Beta-carboline-thiazole conjugate as well as preparation method and anti-tumor application thereof

Abstract

The invention discloses beta-carboline-thiazole conjugates as well as a preparation method and anti-tumor application thereof, and belongs to the technical field of medicinal chemistry. Wherein the structure of the compound 8 is as shown in the specification, tryptophan protected by N-terminal t-butyloxycarboryl is taken as a starting raw material, and simple construction of the beta-carboline-thiazole conjugate is completed through a one-kettle thiazole formation reaction, acid-catalyzed Boc protecting group removal and Pictet-Spengler cascade reaction. The compound 8 has the beneficial effects that the structure is novel, the compound 8 has a good killing effect on a human gastric cancer cell strain MKN45, the IC50 value is 3.8 mu M, the compound 8 has a good inhibiting effect on a human glioblastoma cell strain U87, the raw materials of the preparation method are cheap and easy to obtain, the preparation process is simple and convenient, and the compound 8 is suitable for large-scale industrial production; .

Description

Technical Field

[0001] The present invention relates to a class of compounds and preparation methods and applications thereof, in particular to a class of β-carboline-thiazole conjugates and preparation methods and anti-tumor applications thereof, belonging to the technical field of medicinal chemistry. Background Art

[0002] Cancer is a major disease that threatens human health and seriously affects the lives of many people. With the increasing resistance to existing anti-tumor drugs, the development of new skeleton anti-tumor drugs has become increasingly urgent.

[0003] β-Carboline is an indole alkaloid containing a tricyclic pyridine [3,4-b] indole structure. As a key pharmacophore, it is not only widely present in natural active products but has also been shown to play an important role in anti-tumor lead drug molecules. Harmonica, a β-carboline natural product isolated from Peganum harmala, was found to have excellent anti-tumor effects as a lead compound for chemical structure modification. β-Carboline derivatives have been shown to effectively inhibit topoisomerases, cyclin-dependent kinases, and DNA synthesis, and inhibit intracellular DNA replication through intercalation and insertion, thereby inhibiting tumor cell proliferation. In recent years, modifying the β-carboline skeleton to introduce sulfonamides, podophyllotoxins, and other molecules to prepare novel β-carboline backbone molecules has been proven to be an effective means of developing new anti-tumor molecules.

[0004] Thiazole is an important pharmacophore and is widely present in anti-tumor drugs. However, β-carboline-thiazole conjugates are rarely reported. In particular, there are currently no reports on β-carboline C-3 thiazole-substituted skeleton compounds, and their anti-tumor activity is also unknown. Summary of the Invention

[0005] The purpose of the present invention is to innovatively integrate the two pharmacophores of β-carboline and thiazole to provide a new type of β-carboline-thiazole conjugate with a new skeleton, as well as a preparation method and anti-tumor application of such conjugate.

[0006] In order to achieve the above objectives, the present invention adopts the following technical solutions: A class of β-carboline-thiazole conjugates, the structure of which is shown below:

[0007] Wherein, R1 is any one of the following structures: 、 、 、 、 .

[0008] The preparation method of the aforementioned β-carboline-thiazole conjugate comprises the following steps: Step 1: Dissolve Boc-D-tryptophan in dichloromethane, add pentafluorophenyl diphenylphosphinate and triethylamine in sequence, stir at room temperature, add dimethyl azidocystine and triphenylphosphine, react at 45°C for 5h, remove the solvent by vacuum rotary evaporation to obtain a thiazoline product, dissolve the obtained thiazoline product in dichloromethane, add 1,8-diazabicyclo[5,4,0]undec-7-ene and trichlorobromomethane, react at room temperature for 2h, after completion of the reaction, quench the reaction, extract with dichloromethane and combine the organic phases, dry the organic phases, remove the solvent, and use V 石油醚 :V 乙酸乙酯 =5:1, and the solvent was removed to obtain compound 3 as a yellow oil; Step 2: Compound 3 was dissolved in dichloromethane, 4-fluorobenzaldehyde, vanillin, 3-chloro-4-fluorobenzaldehyde, 4-trifluoromethylbenzaldehyde or 3-fluoro-4-cyanobenzaldehyde were added at room temperature, trifluoroacetic acid was added dropwise at 0°C, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction was quenched, extracted with dichloromethane and the organic phases were combined, dried, and the solvent was removed. The product was dissolved in tetrahydrofuran, potassium permanganate was added, and the reaction was carried out at room temperature for 3 hours. V 石油醚 :V 乙酸乙酯 =3:1 or 2:1, pass through a column, and dry.

[0009] Preferably, in step 1, the molar ratio of Boc-D-tryptophan, pentafluorophenyldiphenylphosphinate, triethylamine, dimethyl azidocystine, triphenylphosphine, 1,8-diazabicyclo[5,4,0]undec-7-ene and bromotrichloromethane is 4:4:8:1:10:6:6.

[0010] Preferably, in step 2, the molar ratio of compound 3 to 4-fluorobenzaldehyde, vanillin, 3-chloro-4-fluorobenzaldehyde, 4-trifluoromethylbenzaldehyde or 3-fluoro-4-cyanobenzaldehyde is 2:3.

[0011] The use of the aforementioned β-carboline-thiazole conjugate in the preparation of an anti-tumor drug, wherein the tumor is human glioblastoma or gastric cancer, and the β-carboline-thiazole conjugate is: .

[0012] The present invention is beneficial in that: (1) The β-carboline-thiazole conjugate provided by the present invention has a novel structure and has a good killing effect on the human gastric cancer cell line MKN45, with IC 50 The lowest value can reach 3.8 μM (compound 8), which has a good inhibitory effect on the human glioblastoma cell line U87 (compound 8); (2) The preparation method provided by the present invention can synthesize β-carboline-thiazole conjugates in two steps. The raw materials are cheap and easily available, the preparation process is simple, and it is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 This is a graph showing the half-maximal inhibition evaluation of compound 8 on human gastric cancer cell line MKN45; Figure 2 This is a graph showing the half-maximal inhibition evaluation of compound 8 on the human glioblastoma cell line U87. DETAILED DESCRIPTION

[0014] The present invention is described in detail below with reference to specific embodiments.

[0015] 1. Structure of β-carboline-thiazole conjugates The present invention innovatively combines the two pharmacophores of β-carboline and thiazole, and the structure of the provided β-carboline-thiazole conjugate is shown below:

[0016] Wherein, R1 is any one of the following structures: 、 、 、 、 .

[0017] 2. Preparation Method of β-Carboline-Thiazole Conjugate

[0018]

[0019] Example 1

[0020] Step 1: Dissolve commercially available Boc-D-tryptophan (compound 1, 1 mmol) in dry dichloromethane (DCM, 50 mL), add pentafluorophenyl diphenylphosphinate (FDPP, 1 mmol) and triethylamine (Et3N, 2 mmol) in sequence, stir at room temperature for 5 min, add dimethyl azidocystine (compound 2, 0.25 mmol) and triphenylphosphine (PPh3, 2.5 mmol), react at 45 ° C for 5 h, and remove the solvent by vacuum rotary evaporation to obtain the thiazoline product without purification. The obtained thiazoline product was dissolved in dry DCM (50 mL), and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 1.5 mmol) and bromotrichloromethane (CBrCl3, 1.5 mmol) were added. The reaction was allowed to proceed at room temperature for 2 h. After completion of the reaction, saturated ammonium chloride solution (80 mL) was added to the reaction system to quench the reaction. The mixture was extracted with dichloromethane (80 mL each time, 3 times) and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum rotary evaporation. The mixture was then dried with V 石油醚 :V 乙酸乙酯 =5:1, and the solvent was removed by column evaporation under vacuum to obtain a yellow oil (compound 3) with a yield of 79%.

[0021] Compound 3 1 The H NMR and ESI-HRMS data are as follows: 1 H NMR (400MHz, CDCl3) δ 8.14 (s, 1H), 8.03 (s, 1H), 7.45 (d, J= 7.6 Hz, 1H), 7.35 (d, J= 7.6 Hz, 1H), 7.18 (dd, J= 7.6Hz, J= 7.6 Hz, 1H), 7.08 (dd, J= 7.6Hz, J= 7.6 Hz, 1H), 6.69 (d, J= 0.8Hz, 1H), 5.39 (s, br, 2H), 3.98 (s, 3H), 3.55 (d, J= 13.2 Hz, 1H), 3.45 (dd, J= 4.0Hz, J= 13.2Hz, 1H), 1.28 (s, 9H); ESI-HRMS: C 20 H 23 N3O4S([M+Na] + ) Calculated value 424.1302, theoretical value 423.2308.

[0022] Step 2: Compound 3 (1 mmol) was dissolved in dry DCM (20 mL), 4-fluorobenzaldehyde (1.5 mmol) was added at room temperature, trifluoroacetic acid (TFA, 1 mL) was added dropwise at 0 ° C, and the reaction was carried out at room temperature for 2 h. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution (50 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with dichloromethane (40 mL each time, 3 times) and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum rotary evaporation. The product was dissolved in dry tetrahydrofuran (THF, 30 mL), potassium permanganate (KMnO4, 1.5 mmol) was added, and the reaction was carried out at room temperature for 3 h. 石油醚 :V 乙酸乙酯 =2:1, passed through a column, and dried to obtain a light yellow solid (Compound 4) with a yield of 70%.

[0023] Compound 4 1 H NMR, 13 The C NMR and ESI-HRMS data are as follows: 1 H NMR (500MHz, CDCl3) δ 8.83 (s, 1H), 8.74 (s, 1H), 8.15 (s, 1H), 8.03 (d, J=7.9Hz, 1H), 7.95 (t, J=7Hz, 2H), 7. 51-7.46 (m, 2H), 7.25 (t, J=6.5Hz, 1H), 7.21 (d, J=9Hz, 1H), 3.94 (s, 3H), 1.18 (s, 1H); 13 C NMR (125MHz, CDCl3) δ 171.66, 164.19, 162.21, 162.18, 147.30, 140.97, 140.76, 134.02, 133.77, 133.74, 130.77 , 129.99, 129.92, 128.96, 128.79, 122.13, 120.98, 116.21, 116.04, 111.70, 110.85, 52.39; ESI-HRMS: C 22 H 14 FN3NaO2S([M+Na] + ) Calculated value 420.0681, theoretical value 426.0683.

[0024] Example 2

[0025] Step 1: It is exactly the same as step 1 of Example 1 and will not be repeated here.

[0026] Step 2: Compound 3 (1 mmol) was dissolved in dry DCM (20 mL), 3-chloro-4-fluorobenzaldehyde (1.5 mmol) was added at room temperature, TFA (1 mL) was added dropwise at 0 ° C, and the reaction was carried out at room temperature for 2 h. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution (50 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with dichloromethane (40 mL each time, 3 times) and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum rotary evaporation. The product was dissolved in dry THF (30 mL), KMnO4 (1.5 mmol) was added, and the reaction was carried out at room temperature for 3 h. 石油醚 :V 乙酸乙酯 =3:1, passed through a column, and dried to obtain a light yellow solid (Compound 5) with a yield of 69%.

[0027] Compound 5 1 H NMR, 13 The C NMR and ESI-HRMS data are as follows: 1 H NMR (500 MHz, d- DMSO) δ 11.92 (s, 1H), 8.87 (s, 1H), 8.50 (s, 1H), 8.45 (d, J =7.5Hz,1H),8.19(d, J =7.1Hz, 1H), 8.06 (s, 1H), 7.68 (t, J =9.0Hz, 2H), 7.60(t, J =8.0Hz, 1H), 7.31(t, J =7.5Hz, 1H), 3.90 (s, 3H); 13 C NMR (125 MHz, d- DMSO)δ 171.0, 161.9, 157.2, 147.2, 142.3, 140.1, 139.7, 135.4, 134.2, 130.6, 12 9.8, 129.5, 122.8, 121.6, 120.8, 117.9, 117.7, 113.1, 111.0, 79.7, 52.5; ESI-HRMS: C 22 H 13 ClFN3NaO2S([M+Na] + ) Calculated value 460.0293, theoretical value 460.0291.

[0028] Example 3

[0029] Step 1: It is exactly the same as step 1 of Example 1 and will not be repeated here.

[0030] Step 2: Compound 3 (1 mmol) was dissolved in dry DCM (20 mL), vanillin (1.5 mmol) was added at room temperature, TFA (1 mL) was added dropwise at 0 ° C, and the reaction was carried out at room temperature for 2 h. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution (50 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with dichloromethane (40 mL each time, 3 times) and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum rotary evaporation. The product was dissolved in dry THF (30 mL), KMnO4 (1.5 mmol) was added, and the reaction was carried out at room temperature for 3 h. 石油醚 :V 乙酸乙酯 =2:1, passed through a column, and dried to obtain a light yellow solid (Compound 6) with a yield of 65%.

[0031] Compound 6 1 H NMR, 13 The C NMR and ESI-HRMS data are as follows: 1 H NMR (500 MHz, d -DMSO) δ 11.98 (s, 1H), 8.95 (d, J=9.5Hz, 2H), 8.56 (s, 1H), 8.48 (d, J=7.5Hz, 1H), 7.64 (d, J=8. 5Hz, 1H), 7.60 (t, J=9Hz, 1H), 7.30 (t, J=8Hz, 1H), 3.88 (s, 3H), 1.25 (t, J=20.5Hz, 3H); 13 C NMR (125 MHz, d -DMSO) δ 171.4, 161.9, 147.2, 141.7, 140.1, 137.4, 134.3, 130.4, 129.3, 128.9, 123.1, 121.4, 120.5, 112.8, 111.5, 79.6, 52.5, 31.6; ESI-HRMS: C 23 H 17 N3NaO4S([M+Na] + ) Calculated value 454.0833, theoretical value 454.0832.

[0032] Example 4

[0033] Step 1: It is exactly the same as step 1 of Example 1 and will not be repeated here.

[0034] Step 2: Compound 3 (1 mmol) was dissolved in dry DCM (20 mL), 4-trifluoromethylbenzaldehyde (1.5 mmol) was added at room temperature, TFA (1 mL) was added dropwise at 0 ° C, and the reaction was carried out at room temperature for 2 h. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution (50 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with dichloromethane (40 mL each time, 3 times) and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum rotary evaporation. The product was dissolved in dry THF (30 mL), KMnO4 (1.5 mmol) was added, and the reaction was carried out at room temperature for 3 h. 石油醚 :V 乙酸乙酯 =2:1, passed through a column, and dried to obtain a light yellow solid (Compound 7) with a yield of 71%.

[0035] Compound 7 1 H NMR, 13 The C NMR and ESI-HRMS data are as follows: 1 H NMR (500 MHz, d -DMSO)δ 11.93 (s, 1H), 8.90 (s, 1H), 8.51 (s, 1H), 8.45 (d, J =7.5Hz,1H),8.25(d, J =7.5Hz, 2H), 7.98(d, J =8.0Hz, 2H), 7.66(d, J =8.5Hz,1H),7.60(t, J =8Hz,1H),7.31(t, J =7.5Hz, 1H), 3.90 (s, 3H); 13 C NMR (125 MHz, d -DMSO)δ 170.94, 161.84, 147.16, 142.34, 141.55, 140.42, 140.25, 134.53, 131.07, 130.56 , 129.79, 129.46, 126.17, 126.14, 122.82, 121.55, 120.83, 113.07, 111.26, 52.48; ESI-HRMS: C 23 H 14 F3N3NaO2S([M+Na] + ) Calculated value 476.0651, theoretical value 476.0645.

[0036] Example 5

[0037] Step 1: It is exactly the same as step 1 of Example 1 and will not be repeated here.

[0038] Step 2: Compound 3 (1 mmol) was dissolved in dry DCM (20 mL), 3-fluoro-4-cyanobenzaldehyde (1.5 mmol) was added at room temperature, TFA (10 mL) was added dropwise at 0 ° C, and the reaction was carried out at room temperature for 2 h. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution (50 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with dichloromethane (40 mL each time, 3 times) and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum rotary evaporation. The product was dissolved in dry THF (30 mL), KMnO4 (1.5 mmol) was added, and the reaction was carried out at room temperature for 3 h. 石油醚 :V 乙酸乙酯 =2:1 passed through a column and dried to obtain a light yellow solid (Compound 8) with a yield of 73%.

[0039] Compound 8 1 H NMR, 13 The C NMR and ESI-HRMS data are as follows: 1 H NMR (500 MHz, d -DMSO) δ 11.90 (s, 1H), 8.80 (s, 1H), 8.45 (s, 1H), 8.38 (d, J =8Hz,1H),8.12(t, J =8Hz,1H),8.03(t, J =9Hz, 2H), 7.62(d, J =8Hz,1H),7.58(t, J =8Hz,1H),7.27(t, J =8Hz, 1H), 3.89 (s, 3H); 13 C NMR (126 MHz, deuterated methanol) δ 171.3, 162.8, 162.6, 147.9, 145.4, 143.1, 140.9, 138.8, 135.5, 135.1, 132.4, 131.4, 130.4, 126.5, 126.4, 123.6, 122.1, 121.7, 117.1, 115.3, 113.8, 112.6, 53.3; ESI-HRMS: C 23 H 13 FN4NaO2S([M+Na] +) Calculated value 451.0636, theoretical value 451.0635.

[0040] 3. Pharmacological studies of β-carboline-thiazole conjugates The inhibitory activities of compounds 4, 5, 6, 7 and 8 on the human glioblastoma cell line U87 and the human gastric cancer cell line MKN45 were detected.

[0041] The MTT assay was used to determine the half-maximal inhibitory concentration (IC50) of the above compounds on two human tumor cell lines: human glioblastoma cell line U87 and human gastric cancer cell line MKN45. 50 ).

[0042] Detection principle: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) can penetrate the cell membrane and enter the cell. The succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to blue-purple needle-shaped formazan crystals that are insoluble in water and deposited in the cells. The crystals can be dissolved by dimethyl sulfoxide (DMSO). The absorbance of the crystals can reflect the cell survival rate. The half inhibitory concentration (IC 50 ) is defined as the drug concentration when 50% of the tumor cells survive. According to the measured optical density (OD value), a standard curve of cell survival rate is prepared, and the corresponding drug concentration is then obtained on the curve.

[0043] The determination method is as follows: (1) Human glioblastoma cell line U87 or human gastric cancer cell line MKN45 were seeded into 96-well plates at a density of 2000 cells / well and cultured in a CO2 incubator for 24 h; (2) The test compound (stock concentration 10 mM) was serially diluted to 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.627 μM, 0.3125 μM, and 0.15625 μM; (3) Set up three sets of parallel wells for each concentration, add the test compound to the seeded cells, and continue to culture for 72 hours; (4) Remove the 96-well plate from the CO2 incubator, add 20 μL of MTT solution (concentration 5 mg / mL) to each well, and continue incubating in the CO2 incubator for 2 h; (5) Discard the upper layer of liquid, add 150 μL of DMSO to each well, and shake gently for 15 minutes to completely dissolve the formazan crystals; (6) Use an enzyme-labeled analyzer to measure the absorbance of each well at 570 nm and calculate the cell survival rate.

[0044] Three parallel experiments were performed, and the experimental results were averaged. The cell viability of the human glioblastoma cell line U87 and the human gastric cancer cell line MKN45 is shown in Table 1.

[0045] Table 1 Effects of the test compounds on the viability of U87 and MKN45 cells

[0046] From Table 1 we can see that: (1) At a concentration of 10 μM, compounds 4, 5, 6, and 7 showed no inhibitory activity against the human glioblastoma cell line U87. Compound 8 had a strong inhibitory activity against the human glioblastoma cell line U87, with a cell survival rate of 71.9%; (2) At a concentration of 10 μM, compounds 4, 5, 6, and 7 showed no inhibitory activity against the human gastric cancer cell line MKN45, while compound 8 showed significant inhibitory activity against the human gastric cancer cell line MKN45, with a cell survival rate of only 15.0%.

[0047] The half-maximal inhibition evaluation of compound 8 on human gastric cancer cell line MKN45 is shown in the figure Figure 1 The half-maximal inhibition evaluation of human glioblastoma cell line U87 is shown in the figure Figure 2 The half-maximal inhibitory concentration (IC 50 The evaluation results are shown in Table 2.

[0048] Table 2 IC of compound 8 against U87 and MKN45 50 value

[0049] From Table 2 we can see that: (1) Compound 8 has a good inhibitory effect on human glioblastoma cell line U87, IC 50 The value is 6.7 μM; (2) Compound 8 has a significant killing effect on human gastric cancer cell line MKN45, IC 50 The value is 3.8 μM.

[0050] Hypothesized anti-tumor mechanism: β-carboline derivatives are generally believed to possess topoisomerase I or topoisomerase II inhibitory activity, stabilizing the "cleavable complex" formed by topoisomerase and DNA, preventing the reconnection of broken DNA single strands and causing DNA double-strand breaks. The cyano group in compound 8 is a strong electron-withdrawing group that significantly alters the electron cloud distribution of the carboline parent ring, enhancing the planarity of the aromatic ring and the stability of the conjugated system, making compound 8 more likely to insert into DNA double-helix base pairs and interfere with DNA replication and transcription. The fluorine atom in the structure of compound 8 has high electronegativity, which may enhance the binding of compound 8 to the target through electrostatic interactions.

[0051] It should be noted that the above embodiments are merely examples for the purpose of clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. A person skilled in the art would be able to make other variations or modifications based on the above description. It is not possible to enumerate all embodiments here. Any obvious variations or modifications arising from the technical solution of the present invention remain within the scope of protection of the present invention.

Claims

1. β-Carboline-thiazole conjugate, characterized in that The structure is as follows: ； Wherein, R1 is any one of the following structures: 、 、 、 、 。 2. The method for preparing the β-carboline-thiazole conjugate according to claim 1, characterized in that: The following steps are involved: Step 1: Dissolve Boc-D-tryptophan in dichloromethane, add pentafluorophenyl diphenylphosphinate and triethylamine in sequence, stir at room temperature, add dimethyl azidocystine and triphenylphosphine, react at 45°C for 5h, remove the solvent by vacuum rotary evaporation to obtain a thiazoline product, dissolve the obtained thiazoline product in dichloromethane, add 1,8-diazabicyclo[5,4,0]undec-7-ene and trichlorobromomethane, react at room temperature for 2h, after completion of the reaction, quench the reaction, extract with dichloromethane and combine the organic phases, dry the organic phases, remove the solvent, and use V 石油醚 :V 乙酸乙酯 =5:1, and the solvent was removed to obtain compound 3 as a yellow oil; Step 2: Compound 3 was dissolved in dichloromethane, 4-fluorobenzaldehyde, vanillin, 3-chloro-4-fluorobenzaldehyde, 4-trifluoromethylbenzaldehyde or 3-fluoro-4-cyanobenzaldehyde were added at room temperature, trifluoroacetic acid was added dropwise at 0°C, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction was quenched, extracted with dichloromethane and the organic phases were combined, dried, and the solvent was removed. The product was dissolved in tetrahydrofuran, potassium permanganate was added, and the reaction was carried out at room temperature for 3 hours. V 石油醚 :V 乙酸乙酯 =3:1 or 2:1, pass through a column, and dry.

3. The preparation method according to claim 2, characterized in that In step 1, the molar ratio of Boc-D-tryptophan, pentafluorophenyldiphenylphosphinate, triethylamine, dimethyl azidocystine, triphenylphosphine, 1,8-diazabicyclo[5,4,0]undec-7-ene and bromotrichloromethane is 4:4:8:1:10:6:

6.

4. The preparation method according to claim 2, characterized in that In step 2, the molar ratio of compound 3 to 4-fluorobenzaldehyde, vanillin, 3-chloro-4-fluorobenzaldehyde, 4-trifluoromethylbenzaldehyde or 3-fluoro-4-cyanobenzaldehyde is 2:

3.

5. Use of the β-carboline-thiazole conjugate according to claim 1 in the preparation of anti-tumor drugs, wherein: The tumor is human glioblastoma or gastric cancer, and the β-carboline-thiazole conjugate is: 。

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