Brucea javanica bitter alcohol quinoline derivative as well as preparation method and application thereof

Abstract

The invention discloses a brucea javanica bitter alcohol quinoline derivative as well as a preparation method and application thereof, and relates to the technical field of medicinal chemistry and tumor treatment. The structural formula of the brucea javanica bitter alcohol quinoline derivative is as shown in a formula (I): # imgabs0 #; r in the formula (I) is a substituted quinoline acyl group, the brucea javanica quinoline derivative prepared by introducing a quinoline group into a brucea javanica mother nucleus has high anti-tumor activity, strong target spot selectivity and excellent chemical stability and metabolic stability, provides a novel candidate drug for tumor treatment, and has broad application prospects. The application potential in tumor treatment is obviously improved; the brucea javanica bitter alcohol quinoline derivative is prepared by one step through esterification reaction, and the preparation method is simple and easy to operate.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry and tumor treatment technology, and in particular to a brucea bruceiol quinoline derivative and a preparation method and application thereof. Background Art

[0002] Brucea javanica is a traditional Chinese medicinal material that is widely used in the treatment of various diseases, especially in the field of anti-tumor. One of its main active ingredients is brusatol, which has been shown to have significant anti-cancer activity. It mainly exerts its anti-tumor effects by inhibiting tumor protein synthesis, inducing cell apoptosis, inhibiting tumor invasion and metastasis, and inhibiting inflammatory pathways. It has shown significant inhibitory effects on various tumor cell lines such as breast cancer, lung cancer and liver cancer. However, the application of brusatol faces the following limitations: (1) Low solubility and bioavailability: brusatol has low water solubility, which limits its drug absorption and distribution, thereby reducing its efficacy and affecting its clinical application; (2) Insufficient tumor selectivity: brusatol also shows certain toxicity to normal cells and may cause serious side effects; (3) Poor stability: brusatol may be degraded or inactivated in the complex environment of the body, thus affecting its therapeutic effect.

[0003] How to improve the selectivity, stability and safety of brucea brucea to solve the limitations of the application of natural brucea brucea and provide new brucea brucea drug candidates for tumor treatment is one of the technical problems that need to be solved urgently in this field.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] The purpose of the present invention is to provide a brucea brucea quinoline derivative and a preparation method and application thereof, so as to solve the above technical problems.

[0006] The present invention is achieved in that: In the first aspect, an embodiment of the present invention provides a brucea brucea quinoline derivative, the structural formula of which is shown in formula (I): ; In formula (I), R is a substituted quinoline acyl group, and the structural formula of R is selected from At least one of, wherein n is selected from any one of 0, 1 and 2; In the structural formula of the substituted quinoline group, R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen atoms, hydroxyl groups, halogen substituents, alkyl and alkoxy groups, nitro and cyano groups, carbonyl and carboxyl groups, sulfur-containing groups, amino groups and their derivatives, phenyl, diphenyl, tolyl, benzyl, 2,4,6-trimethylphenyl, cumyl, di(tert-butyl)phenyl, anthracenyl, indenyl, naphthyl, halogenated aryl, tolyloxy, xylyloxy, 2,4,6-trimethylphenyloxy, diphenyl, anilino, p-toluidino, toluenesulfonyl, allylbenzyl or allylphenyl, furanyl, pyridyl, 2-pyridyl, indol-1-yl, chloromethylbenzyl or chloromethylphenyl, trifluoromethylbenzyl or trifluoromethylphenyl, hydroxybenzyl or hydroxyphenyl, methoxybenzyl or methoxyphenyl, ethoxybenzyl or ethoxyphenyl, methoxyethoxybenzyl or methoxyethoxyphenyl, allyloxybenzyl or allyloxyphenyl, phenoxybenzyl or phenoxyphenyl, acetoxybenzyl or acetoxyphenyl, benzoyloxybenzyl or benzoyloxyphenyl, methylthiobenzyl or methylthiophenyl, phenylthiobenzyl or phenylthiophenyl , methylaminobenzyl or methylaminophenyl, dimethylaminobenzyl or dimethylaminophenyl, ethylaminobenzyl or ethylaminophenyl, diethylaminobenzyl or diethylaminophenyl, acetylaminobenzyl or acetylaminophenyl, carboxybenzyl or carboxyphenyl, methoxycarbonylbenzyl or methoxycarbonylphenyl, ethoxycarbonylbenzyl or ethoxycarbonylphenyl, phenoxycarbonylbenzyl or phenoxycarbonylphenyl, chlorophenoxycarbonylbenzyl or chlorophenoxycarbonylphenyl, N-cyclohexylcarbamoyloxybenzyl or N-cyclohexylcarbamoyloxyphenyl, allyloxycarbonylbenzyl The invention further comprises at least one of an alkyl or allyloxycarbonylphenyl, a carbamoylbenzyl or carbamoylphenyl, an N-methylcarbamoylbenzyl or N-methylcarbamoylphenyl, an N,N-dipropylcarbamoylbenzyl or N,N-dipropylcarbamoylphenyl, an N-phenylcarbamoylbenzyl or N-phenylcarbamoylphenyl, a nitrobenzyl or nitrophenyl, a cyanobenzyl or cyanophenyl, a thiobenzyl or thiophenyl, a sulfate-benzyl or sulfate-phenyl, a phosphonobenzyl or phosphonophenyl, a phosphate benzyl or phosphate phenyl, and a morpholinobenzyl or morpholinophenyl group.

[0007] In a second aspect, an embodiment of the present invention provides a method for preparing the aforementioned brucea brucea quinoline derivatives, comprising: The brucein, substituted quinolinic acid, a condensing agent and a catalyst are mixed and subjected to an esterification reaction to obtain a reaction mixture; the reaction mixture is washed and purified to obtain a brucein quinoline derivative; Among them, the molar ratio of brucea bruceiol, substituted quinolinic acid, condensation agent and catalyst is (0.9-1.1): (1.4-1.6): (1.5-2.5): (0.5-1.5).

[0008] In a third aspect, an embodiment of the present invention provides an application of the aforementioned brucea brucea quinoline derivatives in anti-tumor drugs, wherein the tumor is selected from at least one of liver cancer, lung cancer, colon cancer, breast cancer and melanoma.

[0009] In a fourth aspect, an embodiment of the present invention provides a drug, the active ingredient of which contains the aforementioned brucea brucea quinoline derivative.

[0010] The present invention has the following beneficial effects: The brucea brucea alcohol quinoline derivatives provided in an embodiment of the present invention are prepared by introducing a quinoline group into the brucea brucea alcohol mother nucleus, and the brucea brucea alcohol quinoline derivatives have high anti-tumor activity, strong target selectivity, and excellent chemical stability and metabolic stability, providing a new candidate drug for tumor treatment, thereby significantly improving its application potential in tumor treatment; the brucea brucea alcohol quinoline derivatives are prepared in one step through an esterification reaction, and the preparation method is simple and easy to operate. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0012] Figure 1 are high-resolution mass spectra of compounds Z-1 to Z-5; Figure 2 are high-resolution mass spectra of compounds Z-6 to Z-10; Figure 3 is the high-resolution mass spectra of compounds Z-11 to Z-15; Figure 4 is the high-resolution mass spectra of compounds Z-16 to Z-20; Figure 5 Results of cell cloning experiments; Figure 6 Results of the wound healing migration experiment; Figure 7 The results of cell apoptosis experiments; Figure 8 The results of the cell mitochondrial membrane potential experiment; Fig. 9 Results of cell cycle experiments; Fig.10 The results are from Western blot experiments. DETAILED DESCRIPTION

[0013] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0014] Quinoline is an important drug skeleton and is widely used in the development of anti-tumor drugs. Its structure consists of a six-membered aromatic ring and a nitrogen atom, which has good aromaticity and molecular planarity, enabling it to effectively interact with biological macromolecules (such as proteins and DNA). The nitrogen atom of quinoline enhances the binding force with tumor cell targets through hydrogen bonds and electrostatic interactions, thereby improving the targeting of drugs. For example, quinoline compounds can inhibit the activity of tumor-related targets such as tyrosine kinase and DNA topoisomerase, and prevent tumor cell proliferation. In addition, structural modification of quinoline can optimize pharmacokinetic properties, improve the solubility, membrane permeability and metabolic stability of drugs, and increase their bioavailability and in vivo half-life. These characteristics make quinoline compounds widely used in anti-tumor drugs, especially in the treatment of tumors such as lung cancer, breast cancer and colorectal cancer, showing important potential.

[0015] The present invention aims to solve the limitations of the application of natural brucein, provide a new candidate drug for tumor treatment, and provide an innovative direction with important theoretical significance and application value, brucein quinazoline derivatives. Structural modification is an important strategy in medicinal chemistry to improve the activity, selectivity and safety of compounds.

[0016] In the first aspect, an embodiment of the present invention provides a brucea brucea quinoline derivative, the structural formula of which is shown in formula (I): ; In formula (I), R is a substituted quinoline acyl group, and the structural formula of R is selected from At least one of, wherein n is selected from any one of 0, 1 and 2; In the structural formula of the substituted quinoline group, R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen atoms, hydroxyl groups, halogen substituents, alkyl and alkoxy groups, nitro and cyano groups, carbonyl and carboxyl groups, sulfur-containing groups, amino groups and derivatives thereof, phenyl, diphenyl, tolyl, benzyl, 2,4,6-trimethylphenyl, cumyl, di(tert-butyl)phenyl, anthracenyl, indenyl, naphthyl, halogenated aryl, p-toluidinyl, dimethylphenyloxy, 2,4,6-trimethylphenyloxy, diphenyl, anilino, toluamino, toluenesulfonyl, allyl, benzyl or allylphenyl, furanyl, pyridyl, 2-pyridyl, indol-1-yl, chloromethylbenzyl or chloromethylphenyl, trifluoromethylbenzyl or trifluoromethylphenyl, hydroxybenzyl or hydroxyphenyl, methoxybenzyl or methoxyphenyl, ethoxybenzyl or ethoxyphenyl, methoxyethoxybenzyl or methoxyethoxyphenyl, allyloxybenzyl or allyloxyphenyl, phenoxybenzyl or phenoxyphenyl, acetoxybenzyl or acetoxyphenyl, benzoyloxybenzyl or benzoyloxyphenyl, methylthiobenzyl or methylthiophenyl, phenylthiobenzyl or phenylthiobenzene yl, methylaminobenzyl or methylaminophenyl, dimethylaminobenzyl or dimethylaminophenyl, ethylaminobenzyl or ethylaminophenyl, diethylaminobenzyl or diethylaminophenyl, acetylaminobenzyl or acetylaminophenyl, carboxybenzyl or carboxyphenyl, methoxycarbonylbenzyl or methoxycarbonylphenyl, ethoxycarbonylbenzyl or ethoxycarbonylphenyl, phenoxycarbonylbenzyl or phenoxycarbonylphenyl, chlorophenoxycarbonylbenzyl or chlorophenoxycarbonylphenyl, N-cyclohexylcarbamoyloxybenzyl or N-cyclohexylcarbamoyloxyphenyl, allyloxycarbonyl At least one of benzyl or allyloxycarbonylphenyl, carbamoylbenzyl or carbamoylphenyl, N-methylcarbamoylbenzyl or N-methylcarbamoylphenyl, N,N-dipropylcarbamoylbenzyl or N,N-dipropylcarbamoylphenyl, N-phenylcarbamoylbenzyl or N-phenylcarbamoylphenyl, nitrobenzyl or nitrophenyl, cyanobenzyl or cyanophenyl, thiobenzyl or thiophenyl, sulfate-benzyl or sulfate-phenyl, phosphonobenzyl or phosphonophenyl, phosphatebenzyl or phosphatephenyl, and morpholinobenzyl or morpholinophenyl.

[0017] It should be noted that the brucein quinoline derivatives provided by the present invention have high anti-tumor activity, strong target selectivity, and excellent chemical stability and metabolic stability, which effectively solves the limitations of the application of natural brucein and provides a new candidate drug for tumor treatment. Among them, the structural formula of brucein is: .

[0018] Specifically, the present invention can achieve the following purposes by introducing quinoline groups into the brucea brucea parent nucleus: (1) enhancing water solubility: polar functional groups can be introduced into the quinoline ring, which can significantly improve the water solubility of the compound; (2) improving tumor selectivity: the nitrogen atoms and aromatic rings in the quinoline skeleton can tightly bind to specific tumor-related targets (such as tyrosine kinase, DNA topoisomerase, etc.) through a variety of interactions. This high affinity and specificity can significantly enhance the targeting of drugs to tumor cells and reduce nonspecific effects on normal cells; (3) improving stability: the quinoline skeleton can significantly enhance the chemical and metabolic stability of drugs through its unique aromaticity, nitrogen atom characteristics and easy structural modification.

[0019] For example, in an optional embodiment of the present invention, halogen substituents such as -F, -Cl, -Br and -I; alkoxy groups such as -OCH3 and -OC2H5; carbonyl and carboxyl groups such as -COOR (ester group), -COOH (carboxyl group) and -CO-; sulfur-containing groups such as -SH (thiol group) and -SO3H (sulfonic acid group); amine groups and their derivatives such as -NH2, -NH- and -NR2.

[0020] It should be noted that the group is an atom or atom group with special properties in the molecule of an organic compound, and is the basic unit of an organic compound. They form a variety of organic compounds through specific connection methods and permutations and combinations; the presence of chemical groups not only determines the physical properties of organic compounds, such as their color, smell, melting point, boiling point, etc., but also has a more profound impact on the chemical reactivity and biological activity of the compound; as a substituent in an organic compound, in a chemical reaction, the group can significantly change the reactivity and physical properties of the compound, play different roles, and thus achieve the purpose of organic synthesis, which is particularly important in drug design. And structural modification is an important strategy to improve the activity, selectivity and safety of compounds in medicinal chemistry. Therefore, by in-depth study and understanding of the properties and functions of chemical groups, organic compounds with specific functions and properties can be better designed and synthesized, bringing more convenience and welfare to human production and life. In an embodiment of the present invention, in the structural formula of the substituted quinoline acyl group, the specific groups of R1, R2, R3, R4, R5 and R6 can be reasonably selected according to actual needs.

[0021] In an optional embodiment of the present invention, in the structural formula of the substituted quinoline group, R1, R2, R3, R4, R5 and R6 are independently selected from at least one of a hydrogen atom, a hydroxyl group, a halogen substituent, a phenyl group and an alkyl group.

[0022] In an optional embodiment of the present invention, the structural formula of the brucea quinoline derivative is selected from at least one of the following structural formulas: , , , , , , , , , , , , , , , , , , and .

[0023] In a second aspect, an embodiment of the present invention provides a method for preparing the aforementioned brucea brucea quinoline derivatives, comprising: The brucein, substituted quinolinic acid, a condensing agent and a catalyst are mixed and subjected to an esterification reaction to obtain a reaction mixture; the reaction mixture is washed and purified to obtain a brucein quinoline derivative; Among them, the molar ratio of brucea bruceiol, substituted quinolinic acid, condensation agent and catalyst is (0.9-1.1): (1.4-1.6): (1.5-2.5): (0.5-1.5).

[0024] It should be noted that after brucea bruceiol, substituted quinolinic acid, condensation agent and base catalyst are accurately weighed and placed in a reaction bottle, a solvent is added to carry out an esterification reaction.

[0025] The amounts of brucein and substituted quinolinic acid in the reactants are closely related to their structural formulas; if the amount of substituted quinolinic acid is too much or the amount of brucein is too little, by-products will appear, resulting in insufficient product purity and reduced yield.

[0026] In an optional embodiment of the present invention, the reaction temperature of the esterification reaction is 38° C.-45° C., and the reaction time is 7.5 h-9 h.

[0027] In an optional embodiment of the present invention, the condensing agent is selected from at least one of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), N'N-carbonyldiimidazole (CDI), 1-hydroxybenzotriazole (HOBT), O-(7-azabicyclo[2.2.1]hept-3-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (PyBOP) and 1-hydroxy-7-azabenzotriazole (HOAT).

[0028] The catalyst is selected from at least one of 4-dimethylaminopyridine (DMAP), triethylamine (Et3N), diethylamine and N,N-diisopropylethylamine (DIPEA).

[0029] It should be noted that the main purpose of the condensing agent in the esterification reaction is dehydration and activation, promoting the reaction of carboxylic acid and alcohol to generate ester compounds; it has the functions of activating carboxyl groups, improving coupling efficiency and dehydration. The catalyst plays the role of a catalyst in the esterification reaction, increasing the reaction rate, reducing the reaction temperature, and making the reaction more efficient; it has the characteristics of fast reaction speed, mild reaction conditions, small dosage and high yield. The specific types of condensing agents and catalysts used can be reasonably selected according to actual needs.

[0030] The catalyst used in the embodiment of the present invention is a base catalyst, which reacts with carboxylic acid to generate a base salt intermediate, which helps the esterification reaction; in addition, in the esterification reaction, carboxylic acid reacts with alcohol to generate ester and water, and the base catalyst can neutralize the generated new acid, thereby inhibiting the occurrence of side reactions.

[0031] In an optional embodiment of the present invention, the molar ratio of the condensing agent to the catalyst is (1.9-2.1): (1.1-1.5).

[0032] For example, the molar ratio of the condensing agent to the catalyst can be selected from any one of 1.9:1.1, 2:1.1, 2:1.3, 2:1.4 and 2:1.5, or other values ​​within the range of (1.9-2.1):(1.1-1.5).

[0033] In an optional embodiment of the present invention, the solvent for the esterification reaction is selected from any one of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and toluene.

[0034] It should be noted that the solvent is mainly used to dissolve the reactants, and the amount of solvent added is appropriate to dissolve the reactants. The specific amount is reasonably adjusted according to the actual amount of reactants.

[0035] In an optional embodiment of the present invention, washing includes: after the reaction mixture is diluted with dichloromethane, washing twice with aqueous hydrochloric acid solution and twice with saturated brine; combining the organic phases obtained by washing to obtain a crude product of brucea brucei quinoline derivative; wherein the acid water is aqueous hydrochloric acid solution, and its concentration is 1 mol / L-2 mol / L.

[0036] It should be noted that the purpose of diluting with dichloromethane is to dilute the reaction system to facilitate subsequent extraction; the purpose of acid water is to remove the water-soluble condensing agent and catalyst in the reaction system to prevent them from affecting the purity of the product; if the concentration of acid water is too high, the ester bond structure of the brucea brucea quinoline derivative will be destroyed and the yield will be reduced; if the concentration is too low, the water-soluble condensing agent and catalyst cannot be completely removed, affecting the purification of the product.

[0037] The purpose of salt water is to break the emulsion; the specific washing is to wash the product alternately with acid water and salt water. When the thin layer plate detects that there is no catalyst, it can be determined that it is clean.

[0038] In an optional embodiment of the present invention, the crude product is purified by any one of recrystallization, slurrying, column chromatography and thin layer chromatography purification; wherein the column chromatography is silica gel column chromatography, and the mobile phase is dichloromethane (DCM) and methanol (MeOH) in a volume ratio of (28-35):1.

[0039] It should be noted that the silica gel column chromatography used in the embodiment of the present invention has a mobile phase of dichloromethane and methanol in a volume ratio of 30:1. In other embodiments of the present invention, other methods can be selected to purify the crude product according to actual needs. If column chromatography is used, the mobile phase material and amount used can be reasonably adjusted according to actual conditions.

[0040] In a third aspect, an embodiment of the present invention provides an application of the aforementioned brucea brucea quinoline derivatives in anti-tumor drugs, wherein the tumor is selected from at least one of liver cancer, lung cancer, colon cancer, breast cancer and melanoma.

[0041] It should be noted that the drug has at least one of the following uses: (1) Inhibit tumor cell proliferation; (2) Inhibit tumor cell migration; (3) Inducing cell apoptosis; (4) Decrease the mitochondrial membrane potential of cells; (5) Tumor cells are arrested in the G2 phase in a drug concentration-dependent manner; (6) Reduce the expression of Cyclin B and CDK1 in tumor cells.

[0042] In a fourth aspect, an embodiment of the present invention provides a drug, the active ingredient of which contains the aforementioned brucea brucea quinoline derivative.

[0043] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0044] Example 1 This embodiment provides a brucea brucea quinoline derivative, the preparation steps of which are as follows: Brucea bruceiol (52 mg, 0.1 mmol, 1 eq) and 2-quinolinecarboxylic acid (26 mg, 0.15 mmol, 1.5 eq) were weighed into a 25 mL round-bottom flask and dissolved by ultrasonication in 15 mL of dichloromethane for 5 min to obtain a first reaction mixture.

[0045] EDCI (38 mg, 0.2 mmol, 2 eq) and DMAP (13 mg, 0.1 mmol, 1.1 eq) were weighed and added to the first reaction mixture, and stirred at 40°C for 8 h to complete the esterification reaction to obtain a second reaction mixture.

[0046] The second reaction mixture was diluted with dichloromethane at a dilution ratio of 1:5; then, the diluted second reaction mixture was washed with acid water and saline; all organic phases in the washing process were combined to obtain a crude product of brucea brucea quinoline derivative; and compound Z-1 was separated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :661.2229, its high resolution mass spectrum is shown in Figure 1 , the structural formula of the related substances is as follows: .

[0047] It should be noted that eq stands for equivalent, which is a unit used in chemistry or biological sciences to express the amount of a substance.

[0048] Example 2 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 3-quinolinecarboxylic acid (26 mg, 0.15 mmol, 1.5 eq). Compound Z-2 was separated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :661.2225, its high resolution mass spectrum is shown in Figure 1 , the structural formula of the related substances is as follows: .

[0049] Example 3 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 4-quinolinecarboxylic acid (26 mg, 0.15 mmol, 1.5 eq). Compound Z-3 was separated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :661.2226, its high resolution mass spectrum is shown in Figure 1 , the structural formula of the related substances is as follows: .

[0050] Example 4 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 5-quinolinecarboxylic acid (26 mg, 0.15 mmol, 1.5 eq). Compound Z-4 was separated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :661.2224, its high resolution mass spectrum is shown in Figure 1 , the structural formula of the related substances is as follows: .

[0051] Example 5 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 6-quinolinecarboxylic acid (26 mg, 0.15 mmol, 1.5 eq). Compound Z-5 was separated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :661.2228, its high resolution mass spectrum is shown in Figure 1 , the structural formula of the related substances is as follows: .

[0052] Example 6 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 7-quinolinecarboxylic acid (26 mg, 0.15 mmol, 1.5 eq). Compound Z-6 was separated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :661.2223, its high resolution mass spectrum is shown in Figure 2 , the structural formula of the related substances is as follows: .

[0053] Example 7 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 8-quinolinecarboxylic acid (26 mg, 0.15 mmol, 1.5 eq). Compound Z-7 was separated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :661.2223, its high resolution mass spectrum is shown in Figure 2 , the structural formula of the related substances is as follows: .

[0054] Example 8 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was chloroquinolinic acid (28 mg, 0.15 mmol, 1.5 eq). Compound Z-8 was separated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :710.1996, its high resolution mass spectrum is shown in Figure 2 , the structural formula of the related substances is as follows: .

[0055] Example 9 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 7-bromoquinoline-4-carboxylic acid (38 mg, 0.15 mmol, 1.5 eq). Compound Z-9 was separated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :740.1334, its high resolution mass spectrum is shown in Figure 2 , the structural formula of the related substances is as follows: .

[0056] Example 10 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was kynurenic acid (37 mg, 0.15 mmol, 1.5 eq). Compound Z-10 was isolated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :678.2178, its high resolution mass spectrum is shown in Figure 2 , the structural formula of the related substances is as follows: .

[0057] Embodiment 11 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was dichloroquinolinic acid (37 mg, 0.15 mmol, 1.5 eq). Compound Z-11 was isolated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :730.1449, its high resolution mass spectrum is shown in Figure 3 , the structural formula of the related substances is as follows: .

[0058] Example 12 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 7-bromoquinoline-3-carboxylic acid (38 mg, 0.15 mmol, 1.5 eq). Compound Z-12 was isolated and purified by silica gel column chromatography (DCM: MeOH = 30:1), [M+H] + :678.2175, its high resolution mass spectrum is shown in Figure 3 , the structural formula of the related substances is as follows: .

[0059] Example 13 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 4-bromoquinoline-8-carboxylic acid (38 mg, 0.15 mmol, 1.5 eq). Compound Z-13 was isolated and purified by silica gel column chromatography (DCM: MeOH = 30:1), [M+H] + :678.2174, its high resolution mass spectrum is shown in Figure 3 , the structural formula of the related substances is as follows: .

[0060] Embodiment 14 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 2-phenyl-4-quinolinecarboxylic acid (37 mg, 0.15 mmol, 1.5 eq). Compound Z-14 was isolated and purified by silica gel column chromatography (DCM: MeOH = 30:1), [M+H] + :738.2542, its high resolution mass spectrum is shown in Figure 3 , the structural formula of the related substances is as follows: .

[0061] Embodiment 15 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 8-quinoline-7-carboxylic acid (28 mg, 0.15 mmol, 1.5 eq). Compound Z-15 was separated and purified by silica gel column chromatography (DCM: MeOH = 30:1), [M+H] + :678.2177, its high resolution mass spectrum is shown in Figure 3 , the structural formula of the related substances is as follows: .

[0062] Example 16 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 2-methyl-6-quinolinecarboxylic acid (23 mg, 0.15 mmol, 1.5 eq). Compound Z-16 was isolated and purified by silica gel column chromatography (DCM: MeOH = 30:1), [M+H] + :676.2384, its high resolution mass spectrum is shown in Figure 4 , the structural formula of the related substances is as follows: .

[0063] Embodiment 17 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 2-(Quinolin-4-yl)acetic acid (28 mg, 0.15 mmol, 1.5 eq). Compound Z-17 was isolated and purified by silica gel column chromatography (DCM: MeOH = 30:1), [M+H] + :676.2385, its high resolution mass spectrum is shown in Figure 4 , the structural formula of the related substances is as follows: .

[0064] Embodiment 18 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 6-quinolinolic acid (28 mg, 0.15 mmol, 1.5 eq). Compound Z-18 was isolated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :676.2383, its high resolution mass spectrum is shown in Figure 4 , the structural formula of the related substances is as follows: .

[0065] Embodiment 19 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 3-quinolin-2-ylpropionic acid (30 mg, 0.15 mmol, 1.5 eq). Compound Z-19 was separated and purified by silica gel column chromatography (DCM: MeOH = 30: 1), [M+H] + :690.2542, its high resolution mass spectrum is shown in Figure 4 , the structural formula of the related substances is as follows: .

[0066] Embodiment 20 This example provides a brucea brucea quinoline derivative, the preparation steps of which are different from those of Example 1 only in that: The substituted quinolinic acid in the reactant was 3-(quinolin-6-yl)propionic acid (30 mg, 0.15 mmol, 1.5 eq). Compound Z-20 was isolated and purified by silica gel column chromatography (DCM: MeOH = 30:1), [M+H] + :690.2540, its high resolution mass spectrum is shown in Figure 4 , the structural formula of the related substances is as follows: .

[0067] Experimental Example 1 Brucea brucea is a highly hydrophobic compound that is poorly soluble in water, which is also the main challenge faced in the development of oral or injectable preparations. This experiment will test the water solubility of the brucea brucea quinoline derivatives prepared in Examples 1-20; specifically as follows: Accurately weigh 0.20 mg of brucea brucea powder and place it in a 15 mL centrifuge tube, add 9.6 mL of methanol, and vortex for 10 min to fully dissolve it to prepare a 40.00 μM brucea brucea standard solution. Weigh 0.10 mg, 0.20 mg, 0.50 mg, and 1.00 mg of brucea brucea powder respectively and place them in a 15 mL centrifuge tube, add 9.6 mL of pure water and vortex for 10 min to fully dissolve it, and obtain a brucea brucea aqueous solution. According to the same steps, prepare a 40.00 μM standard solution of the corresponding brucea brucea quinoline derivative prepared in Example 1-20 and a corresponding aqueous solution of the brucea brucea quinoline derivative prepared in Example 1-20. The prepared brucein standard solution, brucein aqueous solution, brucein quinoline derivative standard solution, and brucein quinoline derivative aqueous solution samples were centrifuged, filtered, and the peak areas of the standards and samples were detected by HPLC. The contents of brucein and brucein derivatives in each sample were calculated based on the peak area and concentration of the standard solution. The chromatographic conditions were: C-18 reversed phase column (4.6 × 100 mm); mobile phase: pure water in phase A, methanol in phase B; gradient method: 0-5 min: phase A 95%-65%, 5-10 min: phase A 65%-5%, flow rate 1.00 mL / min, injection volume 5.00 μL, and detection wavelength 220 nm. The specific results are shown in the table below; Table 1 Determination of water solubility of brucea brucea picroline derivatives (25 ℃)

[0068] The results showed that the water solubility of the bruceiol quinoline derivatives of Examples 1-20 was improved to varying degrees compared with the solubility of bruceiol, and the best could reach 0.50 mg / mL, indicating that the introduction of quinoline groups can improve the water solubility of bruceiol.

[0069] Experimental Example 2 This experimental example verifies the antitumor activity of the brucea brucei alcohol quinoline derivatives prepared in Examples 1-20, as follows: 2.1 Cell culture and passaging Human liver cancer cell line Huh-7 cells, mouse liver cancer cell line Hepa 1-6 cells, human normal liver cancer cell line LO2, human lung cancer cell line A549, mouse lung cancer cell line LLC, human normal lung epithelial cell line BEAS-2B, human colon cancer cell line HCT116, mouse colon cancer cell line CT26, human normal colon cancer cell line FHC, human breast cancer cell line MCF-7, mouse breast cancer cell line 4T1, human normal breast cell line HS578T, human melanoma cells A375, mouse melanoma cells B16, and human normal kidney cells HK-2 were all purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences.

[0070] The above cells were cultured in DMEM / 1640 high-glucose medium containing 10% FBS (fetal bovine serum), passaged when they grew to 80%-90% abundance, and cultured at 37°C and 5% CO2.

[0071] 2.2 Drug preparation The drug to be tested was dissolved in DMSO to prepare a stock solution with a concentration of 10 μmol / mL, and then diluted to a series of concentrations of 31.25 nM, 62.5 nM, 125 nM, 250 nM, 500 nM, and 1000 nM with high-glucose DMEM / 1640 medium containing 10% FBS.

[0072] 2.3 Compound inhibition experiment on tumor cells Take cells in logarithmic growth phase and prepare cell suspension according to the subculture method. Count the cells with a hemocytometer and adjust the cell concentration to 2.5×10 4 / mL, mix thoroughly, and add evenly to the 96-well plate with a pipette according to the volume of 100 μL per well. Add 100 μL of PBS to the edge as an anti-evaporation well, which is not used in the experiment. The 96-well plate was gently shaken and placed in an incubator for overnight culture. The next day, when the cells grew to about 30%-40% of the cell adhesion, 100 μL of the drug-containing culture medium with the specified gradient concentration was added to make the final concentration 1000 nM, 500 nM, 250 nM, 125 nM, 62.5 nM, 31.25 nM, and 3 replicates were set for each concentration. At the same time, the wells without drugs and only cells were set as control wells, and the wells without drugs and cells were set as zero wells. After gently shaking, they were placed in the incubator and continued to be cultured for 48 h. After the drug effect ended, 20 μL of MTT (5 mg / mL) detection solution was added to each well, incubated at 37°C for 2 h, and the supernatant was carefully discarded. 100 μL of DMSO was added to dissolve the generated blue-purple crystalline formazan, and the shaker was gently shaken for 10 min to fully mix it. The absorbance value (A) at 490 nm was detected by an ELISA instrument. The cell inhibition rate = (A control well-A drug well) / (A control well-A zeroing well) × 100%, and the IC was calculated using GraphPad Prism 9.050 The results of the half-inhibitory concentration data of different cell lines detected by MTT method for brucei brucei picroquine derivatives are shown in Table 2-1 - Table 2-2.

[0073] Table 2-1 Data on the half-inhibitory concentration of brucea brucei picrotoxin derivatives detected by MTT assay on different cell lines

[0074] Table 2-2 Data on the half-inhibitory concentration of brucea brucei picrotoxin derivatives detected by MTT assay on different cell lines

[0075] It should be noted that the half-inhibitory concentration data IC 50 It refers to the concentration of a drug or inhibitor required to inhibit a biological process (such as cell growth, enzyme activity, etc.) by 50%. 50 The value is an important indicator for evaluating drug activity; the lower the value, the stronger the inhibitory effect of the drug on the target, which usually means a better therapeutic effect.

[0076] From the half-inhibitory concentration data in Table 2-1 and Table 2-2, it can be seen that the bruceiol quinoline derivatives with better drug activity are Z-8, Z-9, Z-11, Z-12 and Z-13, among which the Z-9 compound has the best activity; the corresponding cells are human liver cancer cell line Huh-7 cells and mouse liver cancer cell line Hepa 1-6 cells. The most active Z-9, as well as Huh-7 cells and Hepa 1-6 cells were selected for further study.

[0077] Experimental Example 3 In this experiment, the most active Z-9 was selected to explore its anti-tumor activity, as follows: 3.1 Cell cloning experiment Hepa 1-6 cells and Huh-7 cells in the logarithmic growth phase were prepared as cell suspensions, and the cell concentration was adjusted to 500 cells / mL. The cells were evenly plated in a 6-well plate with a volume of 2 mL per well and cultured in an incubator overnight until the cells adhered to the wall. Different concentrations of Z-9 were added to the cells for 48 h (the concentrations of Z-9 were 0.01nM, 0.02nM, and 0.04nM). After the action of Z-9 ended, the old culture medium was discarded, and the serum-free culture medium was replaced and cultured for 14 days. When the number of cells in a single cell cluster reached more than 50, the culture was terminated. The supernatant was discarded, washed once with PBS, fixed with 4% paraformaldehyde for 15 min, washed three times with PBS, 3 min each time, stained with 0.1% crystal violet for 15 min, washed with PBS until the washing solution was clear, air-dried, photographed, and counted under an inverted microscope to calculate the colony integration rate. For specific results, see Figure 5 .

[0078] from Figure 5 It can be seen that Z-9 can significantly inhibit the self-cloning ability of Hepa 1-6 and Huh-7 cells, and the number of colonies formed shows a dose-dependent decrease.

[0079] 3.2 Wound healing migration assay The 6-well plate was marked with horizontal lines on the back with a marker pen in advance. Hepa 1-6 and Huh-7 cells in the logarithmic growth phase were prepared as a cell suspension and the cell concentration was adjusted to 5×10 4 Cells were evenly plated in 6-well plates at a volume of 2 mL per well and cultured in an incubator until the cell monolayer confluence reached 90%. A 200 μL pipette tip was used to make cell scratches perpendicular to the well plate, and the cells were washed three times with PBS to remove cell debris. Different concentrations of Z-9 were added to the cells in serum-free DMEM medium for 24 h, and the cell migration state was observed and photographed under an inverted microscope at 0 h and 24 h after the scratch was made. ImageJ software was used to quantify the cell migration area and calculate the migration inhibition rate. The results of the wound healing migration experiment are shown in Figure 6 .

[0080] from Figure 6 It can be seen that compared with the blank control group, after the Hepa 1-6 cells were treated with Z-9 for 24 h, the wound healing rates at 0.5 nM and 2.0 nM concentrations were 28.49% and 9.36%, respectively, while the blank control group was 53.62%, and the wound healing rates decreased by 25.13% and 44.26%. After the Huh-7 cells were treated with Z-9 for 24 h, the wound healing rates at 0.5 nM and 2.0 nM concentrations were 33.51% and 11.81%, respectively, while the blank control group was 58.29%, and the wound healing rates decreased by 24.78% and 46.48%. This shows that Z-9 can significantly inhibit the proliferation of Hepa 1-6 and Huh-7 cells in a concentration-dependent manner.

[0081] 3.3 Cell apoptosis assay Hepa 1-6 and Huh-7 cells in the logarithmic growth phase were digested and centrifuged, and 1×10 5Cells were seeded at 1000 μL / well in a 6-well plate and cultured for 24 h after cell adhesion. Z-9 was applied to Hepa 1-6 and Huh-7 cells at effective concentrations of 1 nM, 4 nM, and 8 nM, respectively, and cultured for another 48 h. The cells were washed with PBS buffer and then digested with trypsin. The digested cells were centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cells were collected. The supernatant was removed, and 195 μL Annexin V-FITC binding solution was added to gently resuspend the cells. 5 μL Annexin V-FITC was added and gently mixed. 10 μL propidium iodide staining solution was added and gently mixed. Incubate at room temperature in the dark for 15 min, and then place in an ice bath. Flow cytometry was used to detect cell apoptosis after the drug effect ended. Related results are shown in Figure 7 .

[0082] It should be noted that Figure 7 The relative protein levels were quantified by ImageJ analysis software. Each experiment was repeated at least 3 times. Compared with the control group, * p < 0.05, ** p < 0.01, *** p < 0.001.

[0083] from Figure 7 The results showed that Z-9 could significantly induce apoptosis of Hepa 1-6 and Huh-7 cells in a concentration-dependent manner.

[0084] 3.4 Cell mitochondrial membrane potential experiment Hepa 1-6 and Huh-7 cells in the logarithmic growth phase were digested with trypsin and centrifuged. 5 100 μg / well were inoculated in 6-well plates, and the cells were cultured for 24 h after attachment. Z-9 was applied to Hepa 1-6 and Huh-7 cells at effective concentrations of 1 nM, 2 nM, and 4 nM, respectively, and cultured for 48 h. The cells were washed with PBS buffer, then digested with trypsin, and the digested cells were centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cells were collected. 1 mL of cell culture medium and 1 mL of JC-1 staining working solution prepared according to the instructions of the Enhanced Mitochondrial Membrane Potential Assay Kit (JC-1) were added and mixed thoroughly. Incubated at 37°C in a cell culture incubator for 30 min. After incubation at 37°C, the cells were centrifuged, the supernatant was removed, and washed twice with JC-1 staining buffer. The cells were resuspended with PBS, stored in an ice box, and the level of mitochondrial membrane potential depolarization was analyzed by flow cytometry.

[0085] It should be noted that Figure 8 The relative protein levels were quantified by ImageJ analysis software. Each experiment was repeated at least 3 times. Compared with the control group, * p <0.05,**p <0.01,*** p <0.001.

[0086] from Figure 8 The results showed that Z-9 could significantly reduce the mitochondrial membrane potential of Hepa 1-6 and Huh-7 cells in a concentration-dependent manner.

[0087] 3.5 Cell cycle assay Hepa 1-6 and Huh-7 cells in the logarithmic growth phase were prepared as cell suspensions, and the cell concentration was adjusted to 2.5×10 4 / mL, and evenly spread into 6-well plates with a volume of 2 mL per well. Culture in an incubator overnight until the cells adhere to the wall, and add different concentrations of Z-9 for 48 hours. Collect the cells by 0.25% trypsin digestion and wash once with PBS. After centrifugation at 1500 rpm for 5 min, discard the supernatant, resuspend the cells in 70% pre-cooled ice ethanol and fix them at 4°C overnight. The next day, collect the cells by centrifugation at 1500 rpm for 5 min and wash once with pre-cooled PBS. Slowly and fully resuspend them in 500 μL staining buffer containing 10 μg / mL RNase and 25 μL PI, and incubate at 37°C in the dark for 30 min. After incubation, store at 4°C in the dark and detect on a flow cytometer, and analyze the data using modfit software. The relevant results are shown in Fig. 9 In addition, western blotting experiments were performed to evaluate the effects of Z-9 on the levels of cell cycle-related proteins in Hepa 1-6 and Huh-7 cells. Fig.10 .

[0088] It should be noted that Fig. 9 The relative protein levels were quantified by ImageJ analysis software. Each experiment was repeated at least 3 times. Compared with the control group, * p <0.05,** p <0.01,*** p <0.001.

[0089] from Fig. 9 The results showed that both Hepa 1-6 and Huh-7 cells were arrested in the G2 phase in a Z-9 concentration-dependent manner.

[0090] from Fig.10 The results showed that Z-9 significantly reduced the expression of Cyclin B and CDK1 in Hepa 1-6 and Huh-7 cells.

[0091] In summary, the brucea brucea alcohol quinoline derivatives provided in the embodiments of the present invention are prepared by introducing a quinoline group into the brucea brucea alcohol nucleus, and the brucea brucea alcohol quinoline derivatives have high anti-tumor activity, strong target selectivity, and excellent chemical stability and metabolic stability; they effectively solve the problems of insufficient activity, poor target selectivity, and poor chemical and metabolic stability in the current application of brucea brucea alcohol, and provide a new candidate drug for tumor treatment, so as to significantly enhance its application potential in tumor treatment; the brucea brucea alcohol quinoline derivatives are prepared in one step through an esterification reaction, and the preparation method is simple and easy to operate.

[0092] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A brucea brucea quinoline derivative, characterized in that: The structural formula of the brucea brucea quinoline derivative is shown in formula (I): ; In formula (I), R is a substituted quinoline acyl group, and the structural formula of R is selected from At least one of, wherein n is selected from any one of 0, 1 and 2; In the structural formula of the substituted quinoline group, R1, R2, R3, R4, R5 and R6 are independently selected from hydrogen atoms, hydroxyl groups, halogen substituents, alkyl and alkoxy groups, nitro and cyano groups, carbonyl and carboxyl groups, sulfur-containing groups, amino groups and their derivatives, phenyl, diphenyl, tolyl, benzyl, 2,4,6-trimethylphenyl, cumyl, di(tert-butyl)phenyl, anthracenyl, indenyl, naphthyl, halogenated aryl, tolyloxy, xyloxy, 2,4,6-trimethylphenyloxy, diphenyl, anilino, p-toluidino, toluenesulfonyl, allyl benzyl or allylphenyl, furanyl, pyridyl, 2-pyridyl, indol-1-yl, chloromethylbenzyl or chloromethylphenyl, trifluoromethylbenzyl or trifluoromethylphenyl, hydroxybenzyl or hydroxyphenyl, methoxybenzyl or methoxyphenyl, ethoxybenzyl or ethoxyphenyl, methoxyethoxybenzyl or methoxyethoxyphenyl, allyloxybenzyl or allyloxyphenyl, phenoxybenzyl or phenoxyphenyl, acetoxybenzyl or acetoxyphenyl, benzoyloxybenzyl or benzoyloxyphenyl, methylthiobenzyl or methylthiophenyl, phenylthiobenzyl or phenylthiobenzene yl, methylaminobenzyl or methylaminophenyl, dimethylaminobenzyl or dimethylaminophenyl, ethylaminobenzyl or ethylaminophenyl, diethylaminobenzyl or diethylaminophenyl, acetylaminobenzyl or acetylaminophenyl, carboxybenzyl or carboxyphenyl, methoxycarbonylbenzyl or methoxycarbonylphenyl, ethoxycarbonylbenzyl or ethoxycarbonylphenyl, phenoxycarbonylbenzyl or phenoxycarbonylphenyl, chlorophenoxycarbonylbenzyl or chlorophenoxycarbonylphenyl, N-cyclohexylcarbamoyloxybenzyl or N-cyclohexylcarbamoyloxyphenyl, allyloxycarbonyl At least one of benzyl or allyloxycarbonylphenyl, carbamoylbenzyl or carbamoylphenyl, N-methylcarbamoylbenzyl or N-methylcarbamoylphenyl, N,N-dipropylcarbamoylbenzyl or N,N-dipropylcarbamoylphenyl, N-phenylcarbamoylbenzyl or N-phenylcarbamoylphenyl, nitrobenzyl or nitrophenyl, cyanobenzyl or cyanophenyl, thiobenzyl or thiophenyl, sulfate-benzyl or sulfate-phenyl, phosphonobenzyl or phosphonophenyl, phosphatebenzyl or phosphatephenyl, and morpholinobenzyl or morpholinophenyl.

2. The brucea brucea quinoline derivative according to claim 1, characterized in that: In the structural formula of the substituted quinoline group, R1, R2, R3, R4, R5 and R6 are independently selected from at least one of a hydrogen atom, a hydroxyl group, a halogen substituent, a phenyl group and an alkyl group.

3. The brucea brucea quinoline derivative according to claim 1, characterized in that: The structural formula of the brucea quinoline derivative is selected from at least one of the following structural formulas: , , , , , , , , , , , , , , , , , , and .

4. A method for preparing the brucea brucea quinoline derivatives as claimed in claim 1, characterized in that: The preparation method comprises: The brucein, substituted quinolinic acid, a condensing agent and a catalyst are mixed and subjected to an esterification reaction to obtain a reaction mixture; the reaction mixture is washed and purified to obtain a brucein quinoline derivative; Among them, the molar ratio of brucea bruceiol, substituted quinolinic acid, condensation agent and catalyst is (0.9-1.1): (1.4-1.6): (1.5-2.5): (0.5-1.5).

5. The preparation method according to claim 4, characterized in that: The condensing agent is selected from at least one of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N'N-carbonyldiimidazole, 1-hydroxybenzotriazole, O-(7-azabicyclo[2.2.1]hept-3-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate and 1-hydroxy-7-azabenzotriazole; The catalyst is selected from at least one of 4-dimethylaminopyridine, triethylamine, diethylamine and N,N-diisopropylethylamine.

6. The preparation method according to claim 4, characterized in that: The solvent for the esterification reaction is selected from any one of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and toluene.

7. The preparation method according to claim 4, characterized in that: The washing comprises: diluting the reaction mixture with dichloromethane, and then washing with acid water and saline; combining the organic phases obtained by washing to obtain a crude product of brucea bruceiol quinoline derivative; The acid water is a hydrochloric acid aqueous solution with a concentration of 1 mol / L-2 mol / L.

8. The preparation method according to claim 7, characterized in that: The purification method of the crude product is selected from any one of recrystallization, beating, column chromatography and thin layer chromatography purification; The column chromatography is silica gel column chromatography, and the mobile phase is dichloromethane and methanol in a volume ratio of (28-35):

1.

9. A use of the brucea brucei quinoline derivatives as claimed in claim 1 in the preparation of anti-tumor drugs, characterized in that: The tumor is selected from at least one of liver cancer, lung cancer, colon cancer, breast cancer and melanoma.

10. A drug, characterized in that The active ingredient of the drug contains the brucea bruceiol quinoline derivative as described in claim 1.

Images