CN117586136A

CN117586136A - Methylene dimethylamino modified curcumin analogue and preparation method and application thereof

Info

Publication number: CN117586136A
Application number: CN202311581370.4A
Authority: CN
Inventors: 李彬; 刘思凡; 刘曙晨; 田瑛; 张广杰; 李敏; 夏梓铭
Original assignee: Academy of Military Medical Sciences AMMS of PLA
Current assignee: Academy of Military Medical Sciences AMMS of PLA
Priority date: 2023-11-24
Filing date: 2023-11-24
Publication date: 2024-02-23

Abstract

The invention discloses a methylene dimethylamino modified curcumin analogue, and a preparation method and application thereof. The structural formula of the curcumin analogue is shown as formula I. According to the invention, a series of curcumin analogues are chemically synthesized by introducing methylene dimethylamino into curcumin molecules, and then the curcumin analogues are combined with hydrochloric acid to form hydrochloride, so that the water solubility of the curcumin analogues is greatly improved. Wherein, part of the compounds exhibit more excellent anti-inflammatory activity and antioxidant activity than curcumin. The curcumin analogue with water solubility and pharmacological activity superior to those of curcumin is synthesized by structurally modifying curcumin, and is expected to be applied to development of novel anti-inflammatory medicaments and anti-tumor medicaments.

Description

Methylene dimethylamino modified curcumin analogue and preparation method and application thereof

Technical Field

The invention belongs to the fields of organic chemical synthesis and medicine, and in particular relates to a curcumin analogue modified by methylene dimethylamino, a preparation method and application thereof.

Background

Curcumin is a natural product separated from curcuma aromatica (Curcuma aromatica Salisb.) and curcuma longa (C.longa L.) of the family Zingiberaceae, has orange-yellow crystalline powder in appearance, has various pharmacological activities of inhibiting inflammatory reaction, resisting oxidation, inhibiting tumor growth, resisting diabetes, protecting nerves and the like, and is proved by a large number of researches to not show obvious toxicity at high dosage. However, due to the poor solubility of curcumin in water and various buffered aqueous solutions, the clinical application of curcumin is greatly limited. Therefore, a great deal of research focuses on improving the water solubility of curcumin, improving the pharmacokinetic properties of curcumin and increasing the bioavailability of curcumin. Salt formation is also a very important method for improving the solubility of medicines, and the water solubility of the lead compound of sildenafil which is a medicine for treating erectile dysfunction is greatly improved due to insufficient solubility after being introduced into methylpiperazine sulfonyl and then salified with citric acid. In light of this, the inventors of the present invention expected an improvement in the structure of curcumin to obtain curcumin analogs with significantly improved water solubility and activity.

Disclosure of Invention

The invention aims to provide a curcumin analogue. The inventor introduces methylene dimethylamino into benzene ring at one side of curcumin, and designs and synthesizes a series of curcumin analogues by changing benzene ring substituent at the other side. Due to the presence of methylenedimethylamino, these analogs can form salts with common acids, greatly enhancing the water solubility of curcumin. And the anti-inflammatory and antioxidant activities of the obtained curcumin analogues in vitro are evaluated, and the anti-inflammatory activity of the compound is found to be obviously superior to that of curcumin.

The curcumin analogue or pharmaceutically acceptable salt thereof provided by the invention has a structural general formula shown in formula I:

further, R in formula I is selected from any one of the following groups:

1-15 of the R substituents correspond to compound 1-15 of the compound of formula I in sequence.

The carbon atom in the curcumin analogues shown in the formula I is selected from at least one of the following: 12c,14c; the H atom is selected from at least one of the following: 1H,2H,3H.

The above-mentioned "pharmaceutically acceptable salts" refer to salts which are suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable effect/risk ratio, and within the scope of sound medical judgment. Pharmaceutically acceptable salts of the compounds of formula I are well known in the art and include, but are not limited to, hydrochloride, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, oxalate, lactate, citrate, tartrate, maleate, and the like.

The invention also provides a preparation method of the curcumin analogue shown in the formula I or pharmaceutically acceptable salt thereof.

The preparation method of the curcumin analogue shown in the formula I or the pharmaceutically acceptable salt thereof provided by the invention comprises the following steps:

1) In the presence of diboron trioxide and trimethyl borate, carrying out condensation reaction on a compound shown in a formula II and 2, 4-pentanedione to obtain a compound shown in a formula III;

wherein R in the compound shown in the formula II is defined as R in the formula I;

2) Reacting vanillin, dimethylamine and formaldehyde to obtain a compound shown in a formula IV;

3) And (3) carrying out condensation reaction on the compound shown in the formula III and the compound shown in the formula IV in the presence of diboron trioxide and trimethyl borate to obtain the compound shown in the formula I.

In the above method step 1), the molar ratio of the compound represented by formula II to 2, 4-pentanedione is 1: (0.8-1.2).

In the step 1) of the method, the molar ratio of the compound shown in the formula II to the diboron trioxide and the trimethyl borate is 1: (2-4): (2-4).

In process step 1) above, the reaction is carried out in a solvent, which may be ethyl acetate.

In the above method step 1), the reaction condition of the condensation reaction is heating.

The step 1) further comprises the step of separating the product by silica gel column chromatography after the reaction is finished, wherein the eluent E (ethyl acetate) is P (petroleum ether) =1:40-1:5 (v/v).

Specifically, the reaction operation of the above step 1) is as follows: adding diboron trioxide into ethyl acetate solution of 2, 4-pentanedione, and stirring the obtained solution at 70-90 ℃ for 0.5-2 h; adding trimethyl borate and ethyl acetate solution of the compound shown in the formula II, and stirring for 0.5-2 h at 70-90 ℃ after the addition; n-butylamine (initiating the condensation reaction of acetylacetone-boron complex and aldehyde) is added, and the mixture is stirred for 0.5h to 2h at the temperature of 90 ℃ to 110 ℃; adding 1N hydrochloric acid into the system, stirring at 40-60deg.C for 0.5-2 hr, adding water, and adding acetic acid into water phaseEthyl ester extraction for 3 times, combining organic phases, adding anhydrous Na ₂ SO ₄ Drying, filtering and concentrating to obtain a crude product; the crude product was separated by column chromatography on silica gel, eluent E (ethyl acetate): P (petroleum ether) =1:40-1:5 (v/v), to give the purified compound of formula III.

In the above method step 2), the molar ratio of vanillin, dimethylamine and formaldehyde is 1: (2-4): (4-6).

In the above process step 2), the reaction is carried out in a solvent, which may be methanol.

In the above method step 2), the reaction condition of the reaction is heating.

The step 2) further comprises the step of separating the product by silica gel column chromatography after the reaction is finished, wherein the eluent E (ethyl acetate) is P (petroleum ether) =1:50-1:3 (v/v).

In the above method step 3, the molar ratio of the compound represented by formula III to the compound represented by formula iv is 1:

(0.8-1.2)。

in the step 3) of the method, the molar ratio of the compound shown in the formula III to the diboron trioxide and the trimethyl borate is 1: (2-4): (2-4).

In process step 3) above, the reaction is carried out in a solvent, which may be ethyl acetate.

In the above method step 3), the reaction condition of the condensation reaction is heating.

The step 3) further comprises the step of separating the product by silica gel column chromatography after the reaction is finished, wherein the eluent E (ethyl acetate) is P (petroleum ether) =1:40-1:5 (v/v).

Specifically, the reaction operation of the step 3) is as follows: adding diboron trioxide into ethyl acetate solution of a compound shown in a formula IV, and stirring the obtained solution at 70-90 ℃ for 0.5-2 h; adding ethyl acetate solution of trimethyl borate and vanillin, and stirring at 70-90deg.C for 0.5-2 hr; adding piperidine, and stirring at 90-110 ℃ for 0.5-2 h; adding 1N hydrochloric acid into the system, stirring at 40-60deg.C for 0.5h-2h, adding water, extracting water phase with ethyl acetate for 3 times, mixing organic phases, adding anhydrous Na ₂ SO ₄ Drying, filtering and concentrating to obtain crude productA material; the crude product was separated by column chromatography on silica gel, eluent E (ethyl acetate): P (petroleum ether) =1:40-1:5 (v/v), to give the purified compound of formula I.

The invention also provides application of the curcumin analogue shown in the formula I or pharmaceutically acceptable salt thereof.

The application includes at least one of the following: 1) The application in preparing anti-inflammatory drugs; 2) The application in preparing antioxidant drugs; 3) The application in preparing antitumor drugs.

Anti-inflammatory or antioxidant drugs prepared by using the compound of the formula I as an active ingredient also belong to the protection scope of the invention.

The invention also provides a pharmaceutical preparation.

The invention provides a pharmaceutical preparation which comprises a curcumin analogue shown in a formula I or pharmaceutically acceptable salt thereof in a therapeutically effective amount and a pharmaceutically acceptable carrier.

In the above pharmaceutical preparation, the curcumin analogue shown in formula I or pharmaceutically acceptable salt thereof can be used as one of the active ingredients or the only active ingredient.

Such pharmaceutically acceptable carriers include, but are not limited to, water-soluble carrier materials (e.g., polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), poorly soluble carrier materials (e.g., ethylcellulose, cholesterol stearate, etc.), enteric carrier materials (e.g., cellulose acetate phthalate, carboxymethyl cellulose, etc.). The materials can be prepared into various dosage forms, including but not limited to tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, freeze-dried powder injection and the like. Can be common preparation, slow release preparation, controlled release preparation and various microparticle administration systems.

For the purpose of shaping the unit dosage form into a tablet, various carriers known in the art can be widely used. Examples of carriers are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like; disintegrants such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oils and the like; absorption promoters such as quaternary ammonium salts, sodium lauryl sulfate, and the like; lubricants such as talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets. For the purpose of formulating the unit dosage form into a pill, various carriers well known in the art can be widely used. Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, kaolin, talc, etc.; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, and the like; disintegrants such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc. For preparing a unit dosage form into a suppository, various carriers well known in the art can be widely used. Examples of carriers include polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, and the like. For preparing unit dosage forms into injectable preparations such as solutions, emulsions, lyophilized powders and suspensions, all diluents commonly used in the art, for example, water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol, polyoxyethylene sorbitol fatty acid esters, etc. may be used. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and further, a conventional cosolvent, a buffer, a pH adjuster, and the like may be added. In addition, colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials may also be added to the pharmaceutical formulation, if desired. The preparation can be administrated by injection, including subcutaneous injection, intravenous injection, intramuscular injection, and intracavity injection; administration via the luminal tract, such as rectally and vaginally; respiratory tract administration, such as via the nasal cavity; mucosal administration.

The invention synthesizes new curcumin analogues through structural modification of curcumin. The solubility of the curcumin analogue or the pharmaceutically acceptable salt thereof in water is better than that of curcumin, and the anti-inflammatory activity and the antioxidant activity of the curcumin analogue or the pharmaceutically acceptable salt thereof are also better than that of curcumin, so that the curcumin analogue or the pharmaceutically acceptable salt thereof is expected to be applied to the development of novel anti-inflammatory medicaments and anti-tumor medicaments.

Drawings

FIG. 1 is a synthetic route diagram of a curcumin analog represented by formula I of the present invention;

FIG. 2 is a diagram of Compound 1 ¹³ C NMR spectrum;

FIG. 3 is a diagram of Compound 1 ¹ H NMR spectrum;

FIG. 4 is a diagram of Compound 2 ¹³ C NMR spectrum;

FIG. 5 is a diagram of Compound 2 ¹ H NMR spectrum;

FIG. 6 is a diagram of Compound 3 ¹³ C NMR spectrum;

FIG. 7 is a diagram of Compound 3 ¹ H NMR spectrum;

FIG. 8 is a diagram of Compound 4 ¹³ C NMR spectrum;

FIG. 9 is a diagram of Compound 4 ¹ H NMR spectrum;

FIG. 10 is a diagram of Compound 5 ¹³ C NMR spectrum;

FIG. 11 is a diagram of Compound 5 ¹ H NMR spectrum;

FIG. 12 is a diagram of Compound 6 ¹³ C NMR spectrum;

FIG. 13 is a diagram of Compound 6 ¹ H NMR spectrum;

FIG. 14 is a diagram of Compound 7 ¹³ C NMR spectrum;

FIG. 15 is a diagram of Compound 7 ¹ H NMR spectrum;

FIG. 16 is a schematic illustration of a combinationObject 8 ¹³ C NMR spectrum;

FIG. 17 is a diagram of Compound 8 ¹ H NMR spectrum;

FIG. 18 is a diagram of Compound 9 ¹³ C NMR spectrum;

FIG. 19 is a diagram of Compound 9 ¹ H NMR spectrum;

FIG. 20 is a diagram of Compound 10 ¹³ C NMR spectrum;

FIG. 21 is a diagram of Compound 10 ¹ H NMR spectrum;

FIG. 22 is a diagram of Compound 11 ¹³ C NMR spectrum;

FIG. 23 is a diagram of Compound 11 ¹ H NMR spectrum;

FIG. 24 is a diagram of Compound 12 ¹³ C NMR spectrum;

FIG. 25 is a diagram of Compound 12 ¹ H NMR spectrum;

FIG. 26 is a diagram of Compound 13 ¹³ C NMR spectrum;

FIG. 27 is a diagram of Compound 13 ¹ H NMR spectrum;

FIG. 28 is a diagram of Compound 14 ¹³ C NMR spectrum;

FIG. 29 is a diagram of Compound 14 ¹ H NMR spectrum;

FIG. 30 is a diagram of Compound 15 ¹³ C NMR spectrum;

FIG. 31 is a diagram of Compound 15 ¹ H NMR spectrum;

FIG. 32 is in vitro anti-inflammatory activity data for curcumin analogs;

FIG. 33 is in vitro antioxidant activity data for curcumin analogs.

Detailed Description

The invention will be further illustrated with reference to the following specific examples, but the invention is not limited to the following examples. The methods are conventional methods unless otherwise specified. The starting materials are available from published commercial sources unless otherwise specified.

Example 1 Synthesis of Compound 15

Compound 15 is of formula I wherein R isIs a compound of (a).

a) To an ethyl acetate solution of 2, 4-pentanedione (0.9 g) was added diboron trioxide (0.21 g), and the resulting solution was stirred at 80℃for 0.5h. A solution of trimethyl borate (0.31 g) and vanillin (0.5 g) in ethyl acetate (8 ml) was added and stirred at 80℃for 0.5h. N-butylamine (0.22 g) was added thereto and stirred at 100℃for 1h. Adding 5ml of 1N hydrochloric acid into the system, stirring at 50deg.C for 0.5h, adding 20ml of water, extracting the water phase with ethyl acetate 3 times (20 ml. Times.3), mixing the organic phases, adding anhydrous Na ₂ SO ₄ Drying, filtering and concentrating to obtain 1g of crude product. The crude product was separated by column chromatography on silica gel, eluting with E: P=1:40-1:5 (v/v), to give 0.6g of the desired product (corresponding compound of formula III).

b) Dimethylamine (40%, 10 g) and formaldehyde (37%, 10.67 g) were mixed and stirred at 70℃for 0.5h. 80ml of methanol solution of vanillin (10 g) was added thereto and stirred at 70℃for 12h. The reaction was concentrated under reduced pressure to remove methanol, the aqueous phase was extracted 3 times with ethyl acetate (20 ml x 3), the organic phases were combined and anhydrous Na was added ₂ SO ₄ Drying, filtering and concentrating to obtain 11.2g of crude product. The crude product was separated by column chromatography on silica gel eluting with the eluent E: p=1:50-1:3 (v/v) to give 6.6g of the target product 3- ((dimethylamino) methyl) -4-hydroxy-5-methoxybenzaldehyde (compound of formula iv).

c) To a solution of 3- ((dimethylamino) methyl) -4-hydroxy-5-methoxybenzaldehyde (0.1 g) in ethyl acetate prepared in step b) was added diboron trioxide (28 mg) and the resulting solution was stirred at 80℃for 0.5h. A solution of trimethyl borate (50 mg) and vanillin (67 mg) in ethyl acetate (2 ml) was added thereto, and the mixture was stirred at 80℃for 0.5h after the addition. Piperidine (41 mg) was added thereto, and the mixture was stirred at 100℃for 1 hour. Adding 2ml of 1N hydrochloric acid to the system, stirring at 50deg.C for 0.5h, adding 10ml of water, extracting the aqueous phase with ethyl acetate 3 times (10 ml. Times.3), mixing the organic phases, adding anhydrous Na ₂ SO ₄ Drying, filtering and concentrating to obtain crude product 35mg. The crude product was separated by column chromatography on silica gel eluting with eluent E: P1:40-1:5 to give the desired product (compound 15) 12mg.

The structure identification results are shown in fig. 2-31.

Solubility in water: the solubility of curcumin in water is only 13.76 mug/ml, and the solubility of the hydrochloride of the compound 5 and the compound 11 with excellent anti-inflammatory and antioxidant activities is 117mg/ml and 285mg/ml respectively, so that the water solubility is greatly improved.

Other compounds 1-14 can be prepared by reference to the preparation of compound 15.

The structure identification result of the compound 1 is shown in figures 2-3;

the structure identification result of the compound 2 is shown in fig. 4-5;

the structure identification results of the compound 3 are shown in fig. 6-7;

the structure identification results of the compound 4 are shown in figures 8-9;

the structure identification results of compound 5 are shown in FIGS. 10-11;

the structural identification results of compound 6 are shown in FIGS. 12-13;

the structure identification results of compound 7 are shown in FIGS. 14-15;

the structure identification results of compound 8 are shown in FIGS. 16-17;

the structural identification results of compound 9 are shown in FIGS. 18-19;

the structural identification results of compound 10 are shown in FIGS. 20-21;

the structural identification results of compound 11 are shown in FIGS. 22-23;

the structural identification results of compound 12 are shown in FIGS. 24-25;

the structure identification results of compound 13 are shown in FIGS. 26-27;

the structural identification of compound 14 is shown in FIGS. 28-29;

the results of structural identification of compound 15 are shown in FIGS. 30-31.

Example 2: inhibition of LPS-induced NO release from RAW264.7 cells by curcumin analogs (Compounds 1-15)

Nitric Oxide (NO) is an important gas signaling and effector molecule that is involved as a second messenger in a variety of biological and pathophysiological processes.

The mouse mononuclear macrophage RAW264.7 is cultivated by DMEM culture solution (containing 10% of domestic fetal calf serum and 1% of double antibody)Culturing at 37deg.C with 5% CO ₂ After 24 hours in the incubator, RAW264.7 cells in logarithmic growth phase are taken for digestion and centrifugation, and the cell number is 3 multiplied by 10 ⁴ Cells were seeded into 96-well plates at a density of 80 μl per well at 37deg.C and 5% CO ₂ Culturing in a cell culture incubator under conditions. After observing cell adhesion for 24 hours under a microscope, dividing the cells into a blank group, a model group (LPS group), a curcumin treatment group and a curcumin analogue treatment group, wherein each group is provided with 3 compound holes, 10 mu L of curcumin solution with the concentration of 10 mu M is firstly added into the curcumin analogue treatment group, 10 mu L of sample solutions with different concentrations (with the final concentration of 5, 10 and 20 mu M respectively) are firstly added into the curcumin analogue treatment group, then 10 mu L of LPS with the final concentration of 1 mu g/ml is added into each hole except the blank group for inflammatory stimulation, and finally 20 mu L of DMEM culture solution with the final concentration of 10 mu L is added into each hole of the blank group and each hole of the model group, so that the volume of each hole is finally 100 mu L. Continuously culturing at constant temperature for 24 hr, measuring NO content with nitrogen monoxide kit, and collecting 50 μl of cell supernatant and NaNO in each well ₂ Standard (0, 1.56, 3.13, 6.25, 12.5, 25, 50, 100, 200 μm) was placed in 96-well plates, 50 μl Griess R1 reagent was added to each well, and after 5min at room temperature in the dark, 50 μl Griess R2 reagent was added, and after 5min at room temperature in the dark, absorbance was measured at 540nm wavelength with an microplate reader within 30 min.

Preparation of a standard curve: the standard NO concentration was plotted on the x-axis with the average absorbance OD value and the y-axis with Excel and a standard curve formula (y= 161.64 x-9.4822) was obtained. The concentration of NO was calculated by substituting each group of OD values into the standard curve. The results are shown in FIG. 32.

As can be seen from fig. 32, the anti-inflammatory activity of compounds 1,5,6,7,8, 10, 11, 12 was better than that of curcumin at a concentration of 20 μm.

Example 3: curcumin analogues (Compounds 1-15) vs H ₂ O ₂ Induced injury protection of PC12 cells

PC12 cells were cultured in DMEM medium (containing 5% of imported fetal calf serum, 10% of horse serum and 1% of diabody) and placed at 37℃in 5% CO ₂ After 24 hours in the incubator, PC12 cells in logarithmic growth phase are taken for digestion and centrifugation, and the cell number is 8 multiplied by 10 ³ Cells were seeded into 96-well plates at a density of 80 μl per well at 37deg.C and 5% CO ₂ Culturing in a cell culture incubator under conditions. After observing cell adhesion for 24 hours under a microscope, dividing the cells into a blank group, an oxidative damage model group and a drug treatment group (curcumin group and compound 1-15 group), wherein each group is provided with 3 compound holes, 10 mu L of sample solutions with different concentrations (the final concentrations are 5, 10 and 20 mu M respectively) are respectively added into the drug treatment group, and then 10 mu L of H with the final concentration of 140 mu M is added into each hole except the blank group ₂ O ₂ And (3) constructing an oxidative damage cell model, adding 20 mu L of DMEM culture solution into each hole of a blank group and 10 mu L of DMEM culture solution into each hole of a model group, and finally achieving 100 mu L of volume of each hole. After continuous constant temperature culture for 24 hours, cell viability detection is carried out by CCK8 method, and CO is placed at 37 DEG C ₂ After 2 hours in the incubator, the absorbance of each well was measured with a microplate reader at a wavelength of 450 nm. According to the cell viability calculation formula (A/A ₀ *100%, A is the average absorbance of the group, A ₀ Average absorbance for the blank group) the viability of each group of cells was calculated. The results are shown in FIG. 33.

As can be seen from FIG. 33, the antioxidant activity of the compounds 5 and 11 was significantly better than that of curcumin at concentrations of 5. Mu.M, 10. Mu.M and 20. Mu.M.

Claims

1. Curcumin analogues or pharmaceutically acceptable salts thereof have a structural general formula shown in formula I:

r in formula I is selected from any one of the following groups:

2. the curcumin analogue or pharmaceutically acceptable salt thereof according to claim 1, wherein: the carbon atom in formula I is selected from at least one of the following: 12c,14c; the H atom is selected from at least one of the following: 1H,2H,3H.

3. A process for the preparation of a curcumin analogue or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2, comprising the steps of:

wherein R in the compound shown in the formula II is defined as R in the formula I in the claim 1;

4. A method of preparation according to claim 3, characterized in that: in the step 1), the molar ratio of the compound shown in the formula II to the 2, 4-pentanedione is 1: (0.8-1.2);

or the molar ratio of the compound shown in the formula II to the diboron trioxide to the trimethyl borate is 1: (2-4): (2-4);

or, the reaction is carried out in a solvent, wherein the solvent is ethyl acetate;

or, the reaction condition of the condensation reaction is heating;

or, the step 1) further comprises a step of separating the product by silica gel column chromatography after the reaction is finished, wherein the eluent E (ethyl acetate) is P (petroleum ether) =1:40-1:5 (v/v).

5. A method of preparation according to claim 3, characterized in that: in the step 2), the molar ratio of vanillin, dimethylamine and formaldehyde is 1: (2-4): (4-6);

or, the reaction is carried out in a solvent, wherein the solvent is methanol;

or, the reaction condition of the reaction is heating;

or, the step 2) further comprises a step of separating the product by silica gel column chromatography after the reaction is finished, wherein the eluent E (ethyl acetate) is P (petroleum ether) =1:50-1:3 (v/v).

6. A method of preparation according to claim 3, characterized in that: in the step 3, the molar ratio of the compound shown in the formula III to the compound shown in the formula IV is 1: (0.8-1.2);

or the molar ratio of the compound shown in the formula III to the diboron trioxide to the trimethyl borate is 1: (2-4): (2-4);

or, the reaction condition of the condensation reaction is heating;

or, the step 3) further comprises a step of separating the product by silica gel column chromatography after the reaction is finished, wherein the eluent E (ethyl acetate) is P (petroleum ether) =1:40-1:5 (v/v).

7. Use of a curcumin analogue of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, comprising at least one of the following:

1) The application in preparing anti-inflammatory drugs;

2) The application in preparing antioxidant drugs;

3) The application in preparing antitumor drugs.

8. A pharmaceutical formulation comprising a therapeutically effective amount of a curcumin analogue of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

9. The pharmaceutical formulation of claim 8, wherein: the pharmaceutical formulation has at least one of the following effects: 1) Anti-inflammatory; 2) Oxidation resistance; 3) Anti-tumor.