Targeted EGFR inhibition tripterine derivatives and application thereof in preparation of antitumor drugs

Abstract

The invention discloses a class of tripterine derivatives for targeted inhibition of EGFR (epidermal growth factor receptor) and application of the tripterine derivatives in preparation of antitumor drugs, and belongs to the technical field of chemical pharmacy. According to the invention, tripterine and thienyl, indolyl or morpholine substituted aryl carboxylic acid are connected together through an ester bond, and a class of tripterine derivative molecules are obtained through semi-synthesis. Molecular docking experiments predict that the derivative molecules have higher EGFR targeting ability than parent nucleus tripterine, and in-vitro antitumor activity research shows that the molecules have higher inhibitory activity on lung cancer tumor cell strains, meanwhile, the toxicity of tripterine is remarkably reduced, and the molecules have certain ability of inhibiting tumor cell migration. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical pharmacy, and specifically relates to a class of tripterygium wilfordii derivatives with targeted inhibition of EGFR and application thereof in the preparation of anti-tumor drugs. Background Art

[0002] Celastrol is a monomer active ingredient extracted from Tripterygium wilfordii, a plant of the genus Tripterygium wilfordii of the Celastraceae family. It belongs to the triterpenoid class of compounds. Many studies have shown that Celastrol has a variety of pharmacological effects, including anti-tumor, anti-inflammatory, antioxidant, immunosuppressive and antiviral effects, and has significant anti-lung cancer effects. Therefore, it is considered to be one of the natural compounds with potential medicinal value. However, the high toxicity and low bioavailability of Celastrol limit its clinical application and development.

[0003] At present, the research on the structural modification of tripterygium wilfordii derivatives is mostly focused on positions 3, 6 and 29, such as Chinese patents CN102796254A, CN105985401A, CN101805390A, etc., which have complicated reaction steps, many types of intermediate reagents and high costs. At the same time, although the modified tripterygium wilfordii derivatives can improve bioavailability or reduce toxic side effects to a certain extent, they often lead to a decrease in tumor inhibitory activity, and have failed to effectively break through the dilemma of tripterygium wilfordii research and development.

[0004] Epidermal growth factor receptor (EGFR) is a transcellular protein receptor with tyrosine kinase activity. Its abnormal expression is seen in a variety of malignant tumors, including but not limited to head and neck squamous cell carcinoma, non-small cell lung cancer, colorectal cancer, etc., and plays an important role in biological processes such as cell proliferation and differentiation. Studies have shown that the incidence of EGFR mutation is high in patients with lung adenocarcinoma, especially in Asian women and non-smoking patients, so it has been selected as one of the main targets for the clinical treatment of lung adenocarcinoma. Currently, the main EGFR-inhibiting targeted therapeutic drugs on the market include gefitinib, ocitabine, etc. The main defects are concentrated in high drug resistance, high gene-dependent selectivity, abnormal liver function and other toxic side effects and high prices, which have not significantly improved the clinical lung cancer treatment rate and survival rate.

[0005] The purpose of this study is to design celastrol derivatives that target and inhibit EGFR based on the celastrol parent core, so as to screen and discover candidate anti-tumor drug compounds with stronger proliferation inhibition activity and lower toxic side effects. Summary of the invention

[0006] The purpose of the present invention is to provide a novel type of tripterygium wilfordii derivatives for targeted inhibition of EGFR and the application thereof in the preparation of anti-tumor drugs.

[0007] The technical solution adopted by the present invention is as follows:

[0008] The present invention first provides a class of tripterygium wilfordii ester derivatives having the following general formula:

[0009]

[0010] Among them, the selection range of R substituents is:

[0011] The present invention also provides a method for preparing the above-mentioned tripterygium wilfordii ester derivatives, which comprises the following steps:

[0012] Thienyl, indole or morpholine substituted aromatic carboxylic acid, dehydrating agent and catalyst are dissolved in an organic solvent, sealed and stirred at room temperature for 30 minutes, and triptolide is added, sealed and stirred at room temperature for 24 hours. After the reaction is completed, the reaction solution is filtered to separate the target compound.

[0013] Wherein, the molar ratio of the aryl carboxylic acid to tripterygium wilfordii is 1.2:1.

[0014] The molar ratio of the dehydrating agent to celastrol is 1.5:1.

[0015] The molar ratio of the catalyst to tripterygium wilfordii is 0.1:1.

[0016] Specifically, the reaction equation is as follows:

[0017]

[0018] Among them, R 1 is a carboxyl group or a butyrate group;

[0019] When R 2 When it is carboxyl, R 3 is H; when R 3 When it is carboxyl, R 2 It is H or methyl.

[0020] The preparation method is as follows: take different substituted thiophene acids (A), indole acid (B), benzothiophene carboxylic acid (C) or 4-morpholine methyl benzoic acid (D) and DCC (N, N-dicyclohexylcarbodiimide), DMAP (4-dimethylaminopyridine) in a conical flask, add anhydrous DCM (dichloromethane) solution, seal and stir at room temperature for 30 minutes, add tripterygium wilfordii, seal and stir at room temperature for 24 hours. After the reaction is completed, filter the reaction solution, separate by thin plate chromatography (V 乙酸乙酯 :V 石油醚 =1:2) to obtain the target compound E.

[0021] Wherein, the molar ratio of compound A, B, C, or D to tripterygium wilfordii is 1.2:1.

[0022] The molar amount of DCC is 1.5 times that of tripterygium wilfordii.

[0023] The molar amount of the DMAP is 0.1 times that of tripterygium wilfordii.

[0024] The present invention further provides a tripterygium wilfordii ester derivative for targeted inhibition of EGFR, and its molecular structure is as follows:

[0025]

[0026] The results of the EGRF molecular docking experiment show that the compound L1-8 prepared in the present invention has a lower binding energy to EGFR than tripterygium wilfordii, indicating a better binding effect, suggesting that the tripterygium wilfordii ester derivatives provided by the present invention have targeting properties for the EGFR protein.

[0027] Pharmacological experiments have confirmed that the compounds L1-8 prepared by the present invention have different degrees of inhibitory activity on the proliferation of human non-small cell lung cancer cell lines A549, H466, and human large cell lung cancer cell line H460. Further studies on compound L3 have confirmed that the compound has the effect of promoting tumor cell apoptosis and significantly reducing the migration ability of cells.

[0028] In view of the above-mentioned pharmacological effects of the compounds, the present invention provides the use of the above-mentioned tripterygium wilfordii ester derivatives in the preparation of anti-tumor drugs.

[0029] Specifically, the tumor is a solid tumor, including but not limited to head and neck cancer, squamous cell carcinoma, lung cancer, breast cancer, esophageal cancer, pancreatic cancer, colorectal cancer, prostate cancer, osteosarcoma cancer, etc.

[0030] Furthermore, the tumor is an EGFR-positive solid tumor, including but not limited to head and neck cancer, squamous cell carcinoma, lung cancer, colorectal cancer, breast cancer, esophageal cancer, pancreatic cancer, prostate cancer and other EGFR-positive tumors.

[0031] The present invention also provides an anti-tumor drug, comprising the above-mentioned tripterygium wilfordii ester derivative as one of the active ingredients, and a pharmaceutically acceptable carrier.

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

[0033] In the present invention, a series of novel celastrol ester derivatives with targeted inhibition of EGFR are synthesized. The binding energy of these novel derivatives to EGFR is lower than that of celastrol nucleus, which means that these celastrol ester derivatives have stronger targeted EGFR inhibition effect, which is a significant improvement in the structural derivation of celastrol. At the same time, the structural modification of this esterification reaction can be completed in only one step, which greatly reduces the reaction cost and makes it possible to reduce the high cost of lung cancer treatment.

[0034] In the present invention, the in vitro tumor cell inhibition activity proves that the ester derivatives of tripterygium wilfordii have no obvious inhibitory effect on the proliferation of human lung epithelial cell line BASE-2B. 50 The values ​​were all greater than 40 μmol / L, indicating that the toxicity of this type of derivatives to normal cells was significantly lower than that of its parent core structure, tripterygium wilfordii.

[0035] In the present invention, the apoptosis experiment proves that the apoptosis rate of human non-small cell lung cancer cell H446 increases with the increase of the concentration of compound L3, and is concentration-dependent. Compared with its parent compound tripterygium wilfordii, the apoptosis rate of compound L3 at the same concentration is nearly 2 times.

[0036] In the present invention, the cell migration experiment proves that the anti-cell migration ability of compound L3 is better than that of the parent compound tripterygium wilfordii and the anticancer drug gefitinib, suggesting better anti-tumor metastasis activity.

[0037] Therefore, the present invention is expected to lay a theoretical foundation for developing tripterygium wilfordii ester derivatives as candidate molecules for anti-lung cancer drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is a graph showing the in vitro proliferation inhibitory activity of celastrol ester derivatives L1-L8 on human non-small cell lung cancer cell lines A549 and H446 and human large cell lung cancer cell line H460 detected by CCK8 detection method.

[0039] Figure 2 The CCK8 assay was used to detect the in vitro proliferation inhibitory activity of tripterygium wilfordii ester derivatives L1~L8 on the human lung epithelial cell line BEAS-2B.

[0040] Figure 3 This is a graph showing the in vitro proliferation inhibitory activity of celastrol ester derivative L3 on human non-small cell lung cancer cell line H446 detected by AnnexinV / PI double staining method.

[0041] Figure 4 The cell scratch experiment was used to detect the anti-cell migration ability of tripterygium wilfordii ester derivative L3.

[0042] Figure 5To predict the binding energy of tripterygium wilfordii ester derivatives L1~L8 to EGFR for molecular docking experiments.

[0043] Figure 6 This is the binding mode of tripterygium wilfordii ester derivative L3 and the EGFR active site. DETAILED DESCRIPTION

[0044] A method for preparing a tripterygium wilfordii derivative comprises the following steps:

[0045] Differently substituted thiophene acids (A), indole acid (B), benzothiophene carboxylic acid (C) or 4-morpholine methyl benzoic acid (D) and dehydrating agent DCC (N, N-dicyclohexylcarbodiimide), catalyst DMAP (4-dimethylaminopyridine) were placed in a conical flask, anhydrous DCM (dichloromethane) solution was added, the flask was sealed and stirred at room temperature for 30 minutes, and triptolide was added, the flask was sealed and stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was filtered and separated by thin plate chromatography (V 乙酸乙酯 :V 石油醚 =1:2) to obtain the target compound E.

[0046]

[0047] Example 1

[0048] R 2 =-COOH, R 3 =H, indole acid B1, preparation of compound L1

[0049] The reaction formula is as follows:

[0050]

[0051] Indole acid B1 (1.2 eq), DCC (1.5 eq) and DMAP (0.1 eq) were placed in a conical flask, anhydrous DCM 20 ml was added, the flask was sealed and stirred at room temperature for 30 minutes, and then Celastrol (1.0 eq) was added, the flask was sealed and stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was filtered and separated by thin plate chromatography (V 乙酸乙酯 :V 石油醚 =1:2) to obtain the target compound L1 in the form of orange powder with a yield of 72% and a melting point of 125.9-131.7°C. Compound L1: 1H NMR (300MHz, CDCl3) δ9.32 (s, 1H), 7.64 (d, J = 8.1Hz, 1H), 7.01 (s, 2H), 6.54 (s, 1H) ),6.36(d,J=7.2Hz,1H),5.70(d,J=7.8Hz,1H),5.30(s,1H),3.49(d,J=4.5Hz,1H ),2.61(s,1H),2.21(s,3H),1.64–1.57(m,6H),1.44(s,3H),1.30–1.25(m,12H), 1.13(s,3H),0.84(d,J=7.0Hz,2H),0.64(s,3H).HR-MS(ESI+)m / z:594.3141[M+H] + .Found:594.3186[M+H] + .

[0052] Example 2

[0053] The preparation reaction formula of 4-morpholinemethylbenzoic acid D, compound L2 is as follows:

[0054]

[0055] The preparation method of compound L2 is the same as the preparation method of compound L1 in Example 1, and compound L2 is obtained in the form of orange powder with a yield of 72% and a melting point of 123.1-128.2°C. Compound L2: 1 H NMR (300 MHz, CDCl 3 )δ7.02(d,J=7.8Hz,2H),6.54(s,2H),6.36(d,J=7.1Hz,2H),5.69(d,J= 7.9Hz,1H),5.30(s,1H),2.96(s,3H),2.89(s,3H),2.22(s,3H),2.00(d, J=12.9Hz,4H),1.64-1.56(m,10H),1.45(s,3H),1.29(s,3H),1.26(d,J=2.7Hz,9H),1.13(s,3H),0.64(s,3H).HR-MS(ESI+)m / z:656.3873[M+H] + .Found:656.3843[M+H] + .

[0056] Example 3

[0057] R 3 =-CH 2 CH 2 COOH, R 2=H, indole acid B2, the preparation reaction formula of compound L3 is as follows:

[0058]

[0059] Referring to the preparation method of compound L1 in Example 1, compound L3 was obtained in the form of orange powder with a yield of 63% and a melting point of 130.8.1-133.2°C. Compound L3: 1 H NMR (600MHz, CDCl3) δ8.03(s,1H),7.54(d,J=7.8Hz,1H),7.29(d,J=4.5Hz,1H),7.05(t,J=7.5Hz,1H ),6.96(d,J=7.2Hz,2H),6.48(s,1H),6.29(d,J=7.1Hz,1H),5.62(d,J=7.1Hz,1H),3.08(dd,J=23.3, 12.9Hz,1H),2.85(d,J=44.3Hz,1H),2.76-2.62(m,2H),2.15(s,3H),1.68(d,J=12.7Hz,5H),1.38(s, 3H),1.22(s,6H),1.19(d,J=6.3Hz,10H),1.06(s,3H),0.57(s,3H).HR-MS(ESI+)m / z:622.3454[M+H] + .Found:622.3436[M+H] + .

[0060] Example 4

[0061] R 1 The 3-position substituent is -COOH, thiophene acid A1, and the preparation reaction formula of compound L4 is as follows:

[0062]

[0063] Referring to the preparation method of compound L1 in Example 1, compound L4 was obtained in the form of orange powder with a yield of 74% and a melting point of 132.0.1-136.1°C. Compound L4: 1 H NMR (300 MHz, CDCl 3)δ8.18(d,J=2.3Hz,1H),7.54(d,J=4.9Hz,1H),7.31(dd,J=5.0,3.0Hz,1H),7.05(d,J=6.9H z,1H),6.57-6.50(m,1H),6.33(d,J=7.2Hz,1H),5.30(s,1H),4.10(dd,J=13.5,6.8Hz,1H), 2.93(d,J=21.9Hz,1H),2.26-2.09(m,6H),1.91-1.54(m,10H),1.48-1.41(m,4H),1.25(d,J =4.8Hz,7H),1.10(d,J=7.1Hz,3H),0.62(d,J=7.3Hz,2H).HR-MS(ESI+)m / z:563.2753[M+H] + .Found:563.2725[M+H] + .

[0064] Example 5

[0065] R 3 =-CH 2 COOH, R 2 =H, indole acid B3, the preparation reaction formula of compound L5 is as follows:

[0066]

[0067] Referring to the preparation method of compound L1 in Example 1, compound L5 was obtained in the form of orange powder with a yield of 71% and a melting point of 129.9-136.1°C. Compound L5: 1 H NMR (300 MHz, CDCl 3 )δ8.02(s,1H),7.72-7.57(m,2H),7.54(s,1H),7.33(d,J=8.2Hz,1H),7. 01(s,2H),6.36(d,J=3.7Hz,1H),5.30(s,2H),3.63(s,3H),2.89(s,3H),2 .05(s,3H),1.92(d,J=3.5Hz,3H),1.30-1.24(m,12H),1.13(d,J=4.0Hz, 5H),1.08(s,4H),1.01(d,J=5.3Hz,3H).HR-MS(ESI+)m / z:608.3298[M+H] + .Found:608.3275[M+H] + .

[0068] Example 6

[0069] R 3 =-CH 2 COOH, R 2 =-CH 3 , indole acid B3, the preparation reaction formula of compound L6 is as follows:

[0070]

[0071] Referring to the preparation method of compound L1 in Example 1, compound L6 was obtained in the form of orange powder with a yield of 71% and a melting point of 122.9-135.2°C. Compound L6: 1 H NMR (300 MHz, CDCl 3 )δ8.02(s,1H),7.03(d,J=7.0Hz,2H),6.55(s,1H),6.36(d,J=7.1Hz,1H),5.74(d,J=7 .8Hz,1H),5.30(s,2H),4.02(dd,J=19.1,9.1Hz,1H),2.96(s,1H),2.89(s,1H),2.22(s ,3H),2.02(t,J=14.9Hz,4H),1.80-1.69(m,8H),1.60(dd,J=11.9,5.8Hz,5H),1.45(s, 3H),1.28(d,J=6.0Hz,7H),1.13(s,3H),0.65(s,3H).HR-MS(ESI+)m / z:622.3454[M+H] + .Found:622.3522[M+H] + .

[0072] Example 7

[0073] Preparation of benzothiophene-2-carboxylic acid C, compound L7

[0074] The reaction formula is as follows:

[0075]

[0076] Referring to the preparation method of compound L1 in Example 1, compound L7 was obtained in the form of orange powder with a yield of 68% and a melting point of 126.3-135.7°C. Compound L7: 1 H NMR (300 MHz, CDCl 3)δ8.11(d,J=8.4Hz,1H),7.96-7.79(m,1H),7.47(tdd,J=20.5,14.3,6.5Hz,2H),7.03(dd,J=15.9,6.5Hz,1H),6.52 (d,J=10.2Hz,1H),6.38-6.22(m,1H),5.30(s,1H),2.92(d,J=21.7Hz,1H),2.22(d,J=5.8Hz,3H),1.96-1.82(m,3H) ,1.76(dd,J=14.3,7.6Hz,2H),1.57(dd,J=17.3,9.3Hz,4H),1.47(d,J=2.8Hz,2H),1.43(s,2H),1.26(dt,J=12.8,9 .3Hz,9H),1.12(s,1H),1.09(s,2H),0.96-0.83(m,2H),0.65(s,1H),0.60(s,1H).HR-MS(ESI+)m / z:611.2753[M+H] + .Found:611.2715[M+H] + .

[0077] Example 8

[0078] R 1 The 2-position substituent is -CH 2 CH 2 CH 2 Preparation of COOH, thiophene acid A2, compound L8

[0079] The reaction formula is as follows:

[0080]

[0081] Referring to the preparation method of compound L1 in Example 1, compound L8 was obtained in the form of orange powder with a yield of 56% and a melting point of 124.0-132.0°C. Compound L8: 1HNMR(300MHz, CDCl3)δ8.02(s,1H),7.13(d,J=3.8Hz,1H),7.02(d,J=7.1Hz,1H),6.96–6.89(m,1H), 6.54(s,1H),6.36(d,J=7.2Hz,1H),5.70(d,J=8.3Hz,1H),5.30(s,1H),4.01(t,J=11.2Hz,1H),3.67 (dd,J=8.2,2.7Hz,1H),2.96(s,1H),2.88(s,1H),2.22(s,3H),2.02(s,2H),1.74(s,8H),1.60(s,6H ),1.45(s,3H),1.29(s,3H),1.26(s,5H),1.13(s,3H),0.64(s,3H).HR-MS(ESI+)m / z:605.3222[M+H] + .Found:605.3255[M+H] + .

[0082] Example 9

[0083] Application of the compound tripterygium wilfordii ester derivatives of the present invention

[0084] (I) In vitro anti-tumor cell proliferation experiment of tripterygium wilfordii ester derivatives

[0085] Human non-small cell lung cancer cell lines A549, H466, and human large cell lung cancer cell line H460 were used as test strains, and CCK-8 colorimetry was used as the detection method. Through the in vitro tumor cell inhibition activity study of the tripterygium wilfordii ester derivatives of the present invention, it was found that the novel structural derivatives had obvious in vitro tumor cell inhibition activity, and the tumor cell inhibition activity of all derivatives was better than that of the commonly used clinical anti-tumor drug gefitinib. The inhibitory activity of compound L3 in the H460 cell line was better than that of the parent core structure tripterygium wilfordii. The results are shown in the attached Figure 1 At the same time, the derivatives had no significant inhibitory effect on the proliferation of human lung epithelial cell line BASE-2B, and IC 50 The values ​​were all greater than 40 μmol / L, indicating that the toxicity of this type of derivatives to normal cells was significantly lower than that of its parent structure, tripterygium wilfordii. The results are shown in the attached Figure 2 .

[0086] Table 1. Antiproliferative activity of tripterygium wilfordii ester derivatives in human lung cancer cells

[0087]

[0088] (II) Cell apoptosis experiment of compound L3

[0089] The flow cytometry experiment was set up into 5 groups, a blank control group (Control), a compound L3 concentration 2μmol / L group, a L3 concentration 4μmol / L group, a parent core structure Celastrol 4μmol / L group (Celastrol), and a gefitinib 4μmol / L group (Gefitinib). The human non-small cell lung cancer cell line H446 was inoculated into a 6-well cell culture plate, and after 24 hours of drug treatment according to the group, the cell apoptosis was analyzed on a flow cytometer. The collected experimental results are shown in the attached Figure 3 . According to the results, when the concentration of compound L3 was 2μmol / L, the proportion of apoptotic cells was equivalent to that of the 4μmol / L Gefitinib treatment group, and much higher than that of the blank control group; when the concentration of L3 was 4μmol / L, the proportion of apoptotic cells was significantly better than that of the same concentration of tripterygium wilfordii, and was about twice that of the same concentration of gefitinib. The above results all indicate that compound L3 has a significant effect on promoting apoptosis of human non-small cell lung cancer cells.

[0090] (III) Cell migration assay of compound L3

[0091] The cell migration experiment was divided into 4 groups: a blank control group (Control), a compound L3 group, a nucleus structure Celastrol group (Celastrol) and a gefitinib group (Gefitinib). The human large cell lung cancer cell line H460 was inoculated into a 6-well plate. When the cell density reached 80%, the cell scratch method was used for the experiment, and photos were taken at 0 hours, 24 hours and 48 hours of treatment, and finally the cell gaps were measured and counted. The results showed that the cells in the blank control group underwent obvious cell migration at 24 hours, and the cell gaps almost completely disappeared after 48 hours. The migration ability of the cells in the L3 group was significantly slowed down at 24 hours, and the cell gaps were significantly larger than those in the Celastrol group and the Gefitinib group at 48 hours, indicating that L3 can significantly reduce the migration ability of cells, suggesting that it has the ability to prevent the metastasis of cancer cells. The results are attached. Figure 4 .

[0092] (IV) Molecular docking experiment of tripterygium wilfordii ester derivatives targeting EGFR

[0093] The L1-L8 series of molecules were energy minimized and optimized by the MM2 position of chem3D and saved as sdf files. They were then imported into Autodock vina software for dehydration, hydrogenation, charge calculation, determination of the root of the ligand, and selection of the torsion bond of the ligand small molecule. The pymol software was used to remove the solvent and ligand small molecules from the imported EGFR protein (PDB: 1XKK), and then the EGFR protein macromolecule was hydrogenated and the charge was calculated in Autodock vina software. The EGFR protein was used as the docking receptor and saved as a Pdbqt file. The docking box coordinates (Grid center: X 17.1816Y 33.9318Z 38.4276; Grid size: X 25.406Y 25.406Z25.406) were determined according to the complex structure of the EGFR kinase domain and the EGFR inhibitor lapatinib, and semi-flexible docking was performed.

[0094] Depend on Figure 5 It can be seen that all tripterygium wilfordii ester derivatives have lower binding energy to EGFR than tripterygium wilfordii, indicating a better binding effect. Among the L1-L8 series of compounds, compound L3 has the lowest binding energy to EGFR, which is -11.64 kcal / mol, significantly lower than the binding energy of tripterygium wilfordii to EGFR (-8.854 kcal / mol). The indole ring structure in compound L3 can form a hydrogen bond with ASPA:855, and other functional groups can also form hydrogen bonds with two amino acids VALA:726 and ARGA:841 of the EGFR protein, which significantly increases the targeting of compound L3 to the EGFR protein. For details, see Figure 6 .

[0095] According to the above conclusions, this type of tripterygium wilfordii ester derivatives have application prospects in the preparation of anti-tumor drugs targeting the inhibition of EGFR.

[0096] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A type of tripterygium wilfordii ester derivative, characterized in that: Having the structure shown in Formula I: Among them, the selection range of R substituents is:

2. The method for preparing the tripterygium wilfordii ester derivatives according to claim 1, characterized in that: The method comprises the following steps: dissolving an aromatic carboxylic acid, a dehydrating agent and a catalyst in an organic solvent, sealing and stirring the mixture at room temperature for reaction for 30 minutes, adding celastrol, sealing and stirring the mixture at room temperature for reaction for 24 hours, filtering the reaction solution after the reaction is completed, and separating and obtaining a target compound, wherein the aromatic carboxylic acid is an aromatic carboxylic acid substituted with a thienyl group, an indole group or a morpholine group.

3. The method for preparing the tripterygium wilfordii ester derivatives according to claim 2, characterized in that: The molar ratio of the aryl carboxylic acid to celastrol is 1.2:

1.

4. The method for preparing the tripterygium wilfordii ester derivatives according to claim 2, characterized in that: The molar ratio of the dehydrating agent to tripterygium wilfordii is 1.5:1; and / or the dehydrating agent is N,N-dicyclohexylcarbodiimide.

5. The method for preparing the tripterygium wilfordii ester derivatives according to claim 2, characterized in that: The molar ratio of the catalyst to celastrol is 0.1:1; and / or the catalyst is 4-dimethylaminopyridine.

6. A tripterygium wilfordii ester derivative for targeted inhibition of EGFR, characterized in that: It has a structure as shown in Formula I, and the molecular structure of the specific compound is as follows:

7. Use of the tripterygium wilfordii ester derivatives according to claim 1 in the preparation of anti-tumor drugs.

8. The use according to claim 7, characterized in that: The tumor is a solid tumor, which includes head and neck cancer, squamous cell carcinoma, lung cancer, breast cancer, esophageal cancer, pancreatic cancer, colorectal cancer, prostate cancer, and osteosarcoma cancer.

9. The use according to claim 7, characterized in that: The tumor is a solid tumor with positive EGFR expression.

10. An anti-tumor drug, characterized in that: It comprises the tripterygium wilfordii ester derivative as claimed in claim 1 as one of the active ingredients, and a pharmaceutically acceptable carrier.

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