Alpha-ketoamide hydrogen peroxide response precursor compound, preparation method and application

Abstract

The invention provides an alpha-ketoamide hydrogen peroxide responsive prodrug compound and a preparation method and application thereof, and relates to the technical field of chemical biologication.According to the alpha-ketoamide hydrogen peroxide responsive prodrug compound, under the action of hydrogen peroxide, an alpha-ketoamide structure is subjected to responsive breakage, and the activity of the alpha-ketoamide hydrogen peroxide responsive prodrug compound is improved. After chemical structure dissimilation and benzyl elimination, diethyl dithiocarbamate is released, the released product is complexed with copper ions to generate a metal drug copper diethyldithiocarbamate CuET, and the metal drug copper diethyldithiocarbamate CuET has a remarkable growth inhibition effect on malignant tumor cells. According to the prepared prodrug compound, the synthesis method is simple, convenient and easy to operate, the controllability is high, and the prodrug compound has a wide application prospect in the field of application of the responsive prodrug compound in malignant tumor treatment.

Description

Technical Field

[0001] The invention relates to the technical field of hydrogen peroxide responsive precursor compounds, in particular to an alpha-ketoamide hydrogen peroxide responsive precursor compound, a preparation method and application thereof. Background Art

[0002] Cancer is a major disease that poses a serious threat to human health and continues to be a major problem in the medical field. Traditional chemotherapeutic drugs have poor selectivity for cancer cells, resulting in serious toxic side effects. Activating active substances in a specific tumor environment can effectively reduce the toxic side effects of chemotherapeutic drugs. Compared with normal cells, tumor cells face different oxidative stresses, with significantly higher levels of reactive oxygen species (ROS) due to insufficient oxygen supply, high energy consumption, and lack of defense mechanisms. Reports have shown that some tumor cells are able to rapidly produce hydrogen peroxide (H2O2), up to 5μM-1.0mM. Therefore, the development of drug prodrug compounds that are activated responsively to H2O2 in tumor cells is a very promising research direction.

[0003] At present, some precursor compounds for inhibiting tumor cells have been reported, for example, compounds containing active functional groups such as phenylboronic acid, oxalic acid and thiazolidinone. However, these compounds are not specific enough for H2O2, resulting in poor targeting of tumor cells, and the inhibitory effect of these compounds on tumor cells is not good. Summary of the invention

[0004] In order to solve the above-mentioned technical problems, the present invention provides an α-ketoamide hydrogen peroxide responsive precursor compound, a preparation method and an application thereof.

[0005] The first aspect of the present invention provides an α-ketoamide hydrogen peroxide responsive drug precursor compound, wherein the α-ketoamide hydrogen peroxide responsive drug precursor compound has a structural formula as shown in general formula (I):

[0006]

[0007] The second aspect of the present invention provides a method for preparing an α-ketoamide hydrogen peroxide responsive drug precursor compound, wherein the α-ketoamide hydrogen peroxide responsive drug precursor compound is the α-ketoamide hydrogen peroxide responsive drug precursor compound provided in the first aspect of the present invention, comprising the following steps:

[0008] 4-nitroacetophenone and selenium dioxide are subjected to an oxidation reaction, followed by a condensation reaction with 4-aminophenylmethanol, followed by bromination with phosphorus tribromide to obtain an intermediate product III; the intermediate product III is reacted with sodium diethyldithiocarbamate trihydrate to obtain the product;

[0009] The structural formula of the intermediate product III is as follows:

[0010]

[0011] In a preferred embodiment, the molar ratio of the intermediate product III to sodium diethyldithiocarbamate trihydrate is 1:1.2-1.5.

[0012] In a preferred embodiment, the intermediate product III further comprises the following steps before reacting with sodium diethyldithiocarbamate trihydrate:

[0013] Dissolve the intermediate III in acetonitrile; dissolve sodium diethyldithiocarbamate trihydrate in ethanol;

[0014] The usage ratio of the intermediate product III to acetonitrile is 0.332 g: 2-10 mL; the usage ratio of sodium diethyldithiocarbamate trihydrate to ethanol is 0.206 g: 5-15 mL;

[0015] In a preferred embodiment, the reaction temperature of the intermediate product III and sodium diethyldithiocarbamate trihydrate is 20-80° C. and the reaction time is 3-7 hours.

[0016] In a preferred embodiment, the specific preparation process of the intermediate product III is as follows:

[0017] Under inert gas protection conditions, 4-nitroacetophenone is reacted with selenium dioxide and purified to obtain intermediate product I;

[0018] The intermediate product I and 4-aminophenylmethanol were dissolved in N,N-dimethylformamide, and 1-ethyl-

[0019] (3-Dimethylaminopropyl)carbodiimide hydrochloride reacts with N,N-diisopropylethylamine and is purified to obtain intermediate II;

[0020] The intermediate product II was dissolved in anhydrous dichloromethane, placed in an ice bath, and phosphorus tribromide was added under nitrogen protection to react and purify to obtain the intermediate product III;

[0021] The above reaction process is as follows:

[0022]

[0023] In a preferred embodiment, during the preparation of the intermediate product I, the molar ratio of 4-nitroacetophenone to selenium dioxide is 1:1.2-2, the reaction temperature is 90-100° C., and the reaction time is 4-6 h.

[0024] In a preferred embodiment, during the preparation of the intermediate product II, the molar ratio of the intermediate product I, 4-aminophenylmethanol, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N,N-diisopropylethylamine is 1:(1-1.5):(0.1-0.2):(1.2-1.8); the reaction time is 1-3h; and the reaction temperature is 20-40°C.

[0025] In a preferred embodiment, during the preparation of the intermediate product III, the molar ratio of the intermediate product II to phosphorus tribromide is 1:(1.5-1.8), the phosphorus tribromide is added dropwise for 25-30 minutes, the ice bath is for 1-2 hours, and the reaction time is 2-3 hours; wherein, phosphorus tribromide is added dropwise slowly, because phosphorus tribromide is highly active and the reaction is exothermic, so an ice bath is used to avoid excessively high temperature of the reaction system.

[0026] The third aspect of the present invention provides an α-ketoamide hydrogen peroxide responsive drug precursor compound or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug, wherein the α-ketoamide hydrogen peroxide responsive drug precursor compound is the α-ketoamide hydrogen peroxide responsive drug precursor compound provided by the first aspect of the present invention.

[0027] The anti-tumor drug responds to H2O2 and releases diethyldithiocarbamate, and the anti-tumor drug can be a drug for treating cervical cancer.

[0028] In a preferred embodiment, the drug is used for preparing an anti-tumor inhibitor.

[0029] In a preferred embodiment, the inhibitor comprises the α-ketoamide hydrogen peroxide responsive prodrug compound and pharmaceutically acceptable excipients.

[0030] The dosage form of the preparation is selected from injection, lyophilized powder for injection, controlled release injection, liposome injection, suspension, implant, embolic agent, capsule, tablet, pill and oral solution.

[0031] The auxiliary materials include one or more of solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, anti-adhesive agents, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids and release retardants.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] (1) The α-ketoamide hydrogen peroxide-responsive drug precursor compound of the present invention has excellent controllability. In the presence of hydrogen peroxide, the α-ketoamide structure responsively breaks, and after chemical structural dissimilarity and benzyl elimination, diethyldithiocarbamate is released. The released diethyldithiocarbamate is complexed with copper ions to generate the metal drug copper diethyldithiocarbamate (CuET). The generated CuET has a good anti-tumor effect.

[0034] (2) In the synthesis method of the present invention, 4-nitroacetophenone is synthesized by oxidation, condensation, bromination and reaction with sodium diethyldithiocarbamate trihydrate, with a considerable yield, a simple and easy-to-operate preparation process and strong practicality. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 Schematic diagram of the synthesis process of the α-ketoamide hydrogen peroxide responsive precursor compound in Example 1 of the present invention.

[0036] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the intermediate product I in Example 1 of the present invention.

[0037] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the intermediate product III in Example 1 of the present invention.

[0038] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of the α-ketoamide hydrogen peroxide responsive precursor compound in Example 1 of the present invention.

[0039] Figure 5 This is a hydrogen nuclear magnetic resonance spectrum of the α-ketoamide hydrogen peroxide responsive precursor compound after hydrogen peroxide response in Example 1 of the present invention.

[0040] Figure 6 This is a diagram showing the cytotoxicity of the α-ketoamide hydrogen peroxide-responsive precursor compound in Example 1 of the present invention. DETAILED DESCRIPTION

[0041] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0042] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. In the embodiments of the present invention, the materials and equipment used can be purchased on the market unless otherwise specified.

[0043] At present, the precursor compounds that inhibit tumor cells mainly achieve the purpose of inhibiting tumor cells by selectively releasing NO in tumor cells under H2O2. Studies have shown that the concentration of copper ions in solid cancers or tumor cells is at least two orders of magnitude higher than that in normal cells and tissues. The inventors found in their research on the prior art that disulfiram (DSF) is a commonly used drug for alcohol detoxification in clinical practice, and its metabolites coordinate with metal ions, but the mechanism is still unclear. The inventors further studied and showed that DSF can be degraded into diethyldithiocarbamate (DTC) in the body. DTC reacts with Cu 2+ The combination can form a metal complex CuET. The metal complex CuET may have an inhibitory effect on cancer cells. Based on this, the inventors developed a precursor compound that inhibits tumor cells and explored the inhibitory effect and mechanism of the compound on cancer cells.

[0044] The present invention mainly provides a precursor compound that can respond to H2O2 and release DTC. The principle of the present invention is to achieve more precise controlled release of DTC under external stimulation through an α-ketoamide hydrogen peroxide-responsive precursor compound. The released DTC can combine with copper ions in cancer or tumor cells to form CuET, thereby enhancing the therapeutic effect of DTC.

[0045] The α-ketoamide hydrogen peroxide responsive precursor compound of the present invention and its preparation method and application are described in detail below through specific examples.

[0046] Example 1

[0047] An α-ketoamide hydrogen peroxide responsive precursor compound has a structural formula as shown in formula (I):

[0048]

[0049] The preparation method of the above-mentioned α-ketoamide hydrogen peroxide responsive precursor compound is as follows: Figure 1 As shown, the following steps are included:

[0050] S1. Take 1.000g 4-nitroacetophenone and dissolve it in 10mL pyridine, add 1.008g selenium dioxide and mix well, stir and react in an oil bath at 90°C under the protection of nitrogen, and monitor the reaction by thin layer chromatography; after 5h, the reaction is completed, the reaction mixture is filtered, 40mL, 1mM hydrochloric acid solution is added to the filtrate for treatment, separated, and the organic layer is collected; 20mL ethyl acetate is added to the water layer for extraction, repeated three times, the organic layers are combined, 50mL, 1mM sodium hydroxide solution is added, and the water layer is collected. After separation, the water layer is acidified to a pH of about 1.5 with 1mM hydrochloric acid, extracted three times with 50mL ethyl acetate, the organic layers are combined, 5g anhydrous sodium sulfate is added, dried for 2h, filtered, and the liquid phase is used to remove the solvent with a rotary evaporator to obtain a crude product 1, and the crude product 1 is separated by column with petroleum ether: ethyl acetate (v / v) = 1:1 as the mobile phase to obtain 1.009g of light yellow solid, which is the intermediate product I, with a yield of 85.4%. The reaction equation is as follows:

[0051]

[0052] After the intermediate product I was dissolved, the results of hydrogen nuclear magnetic resonance spectroscopy were as follows Figure 2 As shown, its structure is characterized. 1 HNMR (400M Hz, CDCl3), δ (ppm): 8.54 / 8.52 (d, 2H), 8.38 / 8.36 (d, 2H), 4.90 (s, 1H).

[0053] S2, weigh 1.000g of intermediate product I and 0.633g of 4-aminophenylmethanol respectively and dissolve them in 10mL of N,N-dimethylformamide, weigh 0.1475g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) and 1.272mL of N,N-diisopropylethylamine, add them in sequence and mix them evenly, stir the reaction at room temperature, and monitor the reaction progress by thin layer chromatography. After 1.5h of reaction, add 50mL of deionized water, extract three times with 50mL of ethyl acetate, collect and combine the organic phases, add 5g of anhydrous sodium sulfate and dry for 2h, filter, and remove the solvent with a rotary evaporator to obtain 1.462g of yellow solid, which is intermediate product II, with a yield of 95.0%, and directly put it into the next step of reaction. The reaction equation is as follows:

[0054]

[0055] S3, weigh 0.301g of intermediate product II and dissolve it in 10mL of anhydrous dichloromethane under nitrogen protection. After ice bathing for 2h, slowly drip 150μL of phosphorus tribromide in batches, and add it in 30min. Remove the ice bath and warm the reaction system to room temperature, and continue to stir and react for 2h. After the reaction is completed, remove the solvent with a rotary evaporator to obtain a crude product II. The crude product II is further separated and purified by column with petroleum ether: ethyl acetate (v / v) = 9:1 to obtain 0.332g of yellow solid, which is the intermediate product III, with a yield of 91.2%; the reaction equation is as follows:

[0056]

[0057] After the intermediate III was dissolved, the results of hydrogen nuclear magnetic resonance spectroscopy were as follows Figure 3 As shown, its structure is characterized. 1 H NMR (400M Hz, CDCl3), δ (ppm): 8.99 (s, 1H), 8.61 / 8.59 (d, 2H), 8.36 / 8.34 (d, 2H), 7.72 / .70 (d, 2H), 7.46 / 7.44 (d, 2H), 4.60 (s, 2H).

[0058] S4, weigh 0.332g of intermediate product III and 0.206g of sodium diethyldithiocarbamate trihydrate respectively, dissolve in 5mL acetonitrile and 10mL methanol, mix the two solutions, and heat in a 50℃ oil bath for reaction for 5h. After the reaction is completed, add 20mL of ethyl acetate and deionized water for extraction, separate and collect the organic phase, then add 5g of anhydrous sodium sulfate, filter, and use a rotary evaporator to remove the solvent to obtain a crude product III; the crude product III is separated and purified by column using petroleum ether: ethyl acetate (v / v) = 5:1 as the mobile phase to obtain 0.376g of yellow solid, i.e., α-ketoamide hydrogen peroxide response precursor compound, with a yield of 95.2%. The reaction equation is as follows:

[0059]

[0060] After dissolving the α-ketoamide hydrogen peroxide-responsive precursor compound, its structure was characterized, such as Figure 4 As shown, 1 H NMR (400 MHz, DMSO-d 6 ),δ(ppm):11.03(s,1H),

[0061] 8.41 / 8.39(d,2H),8.31 / 8.29(d,2H),7.73 / 7.71(d,2H),7.43 / 7.41(d,2H),4.49(s,2H),3.99 / 3.9 8 / 3.96 / 3.95(m,2H),3.76 / 374 / 3.72 / 3.70(m,2H),1.21 / 1.20 / 1.19 / 1.18 / 1.17 / 1.16 / 1.15(m,6H).

[0062] Example 2

[0063] An α-ketoamide hydrogen peroxide responsive precursor compound has a structural formula as shown in general formula (I):

[0064]

[0065] The method for preparing the above-mentioned α-ketoamide hydrogen peroxide responsive precursor compound comprises the following steps:

[0066] S1. Take 1.000g of 4-nitroacetophenone and dissolve it in 12mL of pyridine, and add 1.100g of selenium dioxide, mix the reactants evenly, stir and react in an oil bath at 100°C under the protection of nitrogen, and monitor the reaction by thin layer chromatography. After 6h, the reaction is completed, the reaction mixture is filtered, 40mL of 1mM hydrochloric acid solution is added to the filtrate for treatment, and the organic layer is separated and collected; 20mL of ethyl acetate is added to the water layer for extraction, and the extraction is repeated three times. Combine the organic layers, add 50mL of 1mM sodium hydroxide solution, and collect the water layer. After separation, the aqueous layer was acidified with 1 mM hydrochloric acid to a pH of about 1.5, extracted three times with 50 mL of ethyl acetate, the organic layers were combined, 5 g of anhydrous sodium sulfate was added and dried for 2 h, filtered, and the liquid phase was subjected to a rotary evaporator to remove the solvent to obtain a crude product 1. The crude product 1 was subjected to column separation with petroleum ether: ethyl acetate (v / v) = 1:1 as the mobile phase to obtain 1.041 g of a light yellow solid, which was the intermediate product I, with a yield of 88.1%. The reaction equation is as follows:

[0067]

[0068] S2, weigh 1.000g of intermediate product I and 0.696g of 4-aminophenylmethanol respectively and dissolve them in 10mL N,N-dimethylformamide, weigh 0.1475g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) and 1.272mL of N,N-diisopropylethylamine, add them in sequence and mix them evenly, stir the reaction at room temperature, and monitor the reaction progress by thin layer chromatography. After 2h of reaction, add 50mL of deionized water to the reaction solution, extract three times with 50mL of ethyl acetate, collect and combine the organic phases, add 5g of anhydrous sodium sulfate and dry for 2h, filter, and remove the solvent with a rotary evaporator to obtain 1.4789g of yellow solid, which is intermediate product II, with a yield of 96.1%, and directly put it into the next step of reaction. The reaction equation is as follows:

[0069]

[0070] S3, weigh 0.301g of intermediate product II and dissolve it in 10mL of anhydrous dichloromethane under nitrogen protection. After ice bathing for 2h, slowly drip 160μL of phosphorus tribromide in batches, and add it in 30min. Remove the ice bath and warm the reaction system to room temperature, and continue to stir and react for 2h. After the reaction is completed, remove the solvent with a rotary evaporator to obtain a crude product II. The crude product II is further separated and purified by column with petroleum ether: ethyl acetate (v / v) = 9:1 to obtain 0.337g of yellow solid, which is the intermediate product III, with a yield of 92.5%; the reaction equation is as follows:

[0071]

[0072] S4, weigh 0.332g of intermediate product III and 0.227g of sodium diethyldithiocarbamate trihydrate respectively, dissolve in 6mL acetonitrile and 12mL methanol, mix the two solutions, and heat in a 45℃ oil bath for 6h. After the reaction is completed, add 20mL of ethyl acetate and deionized water for extraction, separate and collect the organic phase, then add 5g of anhydrous sodium sulfate, filter, and use a rotary evaporator to remove the solvent to obtain crude product three. The crude product three is separated and purified by column using petroleum ether: ethyl acetate (v / v) = 5:1 as the mobile phase to obtain 0.375g of yellow solid, i.e., α-ketoamide hydrogen peroxide response precursor compound, with a yield of 95.0%. The reaction equation is as follows:

[0073]

[0074] In order to further illustrate the hydrogen peroxide responsiveness of the drug precursor compound provided by the present invention, we selected the α-ketoamide hydrogen peroxide responsive precursor compound prepared in Example 1 to conduct the following experiment.

[0075] 1. H2O2 responsiveness

[0076] The responsiveness of the α-ketoamide hydrogen peroxide responsive precursor compound in Example 1 was detected by hydrogen nuclear magnetic resonance spectroscopy.

[0077] Weigh 5 mg of α-ketoamide hydrogen peroxide response precursor compound and dissolve it in 0.5 mL of deuterated dimethyl sulfoxide, then add 50 μL of 30% hydrogen peroxide solution, mix the two thoroughly and place them at room temperature for 2 hours before performing nuclear magnetic resonance hydrogen spectrum test. The results are as follows: Figure 5 As shown. Figure 5 It can be seen from the H NMR spectrum of the α-ketoamide hydrogen peroxide response precursor compound without adding hydrogen peroxide solution, that is, Figure 4 By comparison, Figure 5 Multiple new peaks appeared in the chemical shift region of 7.0 to 9.0, which were caused by the shift of the benzene ring due to the change in chemical structure during the chemical structure isomerization after the precursor compound responded. At the same time, the characteristic peak intensity and integral value of the α-ketoamide hydrogen peroxide response precursor compound originally in this region decreased, proving the hydrogen peroxide responsiveness of the precursor compound.

[0078] 2. Hydrogen peroxide response properties and cytotoxicity of α-ketoamide hydrogen peroxide response precursor compounds

[0079] The cell activity after incubation under different conditions was detected by the MTT method. Weigh 43.1 mg of the drug α-ketoamide peroxide response precursor compound and dissolve it in 1 mL of dimethyl sulfoxide for later use; weigh 17.0 mg of copper chloride and dissolve it in 1 mL of ultrapure water for later use. In the following, the solution prepared with the α-ketoamide peroxide response precursor compound is marked as IV solution; a 50 μM copper chloride solution is added to the solution prepared with the drug α-ketoamide peroxide response precursor compound, marked as Cu-IV. HeLa cells, i.e. human cervical cancer cells, were seeded into 96-well plates, with 2×10 4 The cells were incubated for 24 hours in a 37°C incubator containing 10% fetal bovine serum and 5% CO2. After the HeLa cells were incubated with 100 μM hydrogen peroxide solution for 2 hours, the incubation solution was discarded, the cells were washed with PBS, and then incubated with IV solution and Cu-IV solution for 24 hours, labeled as H2O2-IV and H2O2-Cu-IV; the cells in the control group were not treated with hydrogen peroxide solution, and the cells were directly incubated with IV solution and Cu-IV solution for 24 hours after washing, labeled as IV and Cu-IV.

[0080] After the cells were incubated with the sample, the culture medium was discarded, and the cells were washed twice with PBS buffer at pH 7.4 and 0.01 M, and fresh culture medium containing MTT (100 μL, 0.5 mg / mL) was added to each well and incubated for 4 h under normal culture conditions. The supernatant was discarded, washed with PBS buffer, and then DMSO (100 μL) was added to dissolve the formazan. The ultraviolet absorbance at 490 nm, 560 nm and 720 nm was detected with an ELISA instrument, and the ratio calculation can indirectly reflect the level of viable cell force.

[0081] Table 1 Cell viability data of prodrug compounds

[0082]

[0083] According to the above experimental results, combined with cytotoxicity Figure 6 It can be obtained that, under the same concentration and other conditions, as the concentration of the α-ketoamide hydrogen peroxide response precursor compound increases, the toxicity to the HeLa cells is smaller, and when the concentration of the α-ketoamide hydrogen peroxide response precursor compound is 5 μM, the cell survival rate is higher than 96%; when a concentration of 50 μM copper ions or a concentration of 100 μM hydrogen peroxide is added to the system, the HeLa cell survival rates are higher than 90% and 81% respectively when the concentration of the α-ketoamide hydrogen peroxide response precursor compound is 5 μM, and when a concentration of 50 μM copper ions and a concentration of 100 μM hydrogen peroxide are added to the system at the same time, when the concentration of the α-ketoamide hydrogen peroxide response precursor compound is 0.5 μM, the cell survival rate is only 55%, and when the concentration of the α-ketoamide hydrogen peroxide response precursor compound is 5 μM, the cell survival rate is only 10%. The above results show that the α-ketoamide hydrogen peroxide-responsive precursor compound of the present invention has good cell biocompatibility. When it responds to release DTC molecules under hydrogen peroxide conditions and can effectively bind copper ions, it can produce strong cytotoxicity, kill tumor HeLa cells and inhibit their reproduction and growth.

[0084] The above description is only for the purpose of illustrating the preferred implementation examples of the present invention, and is not intended to limit the scope of the present invention. Any modification, improvement, substitution, etc. made within the principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. An α-ketoamide hydrogen peroxide responsive drug precursor compound, characterized in that: The α-ketoamide hydrogen peroxide responsive drug precursor compound has a structural formula as shown in formula (I):

2. A method for preparing an α-ketoamide hydrogen peroxide responsive drug precursor compound according to claim 1, characterized in that: The following steps are involved: 4-nitroacetophenone and selenium dioxide are subjected to an oxidation reaction, followed by a condensation reaction with 4-aminophenylmethanol, and then brominated with phosphorus tribromide to obtain an intermediate product III; The intermediate product III is synthesized by reacting sodium diethyldithiocarbamate trihydrate; The structural formula of the intermediate product III is as follows:

3. The preparation method according to claim 2, characterized in that: The molar ratio of the intermediate product III to sodium diethyldithiocarbamate trihydrate is 1:1.2-1.

5.

4. The preparation method according to claim 3, characterized in that: The intermediate product III also comprises the following steps before reacting with sodium diethyldithiocarbamate trihydrate: Dissolve the intermediate III in acetonitrile; dissolve sodium diethyldithiocarbamate trihydrate in ethanol; The usage ratio of intermediate product III to acetonitrile is 0.332 g: 2-10 mL; The usage ratio of sodium diethyldithiocarbamate trihydrate to ethanol is 0.206 g:5-15 mL.

5. The preparation method according to claim 3, characterized in that: The temperature for the reaction of the intermediate product III with the sodium diethyldithiocarbamate trihydrate is 20 to 80° C. and the time is 3 to 7 hours.

6. The preparation method according to claim 3, characterized in that: The specific preparation process of the intermediate product III is as follows: Under inert gas protection conditions, 4-nitroacetophenone is reacted with selenium dioxide and purified to obtain intermediate product I; The intermediate product I and 4-aminophenylmethanol are dissolved in N,N-dimethylformamide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N,N-diisopropylethylamine are added to react, and purified to obtain the intermediate product II; The intermediate product II was dissolved in anhydrous dichloromethane, placed in an ice bath, and phosphorus tribromide was added under nitrogen protection to react and purify to obtain the intermediate product III.

7. The preparation method according to claim 6, characterized in that: In the preparation process of the intermediate product I, the molar ratio of 4-nitroacetophenone to selenium dioxide is 1:(1.2-2), the reaction temperature is 90-100° C., and the reaction time is 4-6 hours.

8. The preparation method according to claim 6, characterized in that: In the preparation process of the intermediate product II, the molar ratio of the intermediate product I, 4-aminophenylmethanol, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N,N-diisopropylethylamine is 1:(1-1.5):(0.1-0.2):(1.2-1.8); the reaction time is 1-3h; and the reaction temperature is 20-40°C.

9. The preparation method according to claim 6, characterized in that: During the preparation of the intermediate product III, the molar ratio of the intermediate product II to phosphorus tribromide is 1:(1.5-1.8); The phosphorus tribromide is added for 25 to 30 minutes, the ice bath is for 1 to 2 hours, and the reaction time is for 2 to 3 hours.

10. Use of the α-ketoamide hydrogen peroxide responsive drug precursor compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of an anti-tumor drug, characterized in that: The anti-tumor drug can release diethyldithiocarbamate after reacting with H2O2.

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