Targeted tyrosinase degradation compound as well as preparation method and application thereof

Abstract

The invention discloses a compound for targeted degradation of tyrosinase and a preparation method and application thereof.The structure of the compound for targeted degradation of tyrosinase is shown in the formula I. As a tyrosinase degradation agent, the compound can significantly degrade tyrosinase and efficiently delay browning of agaricus bisporus at a low dosage, the preparation method is simple, convenient and efficient, the reaction is mild, and the compound is suitable for industrial production. The method is suitable for large-scale production; the preservative is applied to the technical field of fungus preservation, is high in safety and environment-friendly, and has a great application prospect.

Description

Technical Field

[0001] The invention relates to a compound for targeted degradation of tyrosinase, and also relates to a preparation method and application of the compound. Background Art

[0002] In the field of fresh-keeping technology, Agaricus bisporus is very easy to brown during storage and transportation due to its water content of up to 85%-95%. In particular, freshly picked Agaricus bisporus, which is rich in water, has soft tissue, white color, and no protective tissue on the surface. It is very easy to brown due to dehydration, bumps, etc. during storage and transportation. The storage and fresh-keeping period at room temperature (20-30°C) is only 1-2 days. At present, the storage and transportation conditions of Agaricus bisporus are generally refrigerated (0-4°C). Even under refrigerated conditions, the storage and transportation time exceeds one week and there will be different degrees of dehydration and browning. Moreover, it is inevitable that there will be browning of Agaricus bisporus caused by bumps. Therefore, there is currently no effective method to prevent the browning problem during the storage and transportation of Agaricus bisporus, and it is still urgent to find a simple and effective method to prevent browning.

[0003] Enzymatic browning is the process of phenolic substances in food forming quinones under the catalysis of tyrosinase. The generated quinone compounds will further undergo oxidation reactions and eventually polymerize to form melanin, which leads to the occurrence of food browning. Tyrosinase is the initial enzyme and key enzyme in the process of melanin production in organisms. As an emerging technology for targeted protein degradation, hydrophobic tag technology is constantly developing in the field of biomedicine, and its application to fruits and vegetables has broad prospects. The hydrophobic tag contains a target protein ligand and a hydrophobic part for inducing degradation. The hydrophobic tag is connected to the ligand of the target protein through a linker, simulating endogenous protein misfolding and triggering degradation through the proteasome pathway. Therefore, it is urgent to design a type of hydrophobic tag for targeted degradation of tyrosinase to delay the browning of Agaricus bisporus. Summary of the invention

[0004] Purpose of the invention: The purpose of the present invention is to provide a highly efficient compound for targeted degradation of tyrosinase, and also relates to a method for preparing the above compound and its application as a tyrosinase degrading agent in the field of fungus preservation technology.

[0005] Technical solution: The present invention discloses a compound for targeted degradation of tyrosinase, the structure of which is shown in formula (I):

[0006]

[0007] Wherein, Linker is an alkoxy group having 0 to 6 carbon atoms;

[0008] R is

[0009] Among them, the Linker is

[0010] Wherein, the compound is any of the following:

[0011]

[0012] The preparation of the above compound, when the linker is an alkoxy group with a carbon number of 0, is as follows: kojic acid, reaction material A, and 4-dimethylaminopyridine (DMAP) are dissolved in DMF and ice-bathed to 0°C; 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT) are added and reacted in an ice bath for 1 hour, and then reacted at room temperature overnight to obtain the compound of the present invention that targets the degradation of tyrosinase.

[0013] Wherein, the reaction material A is 9-fluoreneacetic acid or 1-adamantaneacetic acid, the molar ratio of kojic acid: reaction material A: EDC: HOBT is 1.2:1:1:1, and the DMAP quantification is 0.05 g; EDC and HOBT are added to react in an ice bath for 1 to 2 hours and then react at room temperature overnight.

[0014] The preparation of the above compound, when the linker is an alkoxy group with a carbon number of 2-6, comprises the following steps:

[0015] (1) Add reaction material B to DCM, stir at room temperature until dissolved, add 4-methylbenzene-1-sulfonyl chloride, DMAP and triethylamine in sequence, and react at room temperature for 12 h to obtain product 1;

[0016] (2) Kojic acid, product 1, and Cs2CO3 were dissolved in DMF and heated to 60°C in an oil bath. The reaction was complete after TLC iodine fumigation detection. The reaction was stopped, water was added, EA was extracted, the product was washed with saturated brine, and the product 2 was obtained by vacuum concentration.

[0017] (3) Product 2 was dissolved in 4M HCl in dioxane and reacted at room temperature for 30 min. After TLC detection, the reaction was stopped and concentrated in vacuo. EA was added and stirred until completely dissolved. The product was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain product 3.

[0018] (4) The product 3, reaction material A and N,N-diisopropylethylamine (DIPEA) are dissolved in DMF, cooled to 0°C in an ice bath, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) is added, reacted at room temperature, water is added, EA is extracted, washed with saturated brine, concentrated in vacuo, and subjected to silica gel column chromatography to obtain the compound of the present invention that targets the degradation of tyrosinase.

[0019] Wherein, in step (1), the reaction material B is N-Boc-ethanolamine or 2-(2-Boc-aminoethoxy)ethanol or (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamic acid tert-butyl ester, and the molar ratio of reaction material B: 4-methylbenzene-1-sulfonyl chloride: DMAP: triethylamine is 1:2:0.4:2.5; in step (2), the molar ratio of kojic acid: (1) product: Cs2CO3 is 1:1.2:2, and the reaction temperature is 50-70°C; in step (3), the molar amount of 4M HCl in dioxane is 4 times or more of the product of (2); in step (4), the molar ratio of (3) product: reaction material A: DIPEA: HATU is 1:1.2:4:1.2.

[0020] The above-mentioned compound targeting the degradation of tyrosinase can also be used in tyrosinase degrading agents.

[0021] The compound is used as a tyrosinase degradation agent in the field of fungus preservation technology.

[0022] Wherein, the fungus is Agaricus bisporus.

[0023] Principle of the invention: The compound of the present invention that targets the degradation of tyrosinase is connected to the tyrosinase inhibitor kojic acid at one end and the hydrophobic tag R shown in the figure at the other end. The fatty side chain of the hydrophobic polypeptide of tyrosinase is buried inside the globular protein, while the hydrophilic amino acid residues are located on the surface. Even a small increase in surface hydrophobicity can make the protein unstable. Therefore, mimicking the misfolded state of the protein is the first step in degrading the protein. The present invention combines the hydrophobic tag with the target protein tyrosinase, and appears on the protein surface in the form of a hydrophobic patch, mimicking the partially unfolded protein state, and then the target protein is ubiquitinated to degrade the target protein, and the compound is not degraded. After the target protein is degraded, the compound is released and continues to bind to the target protein for recycling. Among them, the kojic acid group is a natural inhibitor of tyrosinase, which can specifically bind to the active site of tyrosinase and fix the compound on the enzyme surface. The hydrophobic tag R is a strong hydrophobic group, which plays a role in mimicking protein misfolding.

[0024] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The compound of the present invention that targets the degradation of tyrosinase is used in a tyrosinase degrader, and can significantly degrade tyrosinase at a low dose. Compared with inhibitors, the dosage is reduced by 70%, and the browning of Agaricus bisporus is effectively delayed, and the shelf life is effectively extended by 5-8 days; (2) The preparation method of the compound of the present invention is simple and efficient, and the reaction is mild, which is suitable for large-scale production. The reaction has no unlimited speed steps, the yield is high, there is no high temperature and high pressure reaction, and no easily made drug or explosive reagents are involved, which is green and environmentally friendly; (3) The compound of the present invention is used in the field of fungus preservation technology. The compound only targets Agaricus bisporus tyrosinase, which is safe and reliable. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the general structural formula of the compound of the present invention;

[0026] Figure 2 is a graph showing the results of an activity test of the compound of the present invention as a tyrosinase degrading agent;

[0027] Figure 3 is a graph showing the effect of the compound of the present invention as a tyrosinase degrading agent on the L* value of Agaricus bisporus;

[0028] Figure 4 This is a graph showing the effect of the compound of the present invention as a tyrosinase degrading agent on the browning degree of Agaricus bisporus. DETAILED DESCRIPTION

[0029] The technical scheme of the present invention is further described below in conjunction with the examples. The test materials used in the examples can all be purchased through conventional channels.

[0030] Example 1

[0031] The synthesis of the compound Jin-OC-qusuan of the present invention has the structural formula:

[0032]

[0033] Synthesis route:

[0034]

[0035] 5-Hydroxy-2-hydroxymethyl-4-pyrone (1.0 g, 7.04 mmol), 1-adamantaneacetic acid (1.14 g, 5.87 mmol) and 4-dimethylaminopyridine (DMAP, 0.05 g, 0.41 mmol) were dissolved in 50 mL of DMF, cooled to 0°C in an ice bath, 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC, 1.09 g, 7.04 mmol) and 1-hydroxybenzotriazole (HOBT, 0.95 g, 7.04 mmol) were added, reacted at 0°C for 1 h, and then reacted at room temperature overnight. When the reaction was complete, the reaction was stopped, water was added, EA was extracted, saturated NaCl was washed, anhydrous NaSO4 was added for drying, vacuum concentration was performed, and silica gel column chromatography was performed to obtain the final product of 1.46 g of white solid. 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),6.42(s,1H),4.35(s,2H),2.26(s,2H),1.94(s,3H),1.70-1.59(m,12H).

[0036] Example 2

[0037] The synthesis of the compound Jin-2C-qusuan of the present invention has the structural formula:

[0038]

[0039] Synthesis route:

[0040]

[0041] Step 1:

[0042] N-Boc-ethanolamine (2.0 g, 12.41 mmol) was added to 100 mL of DCM, stirred at room temperature until dissolved, and 4-methylbenzene-1-sulfonyl chloride (4.72 g, 24.82 mol), DMAP (0.61 g, 4.96 mmol) and triethylamine (4.3 mL, 31.02 mol) were added in sequence. The mixture was reacted at room temperature for 12 h. TLC detection (V petroleum ether: V ethyl acetate = 2:1) showed that the reaction was complete. The reaction was stopped, vacuum concentrated, and silica gel column chromatography (V petroleum ether: V ethyl acetate = 10:1→5:1) was performed to obtain 3.25 g of an oily substance, which was product 1.

[0043] Step 2:

[0044] Weigh kojic acid (1.0 g, 7.04 mmol), step product 1 (2.66 g, 8.45 mmol), and Cs2CO3 (3.04 g, 14.08 mmol) and dissolve them in 60 mL DMF. Heat the mixture in an oil bath to 60°C. TLC iodine fumigation detection (V petroleum ether: V ethyl acetate = 2:1) indicates that the reaction is complete. Stop the reaction, add water, extract with EA, wash with saturated brine, and concentrate in vacuo to obtain 1.88 g of an oily substance, which is product 2, which is directly used for the next step.

[0045] Step 3:

[0046] The product 2 (1.88 g, 6.59 mmol) was weighed and dissolved in 20 mL of 4 M HCl in dioxane. The reaction was allowed to proceed at room temperature for 30 min. TLC detection (V petroleum ether: V ethyl acetate = 1:1) showed that the reaction was complete. The reaction was stopped and concentrated in vacuo. EA was added and stirred until completely dissolved. The product was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 1.42 g of solid, which was the product 3, and the next step of reaction was carried out directly.

[0047] Step 4:

[0048] The product 3 (1.42 g, 6.43 mmol), 1-adamantaneacetic acid (1.50 g, 7.72 mmol) and DIPEA (3.32 g, 4.03 mmol) were dissolved in 50 mL of DMF, cooled to 0°C in an ice bath, HATU (2.93 g, 7.72 mmol) was added, and the reaction was carried out at room temperature. TLC detection (V petroleum ether: V ethyl acetate = 1:3) showed that the reaction was complete, the reaction was stopped, water was added, EA was extracted, the mixture was washed with saturated brine, concentrated in vacuo, and chromatographed on a silica gel column (V petroleum ether: V ethyl acetate = 1:1) to obtain a total product 2C of 1.82 g of a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.97(t,J=5.6Hz,1H),6.30(s,1H),5.71(t,J=6.1Hz,1H),4.29(d,J=6.1Hz,2H),3.83(t,J =5.5Hz,2H),3.40(s,2H),3.34(t,J=5.6Hz,2H),1.86(t,J=3.3Hz,3H),1.83(s,2H),1.61(d,J=12.2Hz,3H),1.57-1.48(m,9H).

[0049] Example 3

[0050] The synthesis of the compound Jin-4C-qusuan of the present invention has the structural formula:

[0051]

[0052] Synthesis route:

[0053]

[0054] Referring to the synthesis method of Example 2, the linker was replaced with 2-(2-Boc-aminoethoxy)ethanol, and other conditions remained unchanged to obtain 1.49 g of a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.65(s,1H),6.49(s,1H),5.28(s,1H),4.45(d,J=5.2Hz,2H),4.03-3.97(m,2H),3.80-3.73(m ,2H),3.57(t,J=5.1Hz,2H),3.39(q,J=5.3Hz,2H),1.92(s,2H),1.90(s,3H),1.64(d,J=12.1Hz,3H),1.57(d,J=7.4Hz,9H).

[0055] Example 4

[0056] The synthesis of the compound Jin-6C-qusuan of the present invention has the structural formula:

[0057]

[0058] Synthesis route:

[0059]

[0060] Referring to the synthesis method of Example 2, the reaction material B was replaced with tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate, and other conditions remained unchanged. 1.57 g of white solid was obtained. 1 H NMR(400MHz, DMSO-d6)δ8.10(s,2H),7.85(d,J=7.4Hz,2H),7.52(d,J=7.4Hz,2H),7.35(t,J=7.4Hz,2H),7.31-7.25(m,2H),6.29(s,1H),4.34 (t,J=7.6Hz,1H),4.27(s,2H),3.95(dd,J=5.7,3.4Hz,2H),3.75-3.69(m,2H),3.54(t,J=5.7Hz,2H),3.35(q,J=5.7Hz,9H),2.54-2.47(m,4H).

[0061] Example 5

[0062] The synthesis of the compound Wu-OC-qusuan of the present invention has the structural formula:

[0063]

[0064] Synthesis route:

[0065]

[0066] 5-Hydroxy-2-hydroxymethyl-4-pyrone (760mg, 5.35mmol), 9-fluoreneacetic acid (1000mg, 4.46mmol), 4-dimethylaminopyridine (DMAP, 0.05g, 0.41mmol) were dissolved in 5ml of anhydrous DMF, cooled to 0℃ in an ice bath, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC, 855mg4.46mmol) and 1-hydroxybenzotriazole (HOBT, 602.5mg, 4.46mmol) were added to react at 0℃ for 1h, and then reacted at room temperature overnight. After the reaction was completed by TLC detection, the reaction solution was poured into water, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column to obtain 1.09g of white powder Wu-0C-qusuan. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.88 (d, J = 7.4 Hz, 2H), 7.75 (d, J = 7.4 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.34 (td, J = 7.5, 1.2 Hz, 2H), 6.52 (s, 1H), 5.83 (t, J = 6.1 Hz, 1H), 4.39 (s, 2H), 3.10 (d, J = 7.0 Hz, 2H). Example 6

[0067] The synthesis of the compound Wu-2C-qusuan of the present invention has the structural formula:

[0068]

[0069] Synthesis route:

[0070]

[0071] Step 1:

[0072] Add N-Boc-ethanolamine (1 g, 6.205 mmol) to 50 ml of DCM, stir at room temperature to dissolve, add p-methylbenzoyl chloride (2.36 g, 12.41 mmol), 4-dimethylaminopyridine (DMAP, 0.305 g, 2.48 mmol) and triethylamine (2.15 ml, 15.501 mmol) in sequence, react at room temperature for 12 h, stop the reaction after the reaction is complete as monitored by TLC, concentrate in vacuo, and obtain 1.21 g of white solid (compound Wu-2C-qusuan-1) by silica gel column chromatography.

[0073] Step 2:

[0074] Compound Wu-2C-qusuan-1 (1 g, 3.17 mmol), 5-hydroxy-2-hydroxymethyl-4-pyrone (0.376 g, 2.65 mmol), and Cs2CO3 (1.143 g, 3.5 mmol) were dissolved in anhydrous DMF and heated to 60°C in an oil bath. The reaction was monitored by TLC iodine evaporation. When the reaction was complete, the reaction was stopped and the reaction solution was poured into water. Ethyl acetate was added for extraction, the mixture was washed with saturated brine, and the mixture was concentrated under reduced pressure. 0.69 g of colorless oil (compound Wu-2C-qusuan-2) was obtained by silica gel column chromatography.

[0075] Step 3:

[0076] Compound Wu-2C-qusuan-2 (0.5 g, 1.75 mmol) was dissolved in 5 mL 4 M HCl in dioxane and reacted at room temperature for 30 min. After TLC detection, the reaction was complete. The reaction was stopped and vacuum filtered to obtain 0.36 g of filter cake (compound Wu-2C-qusuan-3).

[0077] Step 4:

[0078] Compound Wu-2C-qusuan-3 (0.3 g, 1.36 mmol), 9-fluoreneacetic acid (0.365 g, 1.632 mmol) and N,N-diisopropylethylamine (DIPEA, 0.122 mg, 0.857 mmol) were dissolved in 10 mL of DMF, cooled to 0°C in an ice bath, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.681 g, 1.632 mmol) was added, and the reaction was allowed to proceed at room temperature. The reaction was completed when detected by TLC, and the reaction was stopped. Water was added, the product was extracted with ethyl acetate, washed with saturated brine, concentrated in vacuo, and purified by silica gel column chromatography to obtain 0.27 g of the total product Wu-2C-qusuan as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.35(t,J=5.6Hz,1H),8.20(s,1H),7.85(d,J=7.5Hz,2H),7.53(d,J=7.5Hz,2H),7.36(t,J=7.4Hz,2H),7.25( t,J=7.5Hz,2H),6.34(s,1H),4.37(t,J=7.7Hz,1H),3.95(t,J=5.3Hz,2H),3.53(q,J=5.4Hz,2H),3.39(s,3H),2.55(d,J=7.7Hz,2H).

[0079] Example 7

[0080] The synthesis of the compound Wu-4C-qusuan of the present invention has the structural formula:

[0081]

[0082] Synthesis route:

[0083]

[0084]

[0085] Referring to the synthesis method of Example 2, the reaction material B was replaced with 2-(2-Boc-aminoethoxy)ethanol, and other conditions remained unchanged to obtain 1.31 g of white solid. 1H NMR(400MHz, DMSO-d6)δ8.10(s,2H),7.85(d,J=7.4Hz,2H),7.52(d,J=7.4Hz,2H),7.35(t,J=7.4Hz,2H),7.31-7.25(m,2H),6.29(s,1H),4.34 (t,J=7.6Hz,1H),4.27(s,2H),3.95(dd,J=5.7,3.4Hz,2H),3.75-3.69(m,2H),3.54(t,J=5.7Hz,2H),3.35(q,J=5.7Hz,9H),2.54-2.47(m,4H).

[0086] Example 8

[0087] The synthesis of the compound Wu-6C-qusuan of the present invention has the structural formula:

[0088]

[0089] Synthesis route:

[0090]

[0091]

[0092] Referring to the synthesis method of Example 2, the linker was replaced with tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate, and other conditions remained unchanged. 1.42 g of white solid was obtained. 1H NMR(400MHz,Chloroform-d)δ7.70(d,J=7.5Hz,2H),7.48(d,J=7.4Hz,2H),7.40(s,1H),7.33(t,J=7.4Hz,2H),7.27(t,J=3.6Hz,2H ),6.25(s,1H),4.47(t,J=7.4Hz,1H),4.29(s,2H),3.87-3.80(m,2H),3.73-3.67(m,2H),3.65-3.51(m,8H),2.59(d,J=7.5Hz,2H).

[0093] Activity test of the compound targeting tyrosinase degradation of the present invention as a degradation agent:

[0094] Agaricus bisporus was purchased from a local farmer's market in Nanjing without any processing. The four degradation agents (Wu-0C-qusuan, Jin-0C-qusuan, Wu-6C-qusuan, Jin-6C-qusuan) prepared in Example 1, Example 4, Example 5, and Example 8 were added to ultrapure water, and after 5 minutes of ultrasound, the water was injected into the water 1 cm below the center of Agaricus bisporus using a syringe. The injection volume was 100 μL. Storage conditions (temperature: 15°C, humidity: 85%)

[0095] The change in the appearance color of Agaricus bisporus is an important indicator of the freshness of Agaricus bisporus. Figure 2 As shown in the figure, the Wu-0C-qusuan and Jin-6C-qusuan treated Agaricus bisporus groups were whiter in appearance than the other groups. The 0.3% Wu-0C-qusuan treated group with the best appearance was selected to repeat the experiment. The L* was measured by a spectrocolorimeter to evaluate the surface color of the mushroom cap. Each data was measured 3 times. Figure 3 As shown, the L* values ​​of all Agaricus bisporus showed a gradually decreasing trend during the entire storage period, and the degree of browning gradually increased. At the end of storage, the brightness of the treated group was higher than that of the control group. Grind the Agaricus bisporus entity (5 g) with 20 mL of 0.2 mol / L phosphate buffer (pH = 6.8), the phosphate buffer containing 3% (w / v) polyvinyl polypyrrolidone (PVPP) and 0.15 mol / L NaCl, and place it in an ice bath for 10 minutes to extract the pigment. Centrifuge at 10,000 rpm and 4°C for 10 min, take an appropriate amount of supernatant and measure the absorbance at 420 nm to reflect the degree of browning, as shown in FIG. Figure 4 As shown in the figure, the browning degree of the Agaricus bisporus in the tyrosinase degrader treatment group and the control group increased with the extension of storage time. In the first 6 days of storage, the browning degree of the Agaricus bisporus increased rapidly in both groups. In the subsequent experimental period, the browning degree increased slowly, and the growth degree of the control group was significantly higher than that of the treatment group. This shows that the compound has a certain delaying effect on the browning of Agaricus bisporus.

[0096] Therefore, the compound for targeting the degradation of tyrosinase of the present invention, when used in a tyrosinase degrading agent, can significantly degrade tyrosinase at a low dose, and effectively delay the browning of Agaricus bisporus. Moreover, the compound only targets Agaricus bisporus tyrosinase, and is safe and reliable.

Claims

1. A compound for targeting the degradation of tyrosinase, characterized in that: The compound structure is shown in formula (I): Wherein, Linker is an alkoxy group having 0 to 6 carbon atoms; R is 2. The compound according to claim 1, characterized in that The Linker is 3. The compound according to claim 1, characterized in that The compound is any of the following:

4. A method for preparing the compound according to claim 1, characterized in that: When the linker is an alkoxy group with 0 carbon atoms, the preparation method is as follows: kojic acid, reaction material A, and 4-dimethylaminopyridine DMAP are dissolved in N,N-dimethylformamide DMF, and the mixture is cooled to 0°C in an ice bath; 1-ethyl-(3-dimethylaminopropyl)carbodiimide EDC and 1-hydroxybenzotriazole HOBT are added for reaction in an ice bath, and the mixture is reacted at room temperature overnight to obtain a compound that targets the degradation of tyrosinase.

5. The method according to claim 4, characterized in that: The reaction material A is 9-fluoreneacetic acid or 1-adamantaneacetic acid, the molar ratio of kojic acid: reaction material A: EDC: HOBT is 1.1-1.3:1:1:1, and the ice bath reaction time is 1-2 hours.

6. A method for preparing the compound according to claim 1, characterized in that: When the linker is an alkoxy group with a carbon number of 2-6, the preparation method comprises the following steps: (1) Add reaction material B to dichloromethane (DCM), stir at room temperature until dissolved, add 4-methylbenzene-1-sulfonyl chloride, 4-dimethylaminopyridine (DMAP) and triethylamine in sequence, and react at room temperature to obtain product 1; (2) Kojic acid, product 1, and Cs2CO3 are dissolved in N,N-dimethylformamide (DMF), heated in an oil bath until the reaction is complete, and then water is added, extracted with ethyl acetate, washed with water, and concentrated to obtain product 2; (3) dissolving product 2 in HCl in dioxane, reacting at room temperature until the reaction is complete, stopping after concentration, adding ethyl acetate and stirring until completely dissolved, washing with water, drying, and concentrating to obtain product 3; (4) The product 3, reaction material A, and N,N-diisopropylethylamine DIPEA are dissolved in N,N-dimethylformamide DMF, cooled to 0°C in an ice bath, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU is added, reacted at room temperature, water is added, extracted with ethyl acetate, washed with water, concentrated, and subjected to column chromatography to obtain a compound that targets the degradation of tyrosinase.

7. The method according to claim 6, characterized in that: In step (1), the reaction material B is N-Boc-ethanolamine or 2-(2-Boc-aminoethoxy)ethanol or (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamic acid tert-butyl ester, and the molar ratio of reaction material B: 4-methylbenzene-1-sulfonyl chloride: DMAP: triethylamine is 1:2:0.4:2.5-3; in step (2), the molar ratio of kojic acid: product 1: Cs2CO3 is 1:1.2:2, and the reaction temperature is 50-70°C.

8. The method according to claim 6, characterized in that: In step (3), the molar amount of HCl in dioxane is 4 times or more of that of product 2; in step (4), reaction material A is 9-fluoreneacetic acid or 1-adamantaneacetic acid, and the molar ratio of product 3: reaction material A: DIPEA: HATU is 1: 1.1-1.3: 4: 1.

2.

9. Use of the compound targeted for tyrosinase degradation according to claim 1 in a tyrosinase degrading agent.

10. The use according to claim 9, characterized in that: The compound is used as a tyrosinase degradation agent in the technical field of fungus preservation.

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