A class of emladin derivatives targeting and inhibiting egfr and application thereof in preparation of anti-tumor drugs

Abstract

The application discloses a class of triptolide derivatives for targeted inhibition of EGFR and application thereof in preparation of antitumor drugs, and belongs to the technical field of chemical pharmacy. Triptolide and thienyl, indolyl or morpholine-substituted aryl carboxylic acid are connected together through an ester bond to obtain a class of triptolide derivative molecules by semi-synthesis. Molecular docking experiment predicts that the derivative molecules have stronger ability of targeting EGFR than the mother nucleus triptolide, in-vitro antitumor activity research shows that the molecules have strong inhibitory activity on lung cancer tumor cell strains, significantly reduce the toxicity of triptolide, and have certain ability of inhibiting migration of tumor cells.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, specifically relating to a class of EGFR-targeting triptolide derivatives and their application in the preparation of antitumor drugs. Background Technology

[0002] Celastrol is a monomeric active ingredient extracted from *Tripterygium wilfordii*, a plant belonging to the Celastraceae family. It is a triterpenoid compound. Multiple studies have shown that celastrol possesses various pharmacological effects, including antitumor, anti-inflammatory, antioxidant, immunosuppressive, and antiviral properties, and exhibits significant anti-lung cancer activity. Therefore, it is considered 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] Currently, research on structurally modified triptolide derivatives mainly focuses on positions 3, 6, and 29, as exemplified by Chinese patents CN102796254A, CN105985401A, and CN101805390A. These methods involve complex reaction steps, numerous intermediate reagents, and high costs. Furthermore, while modified triptolide derivatives can improve bioavailability or reduce toxicity to some extent, they often lead to decreased tumor-suppressive activity, failing to effectively overcome the challenges in triptolide research and development.

[0004] Epidermal growth factor receptor (EGFR) is a transmembrane protein receptor with tyrosine kinase activity. Abnormal expression of EGFR is seen in various malignant tumors, including but not limited to head and neck squamous cell carcinoma, non-small cell lung cancer, and colorectal cancer, and it plays a crucial role in biological processes such as cell proliferation and differentiation. Studies have shown that EGFR mutations are more prevalent in lung adenocarcinoma patients, especially Asian women and non-smokers, making it one of the main targets for clinical treatment of lung adenocarcinoma. Currently marketed EGFR-inhibiting targeted therapies include gefitinib and ositabine, but their main drawbacks include high drug resistance, high gene-dependent selectivity, toxic side effects such as liver dysfunction, and high cost, resulting in no significant improvement in clinical lung cancer treatment rates and survival rates.

[0005] The aim of this study is to design triptolide derivatives that target and inhibit EGFR based on the triptolide core, in order to screen and discover antitumor drug candidate compounds with stronger inhibitory activity and lower toxicity. Summary of the Invention

[0006] The purpose of this invention is to provide a novel type of triptolide derivative that targets and inhibits EGFR and its application in the preparation of antitumor drugs.

[0007] The technical solution adopted in this invention is as follows:

[0008] This invention first provides a class of triptolide ester derivatives, which have the following general formula:

[0009]

[0010] The selection range of R substituents is as follows:

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

[0012] A thiophene-, indole-, or morpholine-substituted aryl carboxylic acids, along with a dehydrating agent and catalyst, were dissolved in an organic solvent. The mixture was then sealed and stirred at room temperature for 30 minutes. Tripterygium wilfordii was added, and the mixture was sealed and stirred at room temperature for 24 hours. After the reaction was complete, the reaction solution was filtered to obtain the target compound.

[0013] The molar ratio of the aryl carboxylic acid to triptolide is 1.2:1.

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

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

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

[0017]

[0018] Wherein, R1 is a carboxyl group or a butyric acid group;

[0019] When R2 is a carboxyl group, R3 is H; when R3 is a carboxyl group, R2 is H or methyl.

[0020] The preparation method is as follows: Thiophene acids (A), indoleic acid (B), benzothiophene carboxylic acid (C), or 4-morpholinomethylbenzoic acid (D), along with DCC (N,N-dicyclohexylcarbodiimide) and DMAP (4-dimethylaminopyridine), are placed in an Erlenmeyer flask. Anhydrous DCM (dichloromethane) solution is added, and the mixture is sealed and stirred at room temperature for 30 minutes. Tripterygium wilfordii is then added, and the mixture is sealed and stirred at room temperature for 24 hours. After the reaction is complete, the reaction solution is filtered, and the mixture is separated by thin-plate chromatography (V... 乙酸乙酯 V 石油醚 =1:2) to obtain the target compound E.

[0021] The molar ratio of compounds A, B, C, or D to triptolide is 1.2:1.

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

[0023] The molar amount of DMAP is 0.1 times that of triptolide.

[0024] This invention further provides a triptolide ester derivative that targets and inhibits EGFR, the molecular structure of which is shown below:

[0025]

[0026] The results of EGFR molecular docking experiments showed that the compound L1-8 prepared in this invention had a lower binding energy to EGFR than triptolide, indicating a better binding effect and suggesting that the triptolide ester derivatives provided in this invention have EGFR protein targeting properties.

[0027] Pharmacological experiments confirmed that compound L1-8 prepared in this invention exhibits varying degrees of inhibitory activity against the proliferation of human non-small cell lung cancer cell lines A549 and H466, and human large cell lung cancer cell line H460. Further studies on compound L3 confirmed that this compound promotes tumor cell apoptosis and significantly reduces cell migration ability.

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

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

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

[0031] The present invention also provides an antitumor drug comprising the above-mentioned triptolide ester derivatives as one of the active ingredients, and a pharmaceutically acceptable carrier.

[0032] The advantages of this invention compared to existing technologies are as follows:

[0033] In this invention, a series of novel triptolide ester derivatives targeting and inhibiting EGFR were synthesized. These novel derivatives all exhibit lower binding energies to EGFR than the triptolide core, indicating a stronger EGFR-targeting inhibitory effect and representing a significant improvement in triptolide structural derivatization. Furthermore, this esterification reaction requires only a single step, greatly reducing reaction costs and making it possible to lower the high cost of lung cancer treatment.

[0034] In this invention, in vitro tumor cell inhibitory activity demonstrated that triptolide ester derivatives had no significant inhibitory effect on the proliferation of human lung epithelial cell line BASE-2B, IC50. 50 The values ​​were all greater than 40 μmol / L, indicating that the toxicity of this type of derivative to normal cells was significantly lower than that of its parent nucleus structure, triptolide.

[0035] In this invention, apoptosis experiments demonstrated that the apoptosis rate of human non-small cell lung cancer H446 cells increased in a concentration-dependent manner with increasing concentration of compound L3. Compared to its parent compound tripterygium, the apoptosis rate of compound L3 at the same concentration was nearly twice that of its parent compound.

[0036] In this invention, cell migration experiments demonstrated that compound L3 exhibits superior anti-cell migration activity compared to its parent compound tripterygium and the anticancer drug gefitinib, suggesting better anti-tumor metastasis activity.

[0037] Therefore, this invention is expected to lay a theoretical foundation for exploring triptolide ester derivatives as candidate molecules for anti-lung cancer drugs. Attached Figure Description

[0038] Figure 1 The graph shows the in vitro inhibitory activity of triptolide ester derivatives L1-L8 against human non-small cell lung cancer cell lines A549 and H446 and human large cell lung cancer cell line H460, as determined by the CCK8 assay.

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

[0040] Figure 3 The image shows the inhibitory activity of triptolide ester derivative L3 on the in vitro proliferation of human non-small cell lung cancer cell line H446, as detected by Annexin V / PI double staining.

[0041] Figure 4 To detect the anti-cell migration ability of triptolide ester derivative L3 in a cell scratch assay.

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

[0043] Figure 6 This represents the binding mode of triptolide ester derivative L3 to the active site of EGFR. Detailed Implementation

[0044] A method for preparing triptolide derivatives, comprising the following steps:

[0045] Different substituted thiophene acids (A), indoleic acid (B), benzothiophene carboxylic acid (C), or 4-morpholinomethylbenzoic acid (D), along with the dehydrating agent DCC (N,N-dicyclohexylcarbodiimide) and the catalyst DMAP (4-dimethylaminopyridine), were placed in an Erlenmeyer flask. Anhydrous DCM (dichloromethane) solution was added, and the mixture was sealed and stirred at room temperature for 30 minutes. Tripterygium wilfordii was then added, and the mixture was sealed and stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was filtered, and the mixture was 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] R2 = -COOH, R3 = H, indoleic acid B1, preparation of compound L1

[0049] The reaction formula is as follows:

[0050]

[0051] Indoleic acid B1 (1.2 eq), DCC (1.5 eq), and DMAP (0.1 eq) were placed in an Erlenmeyer flask, and 20 ml of anhydrous DCM was added. The mixture was sealed and stirred at room temperature for 30 minutes. Then, triptolide (Celastrol) (1.0 eq) was added, and the mixture was sealed and stirred at room temperature for 24 hours. After the reaction was complete, the reaction solution was filtered, and the mixture was separated by thin-plate chromatography (V... 乙酸乙酯 V 石油醚 The target compound L1 was obtained by mixing the two components in a 1:2 ratio. It was an orange powder in 72% yield with a melting point of 125.9-131.7 °C. Compound L1: 1 H 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 for compound L2, 4-morpholine methyl benzoic acid D, is as follows:

[0054]

[0055] Compound L2 was prepared using the same method as compound L1 in Example 1, yielding compound L2 as an orange powder with a yield of 72% and a melting point of 123.1-128.2℃. Compound L2: 1 H NMR(300MHz, CDCl3)δ7.02(d,J=7.8Hz,2H),6.54(s,2H),6.36(d,J=7.1Hz,2 H),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] R3 = -CH2CH2COOH, R2 = H, indole acid B2, the preparation reaction formula for compound L3 is as follows:

[0058]

[0059] Following the preparation method of compound L1 in Example 1, compound L3 was obtained as an orange powder with a yield of 63% and a melting point of 130.81-133.2℃. Compound L3: 1H 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] R1 is a 3-substituent -COOH, thiophene acid A1, and the preparation reaction formula for compound L4 is as follows:

[0062]

[0063] Following the preparation method of compound L1 in Example 1, compound L4 was obtained as an orange powder with a yield of 74% and a melting point of 132.01-136.1℃. Compound L4: 1 H NMR (300MHz, CDCl3) 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=6.9Hz,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] R3 = -CH2COOH, R2 = H, indole acid B3, the preparation reaction formula for compound L5 is as follows:

[0066]

[0067] Following the preparation method of compound L1 in Example 1, compound L5 was obtained as an orange powder with a yield of 71% and a melting point of 129.9-136.1℃. Compound L5: 1 H NMR(300MHz, CDCl3)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] R3 = -CH2COOH, R2 = -CH3, indole acid B3, the preparation reaction formula for compound L6 is as follows:

[0070]

[0071] Following the preparation method of compound L1 in Example 1, compound L6 was obtained as an orange powder with a yield of 71% and a melting point of 122.9-135.2℃. Compound L6: 1H NMR (300MHz, CDCl3) 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),1.4 5(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] Following the preparation method of compound L1 in Example 1, compound L7 was obtained as an orange powder with a yield of 68% and a melting point of 126.3-135.7℃. Compound L7: 1H NMR (300MHz, CDCl3) 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] R1 is a 2-substituent -CH2CH2CH2COOH, thiophene acid A2, preparation of compound L8

[0079] The reaction formula is as follows:

[0080]

[0081] Following the preparation method of compound L1 in Example 1, compound L8 was obtained as an orange powder with a yield of 56% and a melting point of 124.0-132.0℃. 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 triptolide ester derivatives of the compound of this invention

[0084] (I) In vitro antitumor cell proliferation experiment of triptolide ester derivatives

[0085] Using human non-small cell lung cancer cell lines A549 and H466, and human large cell lung cancer cell line H460 as detection lines, and the CCK-8 colorimetric assay as the detection method, the in vitro tumor cell inhibitory activity of the triptolide ester derivatives of this invention was studied. The results showed that these novel structural derivatives exhibit significant in vitro tumor cell inhibitory activity. The tumor cell inhibitory activity of all derivatives was superior to that of the commonly used clinical antitumor drug gefitinib. Compound L3 showed superior inhibitory activity in the H460 cell line compared to its parent nucleus, triptolide. The results are shown in the appendix. Figure 1 Meanwhile, these derivatives did not show significant inhibitory effects on the proliferation of human lung epithelial cell line BASE-2B, with an IC50 value of [missing information]. 50 The values ​​were all greater than 40 μmol / L, indicating that the toxicity of this type of derivative to normal cells was significantly lower than that of its parent nucleus structure, triptolide. The results are shown in the appendix. Figure 2 .

[0086] Table 1. Anti-proliferative activity of triptolide ester derivatives against human lung cancer cells

[0087]

[0088] (II) Apoptosis experiment of compound L3

[0089] The flow cytometry experiment was set up with 5 groups: a blank control group, a compound L3 concentration of 2 μmol / L group, an L3 concentration of 4 μmol / L group, a celastrol group (containing the parent nucleus structure triptolide) group (4 μmol / L), and a gefitinib group (4 μmol / L). Human non-small cell lung cancer cell line H446 was seeded into 6-well cell culture plates, and after treatment with the corresponding compounds for 24 hours, cell apoptosis was analyzed by flow cytometry. The collected experimental results are shown in the appendix. Figure 3 The results showed that at a concentration of 2 μmol / L, compound L3 resulted in a similar proportion of apoptotic cells as the 4 μmol / L Gefitinib treatment group, but significantly higher than the blank control group. At a concentration of 4 μmol / L, the proportion of apoptotic cells was significantly better than that of triptolide at the same concentration, and approximately twice that of gefitinib at the same concentration. These results suggest that compound L3 has a significant effect on promoting apoptosis in human non-small cell lung cancer cells.

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

[0091] The cell migration assay was set up with four groups: a blank control group, the L3 group, the celastrol group (containing the parent nucleus structure), and the gefitinib group. Human large cell lung cancer cell line H460 was seeded into 6-well plates. When the cell density reached 80%, the cell scratch assay was performed, and images were taken at 0, 24, and 48 hours after treatment. The intercellular space was measured and statistically analyzed. The results showed that the blank control group exhibited significant cell migration at 24 hours, and the intercellular space almost completely disappeared after 48 hours. The L3 group showed significantly slower cell migration at 24 hours, and the intercellular space at 48 hours was significantly larger than that of the celastrol and gefitinib groups, indicating that L3 significantly reduced cell migration and suggests an ability to inhibit cancer cell metastasis. (See attached figure for details.) Figure 4 .

[0092] (IV) EGFR-targeting molecular docking experiments using triptolide ester derivatives

[0093] The L1-L8 series molecules were optimized for energy minimization using the MM2 field in Chem3D and saved as SDF files. These were then imported into Autodock Vina software for dehydration, hydrogenation, charge calculation, ligand root determination, and selection of torsion-resistant bonds in the ligand molecule. PyMOL software was used to remove solvent and ligand molecules from the imported EGFR protein (PDB: 1XKK). Then, in Autodock Vina, hydrogenation was performed on the EGFR protein macromolecule, and its charge was calculated. The EGFR protein was then used as the docking acceptor and saved as a PDBQT file. Based on the EGFR kinase domain and the structure of the EGFR inhibitor lapatinib complex, the docking box coordinates (Grid center: X 17.1816 Y 33.9318 Z 38.4276; Grid size: X 25.406 Y 25.406 Z 25.406) were determined, and semi-flexible docking was performed.

[0094] Depend on Figure 5 It was found that all triptolide ester derivatives had lower binding energies to EGFR than triptolide, indicating better binding performance. Among the L1-L8 series compounds, compound L3 had the lowest binding energy to EGFR at -11.64 kcal / mol, significantly lower than the binding energy of triptolide 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 of the EGFR protein, VALA:726 and ARGA:841, significantly increasing the targeting specificity of compound L3 to the EGFR protein. (See details...) Figure 6 .

[0095] Based on the above conclusions, this type of triptolide ester derivative has the potential to be used in the preparation of anti-tumor drugs that target and inhibit EGFR.

[0096] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A class of emladocyanine ester derivatives targeting the inhibition of EGFR, characterized in that, A compound having a structure as shown in Formula I: ， Formula I wherein the R substituents are selected from: , , , , , , , .

2. The preparation method of the ester derivative of tripterine according to claim 1, characterized in that, The method comprises the following steps: dissolving different substituted thiophene acid, indole acid, benzothiophene carboxylic acid or 4-morpholinyl benzene carboxylic acid, a dehydrating agent and a catalyst in an organic solvent, stirring the mixture at room temperature for 30 minutes, adding celastin, stirring the mixture at room temperature for 24 hours, filtering the reaction solution and separating the compound of Formula I.

3. The method of claim 2, wherein the method is characterized by, The molar ratio of the different substituted thiophene acid, indole acid, benzothiophene carboxylic acid or 4-morpholinyl benzene carboxylic acid to celastin is 1.2:

1.

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

5. The method of claim 2, wherein the emd of tripterine ester is represented by the following formula: ###0002### 5 The molar ratio of the catalyst to celastin is 0.1:1; and / or, the catalyst is 4-dimethylamino pyridine.

6. Use of the celastin ester derivative of claim 1 in the preparation of a tumor drug for targeted inhibition of EGFR.

7. Use according to claim 6, characterized in that, The tumor is a solid tumor selected from head and neck cancer squamous cell carcinoma, lung cancer, breast cancer, esophageal cancer, pancreatic cancer, colorectal cancer, prostate cancer, osteosarcoma cancer.

8. Use according to claim 6, characterized in that, The tumor is a solid tumor with positive EGFR expression.

9. An antitumor agent, characterized by comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The method comprises the celastin ester derivative of claim 1 as one of the active ingredients, and a pharmaceutically acceptable carrier.

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