CN113387963B

CN113387963B - Beta-carboline compound and preparation method and application thereof

Info

Publication number: CN113387963B
Application number: CN202110516881.2A
Authority: CN
Inventors: 陈锦灿; 陈兰美; 罗辉; 郭欣华; 陈伟钢
Original assignee: Southern Marine Science and Engineering Guangdong Laboratory Zhanjiang
Current assignee: Southern Marine Science and Engineering Guangdong Laboratory Zhanjiang
Priority date: 2021-05-12
Filing date: 2021-05-12
Publication date: 2022-03-25
Anticipated expiration: 2041-05-12
Also published as: CN113387963A

Abstract

The invention discloses a beta-carboline compound and a preparation method and application thereof, wherein the structural formula of the beta-carboline compound is shown in the specification

The invention provides a novel beta-carboline compound, which can remarkably improve the bioactivity of the beta-carboline compound on cancer cells by adding 1, 10-phenanthroline groups on the basis of a beta-carboline structure, and has good inhibition effect on cancer cells such as lung cancer, cervical cancer, liver cancer, breast cancer and the like.

Description

Beta-carboline compound and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a beta-carboline compound and a preparation method and application thereof.

Background

Alkaloids are an important natural compound, widely exist in blood and tissues of plants, animals, marine organisms and even human beings, have complex structures and have good biological activity. Carboline is pyridoindole alkaloid, and can be classified into alpha, beta and gamma-carboline according to different cyclization modes. Wherein the beta-carboline alkaloid is widely existed in nature, and the quantity is the most.

Since the first beta-carboline alkaloid Harman was discovered from Peganum harmala (L.) Harman, a large number of novel beta-carbolines were isolated and extracted each year, distributed mainly in plants and marine organisms, and most of them were active well. The beta-carboline alkaloid contains condensed rings, has a highly conjugated system, is mostly yellow powder and has strong fluorescence. The beta-carboline alkaloid has novel structure and alkalinity, can form salt with acid, and is easy to absorb in vivo; but also has good biochemical activity, such as can be made into anticancer enzyme inhibitor, and has antithrombotic, antiviral, antibacterial and antiinflammatory activities.

Antineoplastic drugs have long been of interest. Research shows that the beta-carboline alkaloid has obvious activity of inhibiting cancer cell proliferation and obvious effect of inhibiting tumor angiogenesis. The related technology reports that the beta-carboline alkaloid has an effect on the central nervous system, the beta-carboline derivative can inhibit topoisomerase I and topoisomerase II, is a specific inhibitor of Cyclin Dependent Kinase (CDK), and the inhibition activity of the beta-carboline derivative is in a crucial relation with the total aromaticity of aromatic heterocycles in the structure. The beta-carboline ring is introduced into a DNA targeting side chain and embedded into a DNA molecule, so that the expression of Bcl-2 can be reduced, the expression of death receptor Fas is promoted on the basis of not changing Bax and p53 expression, and the beta-carboline has good antitumor activity.

With the continuous discovery of beta-carboline alkaloids, the beta-carboline alkaloids have various biological activities, but the pure extraction from animals and plants has the disadvantages of low content, high cost and great difficulty, so that the beta-carboline alkaloids need to be prepared in large quantities by organic synthesis.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention provides a novel beta-carboline compound and also provides a preparation method and application of the beta-carboline compound.

Specifically, the technical scheme adopted by the invention is as follows:

the first aspect of the invention provides a beta-carboline compound, which has a structural formula shown as the following formula I:

wherein X comprises aryl and Y comprises H, C_1～10Linear or branched alkyl of (2), C_1～10Linear or branched substituted alkyl groups of (a). The aryl group in the present invention refers to a group containing an aromatic ring, and the aromatic ring includes aromatic monocyclic ring, aromatic polycyclic ring, aromatic heterocyclic ring, and the like.

The beta-carboline compound according to the first aspect of the invention has at least the following beneficial effects:

according to the invention, the 1, 10-phenanthroline group is added on the basis of the beta-carboline structure, so that the biological activity of the beta-carboline compound on cancer cells can be obviously improved.

In some embodiments of the invention, X is selected from the group consisting of:

the second aspect of the present invention provides a preparation method of the above β -carboline compound, wherein the synthetic route is as follows:

the preparation method comprises the following steps:

(1) reacting the compound 1 with thionyl chloride to obtain a compound 2;

(2) compound 2 and

reacting to obtain a compound 3;

(3) reacting the compound 3 with p-methylbenzenesulfonyl chloride to obtain a compound 4;

(4) heating compound 4 under basic conditions to form compound 5;

(5) hydrolyzing the compound 5 to obtain a compound 6;

(6) the compound 6 reacts with 1, 10-phenanthroline-5-amino to obtain a compound I, namely a beta-carboline compound.

The preparation method according to the second aspect of the present invention has at least the following advantageous effects:

in the preparation method, the tryptophan compounds are used as raw materials and react with thionyl chloride to form Schiff base (compound 2, tryptophan methyl ester hydrochloride), so that HCl gas is not directly used, and the preparation method is safer. And cyclizing the compound 2 under the catalytic action of Lewis acid to obtain a tetrahydro beta-carboline structure (a compound 3). The compound 3 is substituted by p-methylbenzenesulfonyl chloride, and then oxidation is eliminated, so that the beta-carboline structure (the compound 5) is obtained. In the oxidation process, a strong oxidant and metal are not used, the condition is mild, and no sensitive group exists in the reaction. Finally, the beta-carboline structure is modified through condensation reaction with 1, 10-phenanthroline-5-amino, so that the antitumor activity of the beta-carboline structure can be improved.

In some embodiments of the invention, in step (1), the molar ratio of the compound 1 to the thionyl chloride is 1: 1 to 1.5; the reaction temperature is 50-110 ℃, and the reaction time is 5-10 h. In practical operation, the compound 1 can be dissolved in an organic solvent (such as methanol, benzene, chloroform, carbon tetrachloride, dichloromethane and the like), thionyl chloride is added at a temperature below 10 ℃ (such as under an ice bath condition), then heating and refluxing are carried out at 50-110 ℃, the solvent is removed after the reaction is finished, and the compound 2 is obtained by cleaning and drying.

In some embodiments of the invention, in step (2), the compound 2 is reacted with

In a molar ratio of 1: 1 to 1.5; the reaction temperature is 60-100 ℃, and the reaction time is 5-20 hours, preferably 10-15 hours; the reaction is carried out under a protective atmosphere.

In some embodiments of the invention, in step (3), the molar ratio of compound 3 to p-methylbenzenesulfonyl chloride is 1: 1 to 1.5; the reaction temperature is 5-40 ℃, and the reaction time is 2-10 h, preferably 3-5 h. The reaction is carried out in the presence of a basic catalyst, and the ratio of the basic catalyst to the p-toluenesulfonyl chloride is 1 mu L: 1 to 1.5 mmol. The basic catalyst comprises any one or more of pyridine, triethylamine, potassium carbonate and 1, 8-diazabicycloundec-7-ene (DBU). In actual operation, pyridine and other basic catalysts and p-methylbenzenesulfonyl chloride can be added at low temperature (such as-10-0 ℃).

In some embodiments of the present invention, in the step (4), the pH of the alkaline condition is 8 to 12, and in practical operation, the alkaline condition can be formed by adding alkaline substances such as potassium carbonate, sodium hydroxide, potassium hydroxide, and the like; the heating temperature is 80-120 ℃, and the heating time is 3-5 h.

In some embodiments of the present invention, in the step (5), the hydrolysis is performed at a pH of 10 to 14. The hydrolysis temperature is 80-110 ℃, and the hydrolysis time is 1-2 h. After the hydrolysis is completed, an acid is added to adjust the reaction system to weak acidity (pH 3 to 5).

In some embodiments of the invention, in step (6), the molar ratio of compound 6 to 1, 10-phenanthroline-5-amino group is 1: 1 to 1.5; the reaction temperature is 10-40 ℃, and the reaction time is 20-24 h. The reaction is carried out in the presence of an activating agent, wherein the activating agent comprises any one or more of 1-Hydroxybenzotriazole (HOBT), benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU), N, N-Diisopropylethylamine (DIEA) and 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (EDCI). Preferably, the activator is a combination of HOBT, DIEA and EDCI, the proportions of which can be adjusted to practice. By way of example, the ratio of HOBT, DIEA and EDCI is 6-12 mmol: 400-600 uL: 6-12 mmol.

The third aspect of the invention is to provide the application of the beta-carboline compound in preparing anti-cancer drugs. More specifically, the application of the beta-carboline compound in preparing anti-lung cancer drugs, anti-cervical cancer drugs, anti-liver cancer drugs and anti-breast cancer drugs is provided.

The fourth aspect of the invention provides a pharmaceutical composition, which contains the beta-carboline compound.

Compared with the prior art, the invention has the following beneficial effects:

The beta-carboline compound has the advantages of simple preparation process, mild conditions, high yield and purity, easy realization and suitability for large-scale production.

Drawings

FIG. 1 is a nuclear magnetic spectrum of Compound 6 (4-BrP. beta. CA) of example 1;

FIG. 2 shows UV absorption spectra of compound I (4-BrPP. beta.C) in example 1 at pH values of 7.50-8.50 (1), 11.50-12.50 (2), and 2.30-3.30 (3), respectively;

FIG. 3 is the NMR spectrum of Compound I (4-BrPP. beta.C) in example 1;

FIG. 4 is a nuclear magnetic spectrum of Compound 6 (4-ClP. beta. CA) in example 2;

FIG. 5 shows UV absorption spectra of compound I (4-ClPP. beta.C) in example 2 at pH values of 7.50-8.50 (1), 11.50-12.50 (2), and 2.30-3.30 (3), respectively;

FIG. 6 is a nuclear magnetic spectrum of Compound I (4-ClPP. beta.C) in example 2;

FIG. 7 is a nuclear magnetic spectrum of Compound 6 (4-FP. beta. CA) in example 3;

FIG. 8 shows UV absorption spectra of compound I (4-FPP. beta.C) of example 3 at pH values of 7.50-8.50 (1), 11.50-12.50 (2), and 2.30-3.30 (3), respectively;

FIG. 9 is a nuclear magnetic spectrum of Compound I (4-FPP. beta.C) in example 3;

FIG. 10 shows the results of the Hoechst 33342 staining test of Compound I (4-BrPP. beta.C) of example 1.

FIG. 11 shows the compound I (4-BrPP. beta.C) Annexin V staining experiment in example 1.

FIG. 12 shows the active oxygen staining experiment of Compound I (4-BrPP. beta.C) of example 1.

Detailed Description

The technical solution of the present invention is further described below with reference to specific examples.

Example 1

Preparing a beta-carboline compound 4-BrPP beta C:

(1) synthesis of Compound 2

Tryptophan (compound 1, 0.82g, 4mmol) was dissolved in 20mL methanol, thionyl chloride (0.29mL, 4mmol) was added dropwise in an ice bath, the solution was condensed and refluxed at 100 ℃ for 7 hours, the solvent was distilled off under reduced pressure, the solution was rinsed with ethyl acetate, filtered with suction, and dried to obtain white powder with a yield of 90.6%.

(2) Synthesis of Compound 3 (4-BrP-4H-. beta.C)

Adding the compound 2(1.019g, 4mmol) into a reaction tube, adding 4-bromobenzaldehyde (0.74g, 4mmol), dissolving in 20mL isopropanol, heating and refluxing at 80 ℃ under the protection of argon for 13h, distilling the obtained liquid under reduced pressure to remove the solvent, adding benzene for rinsing, performing suction filtration, and drying to obtain a light yellow solid with the yield of 94.3%.

(3) Synthesis of Compound 4 (4-BrP-N-Ts-4H-. beta.C)

Compound 3(1.54g, 4mmol) was dissolved in 15mL of dichloromethane, 400 μ L of pyridine and p-toluenesulfonyl chloride (0.76g, 4mmol) were added at-5 deg.C, the mixture was stirred at room temperature for 3h after the freezing was removed, the solvent was removed by distillation under reduced pressure, washed with 10mL of 10% potassium carbonate solution, dried over anhydrous magnesium sulfate, rinsed with petroleum ether, and filtered with suction to give a yellow solid in 96.0% yield.

(4) Synthesis of Compound 5 (4-BrP. beta.C)

Dissolving the compound 4(2.16g, 4mmol) in 10mL of dimethyl sulfoxide, adding potassium carbonate (0.69g, 5mmol), heating and refluxing at 80 ℃ for 3h, cooling to room temperature after the reaction is finished, adding 100mL of water, standing overnight, stirring, filtering, rinsing with water, and drying to obtain the product with the yield of 80.0%.

(5) Synthesis of Compound 6 (4-BrP. beta. CA)

Compound 5(1.52g, 4mmol) was dissolved in ethanol: water (V/V ═ 1:2) (10 mL ethanol, 20mL water), sodium hydroxide (0.40g, 12mmol) was added, the reaction solution was refluxed at 80 ℃ for 1h, the pH of the reaction solution was adjusted to 5 with HCl, suction filtered, and dried to give a yellow solid with a yield of 70%. The nuclear magnetic spectrum of the obtained product is shown in figure 1.

(6) Synthesis of Compound I (4-BrPP. beta.C)

Adding compound 6(1.49g, 4mmol) into HOBT (0.81g, 6mmol), DIEA (400uL), 1, 10-phenanthroline-5-amino (phen-NH)₂0.78g, 4mmol), adding EDCI (1.15g, 6mmol), continuing to react at room temperature for 20h, decompressing and rotary steaming, rinsing with water and suction filtering to obtain the product with yield of 85.8%, purifying the crude product by silica gel columnAnd (4) transforming. Ultraviolet absorption spectra of the obtained product under the conditions that the pH values are 7.50-8.50, 11.50-12.50 and 2.30-3.30 are shown as curves 1-3 of figure 2 in sequence; the nuclear magnetic spectrum is shown in FIG. 3.

Example 2

Preparation of beta-carboline compound 4-ClPP beta C:

(1) synthesis of Compound 2

The same as in example 1.

(2) Synthesis of Compound 3 (4-ClP-4H-. beta.C)

Adding the compound 2(2.03g, 8mmol) into a reaction tube, adding 4-chlorobenzaldehyde (1.12g, 8mmol), dissolving in 30mL isopropanol, heating and refluxing at 100 ℃ under the protection of argon for 12h, distilling the obtained liquid under reduced pressure to remove the solvent, adding benzene, violently stirring, filtering, and drying to obtain a light yellow solid.

(3) Synthesis of Compound 4 (4-ClP-N-Ts-4H-. beta.C)

Compound 3(2.72g, 8mmol) was dissolved in 15mL of dichloromethane, 800. mu.L of pyridine and p-toluenesulfonyl chloride (1.52g, 8mmol) were added at-5 ℃ and after the freezing was removed, stirred at room temperature for 5h, the solvent was removed by distillation under reduced pressure, washed with 10mL of 10% potassium carbonate solution, dried over anhydrous magnesium sulfate, rinsed with petroleum ether and filtered with suction to give a yellow solid.

(4) Synthesis of Compound 5 (4-ClP. beta.C)

Dissolving the compound 4(3.96g, 8mmol) in 5mL of dimethyl sulfoxide, adding potassium carbonate (0.97g, 7mmol), heating and refluxing at 120 ℃ for 5h, cooling to room temperature after the reaction is finished, adding 100mL of water, standing overnight, stirring, filtering, rinsing with water, and drying to obtain the product.

(5) Synthesis of Compound 6 (4-ClP. beta. CA)

Compound 5(2.70g, 8mmol) was dissolved in ethanol: water (V/V ═ 1:2) (10 mL ethanol), sodium hydroxide (0.8g, 20mmol) was added, the mixture was condensed under reflux at 110 ℃, the solution after reaction was adjusted to pH 5 with HCl, filtered with suction, and dried to give a yellow solid. The nuclear magnetic spectrum of the obtained product is shown in FIG. 4.

(6) Synthesis of Compound I (4-ClPP. beta.C)

Add Compound 5(2.58g, 8mmol) to HOBT (1.62g, 12mmol), DIEA (600uL), phen-NH₂(1.56g, 8mmol), EDCI (2.30g, 12mmol) was added, the reaction was continued at room temperature for 24h, rotary evaporation under reduced pressure, rinsing with water and suction filtration to give the product, and the crude product was purified by silica gel column. Ultraviolet absorption spectra of the obtained product under the conditions that the pH values are 7.50-8.50, 11.50-12.50 and 2.30-3.30 are shown as curves 1-3 of figure 5 in sequence; the nuclear magnetic spectrum is shown in FIG. 6.

Example 3

Preparation of beta-carboline compound 4-FPP beta CD:

(1) synthesis of Compound 2

Same as example 1

(2) Synthesis of Compound 3 (4-FP-4H-. beta.C)

Adding the compound 2(1.02g, 4mmol) into a reaction tube, adding 4-fluorobenzaldehyde (0.50g, 4mmol), dissolving in 20mL isopropanol, heating and refluxing at 60 ℃ under the protection of argon for 10h, distilling the obtained liquid under reduced pressure to remove the solvent, adding benzene, violently stirring, filtering, and drying to obtain a light yellow solid.

(3) Synthesis of Compound 4 (4-FP-N-Ts-4H-. beta.C)

Compound 3(1.30g, 4mmol) was dissolved in 15mL of dichloromethane, 400. mu.L of pyridine and p-toluenesulfonyl chloride (0.76g, 4mmol) were added at-5 ℃ and after the freezing was removed, stirred at room temperature for 3h, the solvent was removed by distillation under reduced pressure, washed with 10mL of 10% potassium carbonate solution, dried over anhydrous magnesium sulfate, rinsed with petroleum ether and filtered with suction to give a yellow solid.

(4) Synthesis of Compound 5 (4-FP. beta.C)

Dissolving the compound 3(1.91g, 4mmol) in 8mL of dimethyl sulfoxide, adding potassium carbonate (0.69g, 5mmol), heating and refluxing at 80 ℃ for 4h, cooling to room temperature after the reaction is finished, adding 100mL of water, standing overnight, stirring, filtering, rinsing with water, and drying to obtain the product.

(5) Synthesis of Compound 6 (4-FP. beta. CA)

Compound 5(1.28g, 4mmol) was dissolved in ethanol: water (V/V ═ 1:2) (10 mL ethanol), sodium hydroxide (0.40g, 12mmol) was added, the mixture was condensed and refluxed at 80 ℃ for 1h, the solution after the reaction was adjusted to pH 5 with HCl, and the mixture was filtered off with suction and dried to give a yellow solid. The nuclear magnetic spectrum of the obtained product is shown in FIG. 7.

(6) Synthesis of Compound I (4-FPP. beta.C)

Add Compound 6(1.22g, 4mmol) to HOBT (0.81g, 6mmol), DIEA (400uL), phen-NH₂(0.78g, 4mmol), EDCI (1.15g, 6mmol) was added, the reaction was continued at room temperature for 20h, rotary evaporation under reduced pressure, rinsing with water and suction filtration to give the product, and the crude product was purified by silica gel column. Ultraviolet absorption spectra of the obtained product under the conditions that the pH values are 7.50-8.50, 11.50-12.50 and 2.30-3.30 are shown as curves 1-3 of figure 8 in sequence; the nuclear magnetic spectrum is shown in FIG. 9.

Biological activity assay

(1) Cytotoxicity of compound 6 and compound I in examples 1-3 was tested as follows:

cytotoxicity assays were performed using the MTT method: taking A549, HeLa, HepG-2, MCF-7 and BEAS-2B cells in logarithmic growth phase at 5 × 10³The cells were inoculated into 96-well plates and pre-incubated for 24 h. When the cells adhere to the wall, the culture medium is replaced, and 4-BrP beta CA, 4-BrPP beta C, 4-ClP beta CA, 4-ClPP beta C, 4-FP beta CA and 4-FPP beta C are respectively added in a concentration gradient mode (a DMSO treatment group is used as a control group, and a non-inoculated cell group is used as a blank group). After the incubation was completed, MTT was added to a 96-well plate and incubated at 37 ℃ for 4 hours, followed by carefully aspirating the culture medium, adding 150. mu.L/well DMSO to dissolve the formazan at room temperature, shaking it up, measuring the OD at 490nm using a microplate reader, and calculating the cell viability.

After three independent experiments were repeated, Half the inhibitory concentration (Half-inhibition concentration, IC50) was determined using SPSS 16.0.

The cytotoxicity test data are shown in table 1 below:

TABLE 1 cytotoxicity test results of Compound 6 and Compound I

The test results in Table 1 show that the compound I obtained by adding 1, 10-phenanthroline group to the beta-carboline structure of the compound 6 has IC effect on cancer cells such as lung cancer, cervical cancer, liver cancer, breast cancer, etc₅₀Obviously reduces the activity of the polypeptide, and obviously improves the biological activity to cancer cells. Among them, 4-BrPP beta C is the most significant.

(2) Staining experiments were carried out with compound I of example 1 (4-BrPP. beta.C):

hoechst 33342 staining experiment

Logarithmic growth of A549 cells was inoculated into a Nest confocal dish of 40mm, after the cells adhered to the wall, 4-BrPP beta C and 40. mu.M 4-BrP beta CA at different concentrations were added, and incubation was continued for 24 h. The cells were then washed twice with pre-chilled PBS, fixed with 4% paraformaldehyde at room temperature for 20min, and washed 2 times with chilled PBS. Staining was performed with Hoechst 33342 (2. mu.g/mL) at room temperature for 15 min. The staining solution was removed and washed 2 times with PBS. Then, the nuclei and morphological changes of the cells were observed by an inverted fluorescence microscope.

The results of the staining test are shown in FIG. 10. The result shows that the staining experiment of Hoechst 33342 shows that 40 mu M4-BrP beta CA can not induce A549 cell apoptosis, and 4-BrPP beta C can induce A549 cell apoptosis in a concentration-dependent manner. Proves that the product 4-BrPP beta C obtained by condensing 4-BrP beta CA and 1, 10-phenanthroline-5-amino has better effect.

Annexin V staining assay

A549 cells with logarithmic growth are inoculated in a Nest confocal dish with the diameter of 40mm, and after the cells adhere to the wall, medicines with different concentrations are added for continuous incubation for 24 h. Cells were then washed twice with pre-cooled PBS and stained with Annexin V for 15 min. The staining solution was removed and washed 2 times with PBS. The morphological changes of the cells were then observed with an inverted fluorescence microscope.

The test result is shown in fig. 11, and the Annexin V staining experiment result shows that the apoptosis of the a549 cells can be induced in a concentration-dependent manner after the 4-BrPP β C is acted, and the apoptosis of the a549 cells can not be induced after the 4-BrP β CA is acted.

Reactive oxygen staining test

A549 cells with logarithmic growth are inoculated in a Nest confocal dish with the diameter of 40mm, and after the cells adhere to the wall, medicines with different concentrations are added for continuous incubation for 6 h. Cells were then washed twice with pre-cooled PBS and stained with DCFH-DA for 15 min. The staining solution was removed and washed 2 times with PBS. The morphological changes of the cells were then observed with an inverted fluorescence microscope.

The test result is shown in figure 12, and the result shows that the 4-BrPP beta C causes the active oxygen level in the A549 cells to be increased after the action, thereby causing the apoptosis. However, the active oxygen change in the A549 cells is not obvious after 40 mu M of 4-BrP beta CA acts.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims

1. The beta-carboline compound shown as the following formula I:

I，

wherein X is selected from

、

Or

And Y is selected from H.

2. The method for producing a β -carboline compound according to claim 1, wherein: the synthetic route of the beta-carboline compound is as follows:

the preparation method comprises the following steps:

(1) reacting the compound 1 with thionyl chloride to obtain a compound 2;

(2) compound 2 and

reacting to obtain a compound 3;

(4) heating compound 4 under basic conditions to form compound 5;

(5) hydrolyzing the compound 5 to obtain a compound 6;

(6) reacting the compound 6 with 1, 10-phenanthroline-5-amino to obtain a compound I, namely the beta-carboline compound;

wherein X and Y are as defined in claim 1.

3. The method of claim 2, wherein: in the step (1), the molar ratio of the compound 1 to the thionyl chloride is 1: 1 to 1.5.

4. The method according to claim 3, wherein: in the step (1), the reaction temperature of the compound 1 and thionyl chloride is 50-110 ℃.

5. The method according to claim 4, wherein: in the step (1), the reaction time of the compound 1 and thionyl chloride is 5-10 h.

6. The method of claim 2, wherein: in step (2), the compound 2 is reacted with

In a molar ratio of 1: 1 to 1.5.

7. The method according to claim 6, wherein: in step (2), the compound 2 is reacted with

The reaction temperature is 60-100 ℃.

8. The method according to claim 7, wherein: in step (2), the compound 2 is reacted with

The reaction time is 5-20 h.

9. The method of claim 2, wherein: in step (2), the compound 2 is reacted with

The reaction of (3) is carried out under a protective atmosphere.

10. The method of claim 2, wherein: in the step (3), the molar ratio of the compound 3 to the p-methylbenzenesulfonyl chloride is 1: 1 to 1.5.

11. The method of claim 10, wherein: in the step (3), the reaction temperature of the compound 3 and p-methylbenzenesulfonyl chloride is 5-40 ℃.

12. The method of claim 11, wherein: in the step (3), the reaction time of the compound 3 and p-methylbenzenesulfonyl chloride is 2-10 h.

13. The method according to claim 10, wherein: in the step (3), the reaction of the compound 3 with p-toluenesulfonyl chloride is carried out in the presence of a basic catalyst.

14. The method of claim 2, wherein: in the step (4), the pH value under the alkaline condition is 8-12.

15. The method of claim 2, wherein: in the step (6), the molar ratio of the compound 6 to the 1, 10-phenanthroline-5-amino group is 1: 1 to 1.5.

16. The method of claim 15, wherein: in the step (6), the reaction temperature of the compound 6 and the 1, 10-phenanthroline-5-amino is 10-40 ℃.

17. The method of claim 16, wherein: in the step (6), the reaction time of the compound 6 and the 1, 10-phenanthroline-5-amino is 20-24 hours.

18. The use of the beta-carboline compound of claim 1 in the preparation of an anti-cancer medicament, wherein the anti-cancer medicament is at least one of an anti-lung cancer medicament, an anti-cervical cancer medicament, an anti-liver cancer medicament, and an anti-breast cancer medicament.

19. A pharmaceutical composition characterized by: the pharmaceutical composition contains the beta-carboline compound of claim 1.