
[0027] In the preferred embodiment, in step two, the molar ratio of the intermediate II: azole compound: inorganic base reagent is 1: (1-1.4): (1-2.0), for example 1:1:1, 1:1.1:1.4, 1:1.2:1.6, 1:1.3:1.8, 1:1.4:2.0. The dosage ratio of the reaction system is controlled so that the inexpensive and readily available raw materials are slightly excessive, and the difficult-to-obtain intermediate is ensured to be as completely reacted as possible.
[0028] The reaction temperature of the azole compound, inorganic base reagent and organic solvent is 50°C. After the addition of the intermediate II, the reaction temperature is 60-80°C, for example 60°C, 65°C, 70°C, 75°C, 80°C. The control of the temperature can improve the reaction activity and at the same time reduce the generation of by-products, thereby improving the yield.
[0029] In the preferred embodiment, the organic solvent is acetone, acetonitrile or ethanol. The inorganic base reagent is potassium carbonate or sodium carbonate.
[0030] In the above step one, the preparation method of the flavonoid compound of general formula III is as follows: First, the substituted phenol, ZnCl2, chloroacetonitrile and diethyl ether are fully reacted, HCl gas is passed for 2 hours under an ice salt bath, and then the reaction is stopped after standing overnight, HCl gas is passed for 2 hours, and then the reaction is stopped, and white powder is obtained by filtration. The intermediate IV is obtained by refluxing with hydrochloric acid and cooling.
[0031]
[0032] In the above reaction formula, R1 is hydrogen, alkyl or hydroxyl; R2 is hydrogen or hydroxyl; and R3 is hydrogen or hydroxyl.
[0033] Then, the intermediate IV, R substituent aldehyde, 10% NaOH solution and ethanol solvent are fully reacted at room temperature for 24 hours, and then the reaction solution is acidified with 1 mol / L HCl and filtered to obtain the flavonoid compound of general formula III.
[0034] The technical solutions claimed in the present application are further described below through some examples. However, the examples are used to explain the embodiments of the present application and do not exceed the scope of the subject matter of the present application, and the protection scope of the present application is not limited by the examples. Unless otherwise specified, the materials and reagents used in the present application can be obtained from commercial products in the art.
[0035] Example 1: Preparation of compound III-1
[0036] To a 100 mL round-bottom flask containing compound IV-1 (0.03 mol, 5.60 g), 2-furaldehyde (0.03 mol, 2.88 g) and an appropriate amount of ethanol (25 mL), 10% NaOH (5 mL) was added dropwise, and the reaction was stirred at room temperature for 24 h. TLC tracking was used to determine the completion of the reaction. The reaction mixture was neutralized to pH = 7 with 1 mol / L dilute hydrochloric acid, and then recrystallized from ethanol and dried to obtain 4.48 g of compound III-1, with a yield of 65.60%.
[0037] Example 2: Preparation of compound II-1
[0038] In a 100 mL round-bottom flask, compound III-1 (0.01 mol, 2.28 g), potassium carbonate (0.01 mol, 1.38 g), 1,3-dibromopropane (0.01 mol, 2.01 g) and an appropriate amount of acetonitrile were stirred at 60°C for 16 h. TLC tracking was used to determine the completion of the reaction. The reaction mixture was concentrated, extracted, column chromatography separated, and dried to obtain 1.69 g of compound II-1, with a yield of 48.70%.
[0039] Example 3: Preparation of compound I-1
[0040] In a 100 mL round-bottom flask, 1,2,4-triazole (0.35 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and an appropriate amount of acetonitrile were stirred at 50°C for 1 h, and then cooled to room temperature. Compound II-1 (1.75 g, 5 mmol) was added and the reaction was stirred at 80°C. TLC tracking was used to determine the completion of the reaction. The reaction mixture was concentrated, extracted, column chromatography separated, and dried to obtain 0.65 g of compound I-1, with a yield of 38.4%. Compound I-1: yellow powder; melting point 185-187°C; 1H NMR (500 MHz, CDCl3) δ 8.25 (s,1H, triazole-5-H), 8.13 (s, 1H, triazole-3-H), 8.03 (s, 1H, Fur-5-H), 7.71(s, 1H, flavone-8-H), 7.61 (d, J = 1.2 Hz, 1H, Fur-3-H), 7.05 (d, J = 3.4 Hz,1H, Fur-4-H), 6.83 (s, 1H, flavone-6-H), 6.73 (s, 1H, flavone-5-H), 6.59 (dd, J= 3.2, 1.6 Hz, 1H, flavone-3-H), 4.50 (t, J = 6.7 Hz, 2H, C-H2), 4.12 (t, J =5.8 Hz, 2H, C-H2), 2.54 (p, J = 6.3 Hz, 2H, C-H2) ppm. Example 4: Preparation of compound I-2
[0041] In a 100 mL round bottom flask, 5-methyltetrazole (0.42 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and appropriate amount of acetonitrile, temperature control 50 ℃, stirring reaction 1 h, cooling to room temperature, adding compound II-1 (1.74 g, 5 mmol) to 80 ℃, continue to stir, thin layer chromatography tracking to the end of the reaction, and then concentrated, extracted, column chromatography separation, drying and other post-processing, to get 0.73 g of compound I-2, yield 41.4%.
[0042] Compound I-2: yellow powder; melting point 174-175 ℃; 1H NMR (500 MHz, CDCl3) δ 7.71 (s,1H, Fur-5-H), 7.61 (d, J = 0.9 Hz, 1H, flavone-8-H), 7.28 (s, 1H, Fur-3-H),7.06 (d, J = 3.4 Hz, 1H, flavone-5-H), 6.82 (s, 1H, flavone-6-H), 6.75 (s, 1H,Fur-4-H), 6.61 – 6.58 (m, 1H, flavone-3-H), 4.58 (t, J = 7.0 Hz, 2H, C-H2),4.18 (t, J = 5.6 Hz, 2H, C-H 2, C-H3) ppm. Example 5: Preparation of compound I-3
[0043] In a 100 mL round-bottom flask, 2-methyl-5-nitroimidazole (0.63 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and appropriate amount of acetonitrile, temperature control 50 °C, stirring reaction 1 h, cooling to room temperature, adding compound II-1 (1.74 g, 5 mmol) to 80 °C, continue to stir, thin layer chromatography tracking to the end of the reaction, and then concentrated, extracted, column chromatography separation, drying and other post-processing, to get 0.88 g of compound I-3, yield 44.4%.
[0044] Compound I-3: yellow powder; melting point 174-175 °C; 1 H NMR (500 MHz, CDCl3) δ 7.77 (s,1H, Fur-5-H), 7.76 (d, J = 6.0 Hz, 1H, flavone-8-H), 7.72 (s, 1H, Imi-4-H),7.62 (s, 1H, Fur-3-H), 7.06 (d, J = 3.3 Hz, 1H, Fur-4-H), 6.82 (s, 1H, flavone-5-H), 6.75 (s, 1H, flavone-6-H), 6.59 (s, 1H, flavone-3-H), 4.27 (t, J =7.3 Hz, 2H, C-H2), 4.18 (t, J= 5.4 Hz, 2H, C-H2), 2.48 – 2.42 (m, 5H, C-H2,C-H3) ppm. Example 6: Preparation of compound I-4
[0045] In a 100 mL round-bottom flask, 4-nitroimidazole (0.56 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and appropriate amount of acetonitrile, temperature control 50 °C, stirring reaction 1 h, cooling to room temperature, adding compound II-1 (1.74 g, 5 mmol) to 80 °C, continue to stir, thin layer chromatography tracking to the end of the reaction, and then concentrated, extracted, column chromatography separation, drying and other post-processing, to get 0.64 g of compound I-4, yield 33.4%.
[0046] Compound I-4: yellow powder; melting point 168-169 °C; 1 H NMR (500 MHz, CDCl3) δ 7.77 (d, J= 1.3 Hz, 1H, Fur-5-H), 7.66 (s, 1H, Imi-2-H), 7.54 (d, J = 1.0 Hz, 1H, flavone-8-H), 7.44 (d, J = 7.5 Hz, 1H, Fur-3-H), 7.20 (s, 1H, flavone-5-H), 6.98(d, J = 3.4 Hz, 1H, Fur-4-H), 6.76 (s, 1H, Imi-5-H), 6.67 (s, 1H, flavone-6-H), 6.52 (dd, J = 3.1, 1.5 Hz, 1H, flavone-3-H), 4.30 (t, J = 7.1 Hz, 2H, C- H 2), 4.08 (t, J = 5.6 Hz, 2H, C- H 2), 2.47 – 2.39 (m, 2H, C- H 2) ppm. Example 7: Preparation of compound I-1
[0047] In a 100 mL round-bottom flask, 1,2,4-triazole (0.35 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and appropriate amount of acetone were stirred at 50°C for 1 h, cooled to room temperature, and then compound II-1 (1.75 g, 5 mmol) was added. The reaction was continued to be stirred at 70°C, and thin layer chromatography was used to track the end of the reaction. After the post-treatment of concentration, extraction, column chromatography separation, and drying, 0.61 g of compound I-1 was obtained, with a yield of 36.1%. Example 8: Preparation of compound I-2
[0048] In a 100 mL round-bottom flask, 1,2,4-triazole (0.35 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and appropriate amount of acetone were stirred at 50°C for 1 h, cooled to room temperature, and then compound II-1 (1.75 g, 5 mmol) was added. The reaction was continued to be stirred at 70°C, and thin layer chromatography was used to track the end of the reaction. After the post-treatment of concentration, extraction, column chromatography separation, and drying, 0.61 g of compound I-1 was obtained, with a yield of 36.1%. In vitro CCK-8 cytotoxicity experiment In this experiment, CCK-8 experiment was used to detect the proliferation inhibition effect of the synthesized furan-substituted flavonoid compounds on A549 cells.
[0049] 1. Experimental steps A certain amount of each of the above compounds I-1, I-2, I-3 and I-4 was accurately weighed, a small amount of dimethyl sulfoxide was added to completely dissolve the compounds, and then an appropriate amount of culture solution was added to prepare a mother solution. The cell number was adjusted to 6×10 4 6 / mL according to the cell culture method, 100 μL was inoculated into a 96-well plate, and the plate was incubated at 37°C and 5% CO2 for 24 h. Then, 0.1% DMSO (control group) and 10 μM / L compound I (drug group) were added. After incubation in the incubator for 72 h, 10% CCK-8 was added according to the instructions, and the plate was incubated in the incubator for another 30 min. The plate was detected by an enzyme-labeled instrument at a wavelength of 450 nm.
[0050] The inhibition rates of the control group and the drug group were calculated according to the following formula: cell inhibition rate = (OD 对照组 – OD 药物组 ) / OD 对照组 ×100%.
[0051] 2. Test results According to the CCK-8 inhibition rate calculation formula: cell inhibition rate = [(Ac-As) / (Ac-Ab)]x100% (wherein, Ac: control hole; As: experimental hole; Ab: blank hole), the obtained experimental data are processed to obtain Table 1.
[0052] Table 1 CCK-8 cell inhibition rate
[0053] As shown in Table 1, the inhibition rates of furan-substituted flavonoid compounds I-1, I-2, I-3, I-4 on A549 cells are 10.35%, 54.77%, 26.94%, and 52.62%, respectively, indicating that the synthesized compounds all exhibit certain anti-tumor activity, especially the inhibition rates of compounds I-2 and I-4 reach 54.77% and 52.62%, respectively, so it is known that the derivatives synthesized from 5-methyltetrazole and 4-nitroimidazole have better inhibition effect on cancer cells, can play a good anti-tumor role, and are helpful to solve the clinical treatment problem.
[0054] In vitro cytotoxicity testing of highly active molecules The cells used for testing in the experiment are human embryonic kidney cells HEK293. The effect of high-activity molecule I-2 on the activity of HEK293 cells is determined by using a cell counting kit-8 (CCK8) based on WST-8 reduction assay. HEK293 cells are inoculated into a 96-well plate (5000 cells per well). Then the cells are incubated in a culture medium containing a specific concentration of compound I-2 for 24 hours. Then 10 mL of CCK8 is added to each well. After 4 hours, the unreacted dye is sucked out by a pipette. The optical density is measured by a microplate reader at an absorbance of 570 nm. Finally, the half-inhibitory concentration IC 50 value is calculated by plotting. The OD value is measured by an ELISA plate reader at a wavelength of 450 nm by spectrophotometry.
[0055] The survival rate is represented as follows: cell activity = (treatment group OD / control group OD) x 100%. The results show that compound I-2 still shows low toxicity to HEK293 cells at a high concentration, with an IC 50 value of 316 mg / mL. The above results show that this type of compound has low cytotoxicity to human normal cells.
[0056] Although the present application has been described in connection with the presently preferred exemplary embodiments, it will be understood that the application is not limited to the disclosed embodiments, but instead, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the application.
Claims
1. A furan-substituted flavonoid compound, characterized by, A furan-substituted flavonoid compound represented by the general formula I or a geometric isomer thereof or a pharmaceutically acceptable salt thereof; ， In the general formula I, R1 is hydrogen, alkyl or hydroxyl; R2 is hydrogen or hydroxyl; R3 is hydrogen or hydroxyl; Azole is an azole group; and n = 2, 3, 4, ….
2. The furan substituted flavonoid compound according to claim 1, characterized in that: The Azole is selected from the group consisting of 1,2,4-triazole, 2-methyl imidazole, 4-nitro imidazole, 2-methyl-5-nitro imidazole, benzimidazole, 6-nitro benzimidazole, 2-methyl-5-nitro benzimidazole, 2-methyl benzimidazole, 5,6-dimethyl benzimidazole, 2-mercapto benzimidazole group, 1,2,4-triazole, 5-methyl tetrazole.
3. The method of preparing the furan-substituted flavonoid compound according to claim 1, characterized by, The method comprises: Step one, stirring the flavonoid compound, potassium carbonate and dibromo-substituted alkane in acetonitrile at 60°C to obtain intermediate II, ； Step two, mixing the azole compound, inorganic base reagent and organic solvent, and then adding intermediate II to reflux and stir until the reaction is completed, thereby obtaining the furan-substituted flavonoid compound represented by the general formula I, 。 4. The method of claim 3, wherein: In step two, the molar ratio of intermediate II: azole compound: inorganic base reagent is 1: (1-1.4): (1-2.0).
5. The method of claim 4, wherein: In step two, the reaction temperature of the azole compound, inorganic base reagent and organic solvent is 50°C.
6. The method of claim 5, wherein: After adding intermediate II in step two, the reflux reaction temperature is 60-80°C.
7. The method according to claim 3 or 6, characterized in that: The organic solvent is acetone, acetonitrile or ethanol.
8. The method of claim 7, wherein: The inorganic base reagent is potassium carbonate or sodium carbonate.
9. Use of the furan-substituted flavonoid compound of claim 1 or 2 in the preparation of a medicament for preventing or treating cancer.
10. A pharmaceutical composition, characterized by: The furan-substituted flavonoid compound of claim 1 or 2 and at least one pharmaceutically acceptable excipient, adjuvant or carrier.