Alpha-ketoamide class hydrogen peroxide responsive precursor compounds, methods of making and uses

Abstract

The application provides an alpha-ketone amide peroxide responsive drug precursor compound and a preparation method and application thereof, relates to the field of chemical biotechnology, and the alpha-ketone amide peroxide responsive drug precursor compound in the application is broken under the action of hydrogen peroxide, releases diethyl dithiocarbamate after chemical structure is changed and a benzyl group is eliminated, the released product is combined with copper ions to generate the metal drug copper diethyl dithiocarbamate CuET, and has a remarkable inhibiting growth effect on malignant tumor cells. The prepared drug precursor compound has a simple and easy-to-operate synthesis method, is strong in controllability, and has a wide application prospect in the field of malignant tumor treatment using the responsive drug precursor compound.

Description

TECHNICAL FIELD

[0001] The present application 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

[0002] Cancer is a major disease that seriously threatens human health and continues to be a major problem in the medical field. Due to the poor selectivity of traditional chemotherapeutic drugs on cancer cells, serious toxic side effects are caused. Activation of 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 stress, and the level of reactive oxygen species (ROS) is significantly higher due to insufficient oxygen supply, high energy consumption and lack of defense mechanisms. It has been reported that some tumor cells can rapidly produce hydrogen peroxide (H2O2) up to 5 μM-1.0 mM. Therefore, the development of H2O2-responsive activated prodrug compounds 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 thiazolidine. However, these compounds are not specific to H2O2, resulting in poor targeting of tumor cells, and the inhibitory effect of such compounds on tumor cells is not good. SUMMARY

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

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

[0006]

[0007] The second aspect of the present application provides a preparation method of an alpha-ketoamide hydrogen peroxide responsive prodrug compound, wherein the alpha-ketoamide hydrogen peroxide responsive prodrug compound is the alpha-ketoamide hydrogen peroxide responsive prodrug compound provided in the first aspect of the present application, and the preparation method comprises the following steps:

[0008] After 4-nitroacetophenone is subjected to an oxidation reaction with selenium dioxide, a condensation reaction with 4-aminophenylmethanol is carried out, and then a bromination reaction with phosphorus tribromide is carried out, an intermediate product III is obtained; the intermediate product III is reacted with sodium diethyldithiocarbamate trihydrate to synthesize to obtain a product;

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

[0010]

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

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

[0013] Intermediate product III was dissolved in acetonitrile; sodium diethyldithiocarbamate trihydrate was dissolved in ethanol;

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

[0015] In a preferred embodiment, the intermediate product III reacts with sodium diethyldithiocarbamate trihydrate at a temperature of 20–80°C for a time of 3–7 h.

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

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

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

[0019] (3-Dimethylaminopropyl)carbodiimide hydrochloride was reacted with N,N-diisopropylethylamine, purified, and intermediate product II was obtained.

[0020] Intermediate 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 intermediate III.

[0021] The above reaction process is as follows:

[0022]

[0023] In a preferred embodiment, during the preparation of 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.

[0024] In a preferred embodiment, in the preparation of the intermediate product II, the molar ratio of 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℃.

[0025] In a preferred embodiment, in the preparation of the intermediate product III, the molar ratio of intermediate product II and phosphorus tribromide is 1:(1.5-1.8), the time for dropping phosphorus tribromide is 25-30min, the time for ice bath is 1-2h, and the reaction time is 2-3h; wherein, phosphorus tribromide is slowly added, the purpose of which is that phosphorus tribromide has high activity and the reaction is obviously exothermic, therefore, ice bath is simultaneously used to avoid the temperature of the reaction system being too high.

[0026] The third aspect of the present application provides a use of an alpha-ketoamide peroxide responsive prodrug compound or a pharmaceutically acceptable salt thereof in the preparation of an antitumor drug, wherein the alpha-ketoamide peroxide responsive prodrug compound is the alpha-ketoamide peroxide responsive prodrug compound provided in the first aspect of the present application.

[0027] The antitumor drug is responsive to H2O2 and releases diethyl dithiocarbamate, and the antitumor drug can be a drug for treating cervical cancer.

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

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

[0030] The dosage form of the preparation is selected from injection, injection lyophilized powder, controlled-release injection, liposome injection, suspension, implant, embolism, capsule, tablet, pill and oral liquid.

[0031] The excipient comprises one or more of a solvent, a propellant, a solubilizer, a cosolvent, an emulsifier, a coloring agent, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, a stabilizer, a glidant, a flavoring agent, a preservative, a suspending agent, a coating material, an antiadhesive, a penetration enhancer, a pH regulator, a buffer, a plasticizer, a surfactant, a foaming agent, an antifoaming agent, a thickening agent, an inclusion agent, a humectant, an absorbent, a diluent, a flocculating agent and a deflocculating agent, a filter aid and a release retardant.

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

[0033] (1) The alpha-ketone amide peroxide response prodrug compound in the application has excellent controllability. In the presence of hydrogen peroxide, the alpha-ketone amide structure is broken in response, and after chemical structure isomerization and benzyl elimination, diethyl dithiocarbamate is released. The released diethyl dithiocarbamate is complexed with copper ions to form the metal drug copper diethyl dithiocarbamate (CuET), and the generated CuET has good antitumor effect.

[0034] (2) In the synthesis method of the application, the 4-nitroacetophenone is oxidized, condensed, brominated, and reacted with sodium diethyl dithiocarbamate trihydrate to synthesize the obtained product, which has considerable yield, simple and easy-to-operate preparation process, and strong practicability. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 It is a synthesis process schematic diagram of the alpha-ketone amide peroxide response prodrug compound in Example 1 of the application.

[0036] Figure 2 It is a nuclear magnetic resonance hydrogen spectrum diagram of the intermediate product I in Example 1 of the application.

[0037] Figure 3 It is a nuclear magnetic resonance hydrogen spectrum diagram of the intermediate product III in Example 1 of the application.

[0038] Figure 4 It is a nuclear magnetic resonance hydrogen spectrum diagram of the alpha-ketone amide peroxide response prodrug compound in Example 1 of the application.

[0039] Figure 5 It is a nuclear magnetic resonance hydrogen spectrum diagram of the alpha-ketone amide peroxide response prodrug compound in Example 1 of the application after hydrogen peroxide response.

[0040] Figure 6 It is a cytotoxicity diagram of the alpha-ketone amide peroxide response prodrug compound in Example 1 of the application. DETAILED DESCRIPTION

[0041] In order to make the purpose, technical scheme and advantages of the application clearer and more apparent, the application will be further described in detail below in combination with examples. It should be understood that the specific examples described herein are only used to explain the application and not to limit the application.

[0042] Based on the examples in the application, all other examples obtained by those skilled in the art without creative labor are within the scope of protection of the application. In the examples of the application, the materials and equipment used, if not specifically stated, can be obtained on the market.

[0043] The current precursor compound for inhibiting tumor cells is mainly to release NO in tumor cells selectively under H2O2, so as to achieve the purpose of inhibiting tumor cells. Studies have shown that the concentration of copper ions in solid cancer or tumor cells is at least two orders of magnitude higher than that in normal cells and tissues. The inventors found in the prior art research that disulfiram (DSF) is a commonly used drug for alcohol detoxification in clinical practice, and its metabolite can be coordinated with metal ions, but the mechanism is not clear. Further research by the inventors shows that DSF can be degraded into diethyl dithiocarbamate (DTC) in vivo, and DTC can be combined with Cu 2+ and form a metal complex CuET. The metal complex CuET can inhibit cancer cells, based on which the inventors develop a precursor compound for inhibiting tumor cells and explore the inhibitory effect of the compound on cancer cells and the mechanism of action.

[0044] The present application mainly provides a precursor compound capable of responding to H2O2 and releasing DTC. The principle of the present application is to achieve more precise control of releasing DTC under external stimulation by using the alpha-ketoamide hydrogen peroxide-responsive precursor compound. The released DTC can be combined with copper ions in cancer or tumor cells to form CuET, thereby enhancing the therapeutic effect of DTC.

[0045] The alpha-ketoamide hydrogen peroxide-responsive precursor compound, its preparation method and application will be specifically described below through specific examples.

[0046] Example 1

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

[0048]

[0049] The preparation method of the above alpha-ketoamide hydrogen peroxide-responsive precursor compound is shown in formula (II) and includes the following steps: Figure 1

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

[0051]

[0052] After the intermediate product I was dissolved, its structure was characterized by nuclear magnetic resonance hydrogen spectrum, and the results are shown in Figure 2 1 HNMR (400 MHz, CDC13), δ (ppm): 8.54 / 8.52 (d, 2H), 8.38 / 8.36 (d, 2H), 4.90 (s, 1H).

[0053] S2, 1.000 g of intermediate product I and 0.633 g of 4-aminophenylmethanol were weighed into 10 mL of N,N-dimethylformamide, respectively, 0.1475 g of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCl) and 1.272 mL of N,N-diisopropyl ethylamine were added and mixed uniformly, and the reaction was stirred at room temperature, and the progress of the reaction was monitored by thin layer chromatography. After 1.5 h, the reaction was completed, 50 mL of deionized water was added, and 50 mL of ethyl acetate was extracted three times, the combined organic phase was collected, 5 g of anhydrous sodium sulfate was added and dried for 2 h, filtered, and the solvent was removed by a rotary evaporator to obtain 1.462 g of yellow solid, which was intermediate product II, with a yield of 95.0%, which was directly used in the next step reaction, and the reaction equation is as follows:

[0054]

[0055] ​S3, 0.301 g of the intermediate product II was weighed and dissolved in 10 mL of anhydrous dichloromethane under nitrogen protection. After ice-bath for 2 h, 150 μL of phosphorus tribromide was added dropwise in batches. After 30 min, the ice-bath was removed and the reaction system was warmed to room temperature. The stirring reaction was continued for 2 h. After the reaction was completed, the solvent was removed by rotary evaporation to obtain the crude product II. The crude product II was further column separated and purified with petroleum ether: ethyl acetate (v / v) = 9: 1 to obtain 0.332 g of yellow solid, which was the intermediate product III, with a yield of 91.2%. The reaction equation is as follows:

[0056]

[0057] After the intermediate product III was dissolved, its structure was characterized by nuclear magnetic resonance hydrogen spectrum, as shown in Figure 3 1 H NMR (400 MHz, CDCl3), δ (ppm): 8.99 (s, 1H), 8.61 / 8.59 (d, 2H), 8.36 / 8.34 (d, 2H), 7.72 / 7.70 (d, 2H), 7.46 / 7.44 (d, 2H), 4.60 (s, 2H).

[0058] S4, 0.332 g of the intermediate product III and 0.206 g of sodium diethyldithiocarbamate trihydrate were weighed and dissolved in 5 mL of acetonitrile and 10 mL of methanol, respectively. Then the two solutions were mixed and heated in a 50°C oil bath for 5 h. After the reaction was completed, 20 mL of ethyl acetate and deionized water were added for extraction. The organic phase was collected and then 5 g of anhydrous sodium sulfate was added. After filtration, the solvent was removed by rotary evaporation to obtain the crude product III. The crude product III was column separated and purified with petroleum ether: ethyl acetate (v / v) = 5: 1 as the mobile phase to obtain 0.376 g of yellow solid, which was the α-ketoamide peroxide response precursor compound, with a yield of 95.2%. The reaction equation is as follows:

[0059]

[0060] After the α-ketoamide peroxide response precursor compound was dissolved, its structure was characterized, as shown in Figure 4 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 / 3.98 / 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 alpha-ketoamide hydrogen peroxide-responsive precursor compound has a structural formula as shown in general formula (I):

[0064]

[0065] A preparation method of the alpha-ketoamide hydrogen peroxide-responsive precursor compound comprises the following steps:

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

[0067]

[0068] S2, 1.000 g of intermediate product I and 0.696 g of 4-aminophenylmethanol were weighed into 10 mL of N,N-dimethylformamide, respectively, then 0.1475 g of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1.272 mL of N,N-diisopropylethylamine were added in sequence and mixed uniformly, and the reaction was stirred at room temperature, and the progress of the reaction was monitored by thin layer chromatography. After 2 h, 50 mL of deionized water was added to the reaction solution, and 50 mL of ethyl acetate was used to extract three times, and the organic phase was collected and dried with 5 g of anhydrous sodium sulfate for 2 h, and then filtered, and the solvent was removed by a rotary evaporator to obtain 1.4789 g of yellow solid, which was intermediate product II, with a yield of 96.1%, which was directly used in the next step reaction, and the reaction equation was as follows:

[0069]

[0070] S3, 0.301 g of intermediate product II was weighed into 10 mL of anhydrous dichloromethane under nitrogen protection, and after ice bath for 2 h, 160 μL of phosphorus tribromide was slowly added in batches and dropwise, and 30 min was added. After removing the ice bath, the reaction system was warmed to room temperature, and the reaction was continued for 2 h. After the reaction was completed, the solvent was removed by a rotary evaporator to obtain a crude product two, and the crude product two was further column-separated and purified with petroleum ether: ethyl acetate (v / v) = 9:1 to obtain 0.337 g of yellow solid, which was intermediate product III, with a yield of 92.5%; and the reaction equation was as follows:

[0071]

[0072] S4, 0.332 g of intermediate product III and 0.227 g of sodium diethyldithiocarbamate trihydrate were weighed into 6 mL of acetonitrile and 12 mL of methanol, respectively, and then the two solutions were mixed and heated in a 45°C oil bath for 6 h. After the reaction was completed, 20 mL of ethyl acetate and deionized water were added for extraction, and the organic phase was separated and collected, and then 5 g of anhydrous sodium sulfate was added, filtered, and the solvent was removed by a rotary evaporator to obtain a crude product three. The crude product three was column-separated and purified with petroleum ether: ethyl acetate (v / v) = 5:1 as the mobile phase to obtain 0.375 g of yellow solid, which was an α-ketoamide peroxide response precursor compound, with a yield of 95.0%. The reaction equation was as follows:

[0073]

[0074] In order to further illustrate the hydrogen peroxide response performance of the prodrug compound provided by the present application, the α-ketoamide peroxide response precursor compound prepared in Example 1 was used for the following experiments.

[0075] 1. H2O2 response

[0076] The α-ketoamide peroxide-responsive precursor compound in Example 1 was subjected to responsive detection by nuclear magnetic resonance hydrogen spectrum.

[0077] After 5 mg of the α-ketoamide peroxide-responsive precursor compound was dissolved in 0.5 mL of deuterated dimethyl sulfoxide, 50 μL of 30% hydrogen peroxide solution was added thereto, and the mixture was subjected to nuclear magnetic resonance hydrogen spectrum test after being mixed thoroughly and left at room temperature for 2 h. The results are shown in Figure 5 As can be seen from Figure 5 , compared with the nuclear magnetic resonance hydrogen spectrum of the α-ketoamide peroxide-responsive precursor compound without addition of hydrogen peroxide solution, i.e. Figure 4 , it can be seen that Figure 5 , in the chemical shift region of 7.0-9.0, a plurality of peaks appeared, which were the shifts of the benzene ring due to the chemical structure change in the isomerization of the precursor compound after response. At the same time, the intensity and integral value of the characteristic peaks of the α-ketoamide peroxide-responsive precursor compound in this region were decreased, which proved the hydrogen peroxide responsiveness of the precursor compound.

[0078] 2. Hydrogen peroxide response performance of the α-ketoamide peroxide-responsive precursor compound and cytotoxicity generated thereby

[0079] The cell activity after incubation under different conditions was detected by thiazolyl blue (MTT) method. 43.1 mg of the drug α-ketoamide peroxide-responsive precursor compound was dissolved in 1 mL of dimethyl sulfoxide for standby; 17.0 mg of copper chloride was dissolved in 1 mL of ultrapure water for standby. The solution of the α-ketoamide peroxide-responsive precursor compound prepared in the following was marked as IV solution; the solution of the drug α-ketoamide peroxide-responsive precursor compound was added with copper chloride solution with a concentration of 50 μM, which was marked as Cu-IV. HeLa cells, i.e. human cervical cancer cells, were inoculated into 96-well plates at 2 x 10 4 cells per well, and were incubated in a 37°C incubator containing 10% fetal bovine serum by volume fraction and 5% CO2 for 24 h. After the HeLa cells were incubated with 100 μM hydrogen peroxide solution for 2 h, the incubation solution was discarded, and the cells were washed with PBS, and then were incubated with the IV solution and the Cu-IV solution for 24 h, which were marked as H2O2-IV and H2O2-Cu-IV; the cells in the control group were not treated with hydrogen peroxide solution, and after washing, the cells were directly incubated with the IV solution and the Cu-IV solution for 24 h, which were marked as IV and Cu-IV.

[0080] After the cells are incubated with the sample, the culture medium is discarded, and the cells are washed twice with PBS buffer having a pH of 7.4 and a concentration of 0.01 M. Fresh culture medium containing MTT (100 μL, 0.5 mg / mL) is added to each well, and the cells are incubated under normal culture conditions for 4 h. The supernatant is discarded, the cells are washed with PBS buffer, and DMSO (100 μL) is added to dissolve the formazan. The ultraviolet absorbance of the formazan at 490 nm, 560 nm, and 720 nm is detected using a microplate reader, and the level of viable cells is indirectly reflected by the ratio.

[0081] Table 1 Cell survival rate data of the prodrug compounds

[0082]

[0083] According to the above experimental results, the cytotoxicity of the α-ketoamide peroxide-responsive prodrug compounds is determined according to the following method. Figure 6 It can be seen that, under the same conditions, the cytotoxicity of the α-ketoamide peroxide-responsive prodrug compounds to HeLa cells is small, and the cell survival rate is higher than 96% when the concentration of the α-ketoamide peroxide-responsive prodrug compound is 5 μM. When the concentration of copper ions is 50 μM or the concentration of hydrogen peroxide is 100 μM, the cell survival rate of HeLa cells is higher than 90% and 81%, respectively, when the concentration of the α-ketoamide peroxide-responsive prodrug compound is 5 μM. However, when the concentration of copper ions is 50 μM and the concentration of hydrogen peroxide is 100 μM, the cell survival rate is only 55% when the concentration of the α-ketoamide peroxide-responsive prodrug compound is 0.5 μM, and the cell survival rate is only 10% when the concentration of the α-ketoamide peroxide-responsive prodrug compound is 5 μM. The above results show that the α-ketoamide peroxide-responsive prodrug compound has good cell biocompatibility. When the α-ketoamide peroxide-responsive prodrug compound is released under the action of hydrogen peroxide and effectively binds copper ions, strong cytotoxicity is generated, and the growth of HeLa cells is inhibited.

[0084] The above description is only a preferred embodiment of the present application and is not intended to limit the scope of the present application. Any modification, improvement, replacement, etc. made within the principles of the present application should be included in the protection scope of the present application.

Claims

1. An α-ketoamide hydrogen peroxide-responsive drug prodrug compound, characterized in that, The alpha-ketone amide peroxide response prodrug compound has a structural formula as shown in formula (I): 。 2. A method of preparing an α-ketoamide-based hydrogen peroxide responsive prodrug compound according to claim 1, characterized by, The method comprises the following steps: After 4-nitroacetophenone is oxidized by selenium dioxide, condensation reaction is carried out with 4-aminophenylmethanol, and then bromination is carried out by phosphorus tribromide to obtain an intermediate product III; The intermediate product III is reacted with sodium diethyldithiocarbamate trihydrate to obtain the alpha-ketone amide peroxide response prodrug compound. 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 production method according to claim 3, characterized by, Before the intermediate product III is reacted with sodium diethyldithiocarbamate trihydrate, the following steps are further included: The intermediate product III is dissolved in acetonitrile, and sodium diethyldithiocarbamate trihydrate is dissolved in ethanol; The dosage ratio of the intermediate product III to acetonitrile is 0.332 g: 2-10 mL; The dosage 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 reaction temperature of the intermediate product III with sodium diethyldithiocarbamate trihydrate is 20-80 ℃, and the reaction time is 3-7 h.

6. The preparation method according to claim 3, characterized in that, The specific preparation process of the intermediate product III is as follows: Under the condition of inert gas protection, 4-nitroacetophenone is reacted with selenium dioxide, and purification is carried out to obtain an 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-diisopropyl ethylamine are added for reaction, and purification is carried out to obtain an intermediate product II; The intermediate product II is dissolved in anhydrous dichloromethane, ice bath, and phosphorus tribromide is added under nitrogen protection for reaction, and purification is carried out 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 ℃, and the reaction time is 4-6 h.

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-diisopropyl ethylamine is 1:(1-1.5):(0.1-0.2):(1.2-1.8), the reaction time is 1-3 h, and the reaction temperature is 20-40 ℃.

9. The preparation method according to claim 6, characterized in that, In the preparation process of the intermediate product III, the molar ratio of the intermediate product II to phosphorus tribromide is 1:(1.5-1.8). The addition time of the phosphorus tribromide is 25-30 min, the ice bath time is 1-2 h, and the reaction time is 2-3 h.

10. Use of the α-ketoamide-based hydrogen peroxide responsive prodrug compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor medicament, characterized in that, The antitumor drug and H2O2 can release diethyldithiocarbamate after response.

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