CN110105366B

CN110105366B - Quinoline derivative VCTb9 and application thereof in preparation of anti-cancer drugs

Info

Publication number: CN110105366B
Application number: CN201910455614.1A
Authority: CN
Inventors: 刘思思; 赵靖芳; 李俊; 崔元超; 宋子冰; 高超
Original assignee: Huazhong Agricultural University
Current assignee: Huazhong Agricultural University
Priority date: 2019-05-29
Filing date: 2019-05-29
Publication date: 2021-06-01
Anticipated expiration: 2039-05-29
Also published as: CN110105366A

Abstract

The invention belongs to the field of new drugs, and particularly relates to a quinoline derivative VCTb9 and application thereof in preparing an anti-cancer drug. In addition, the compound has good inhibition effect on lung cancer cells, breast cancer cells and gastric cancer cells, is suitable for developing new drugs for inhibiting the growth of cancer cells, and has wide application prospect.

Description

Quinoline derivative VCTb9 and application thereof in preparation of anti-cancer drugs

Technical Field

The invention belongs to the field of new drugs, and particularly relates to a quinoline derivative VCTb9 and application thereof in preparation of anti-cancer drugs.

Background

According to statistics, 1810 ten thousand new cancer cases and 960 ten thousand cancer death cases are counted in 2018 all over the world. At present, lung cancer is the first malignancy with the greatest threat to life safety, with morbidity and mortality worldwide. Breast cancer is one of the most common malignancies in women, a malignancy that usually occurs in mammary epithelial tissue. According to data statistics, the incidence rate accounts for 7-10% of all malignant tumors of the whole body, the incidence rate of the malignant tumors is usually related to heredity after women are only next to uterine cancer, and between 40-60 years old, the incidence rate of the women before and after menopause is higher, and only about 1-2% of breast patients are male. The chemotherapy medicine for treating lung cancer has been developed for the fourth generation, but the effective rate of a single medicine is lower than 20%, and the single medicine has large side effect and has killing power to normal cells. At present, with the increasing of working and living pressure and the reasons of living habits and the like, the morbidity of the stomach cancer of young people is increased year by year, the five-year survival rate is low, and in addition, the misdiagnosis rate of the stomach cancer is as high as 27 percent, so the mortality of the stomach cancer is increased year by year.

Mammary gland is not an important organ for maintaining human body life activity, and the in-situ breast cancer is not fatal; however, the breast cancer cells lose the characteristics of normal cells, and the cells are loosely connected and easily fall off. Once cancer cells are shed, free cancer cells can be disseminated to the whole body along with blood or lymph fluid to form metastasis, which endangers life. At present, breast cancer becomes a common tumor threatening the physical and mental health of women.

Gastric cancer (gastric cancer) is a malignant tumor originated from gastric mucosal epithelium, the incidence rate of the gastric cancer is the first in various malignant tumors in China, the incidence rate of the gastric cancer is obviously different regionally, and the incidence rate of the gastric cancer is obviously higher in northwest and east coastal areas of China than in south areas. The good hair age is more than 50 years old, and the ratio of the incidence rates of men and women is 2: 1. gastric cancer tends to be younger due to changes in dietary structure, increased working pressure, infection with helicobacter pylori, and the like. Gastric cancer can occur in any part of the stomach, more than half of which occur in antrum, and the greater curvature, lesser curvature, anterior and posterior walls of the stomach can be affected. Most of gastric cancers belong to adenocarcinoma, have no obvious symptoms in the early stage, or have nonspecific symptoms such as epigastric discomfort, eructation and the like, are similar to the symptoms of chronic stomach diseases such as gastritis, gastric ulcer and the like, and are easy to ignore, the gastric cancers can be subjected to targeted therapy, and the targeted therapy can be used for pertinently damaging cancer cells and relieving normal cell damage. At present, the types and the effects of the gastric cancer targeted therapeutic drugs are limited. The targeted therapeutic medicine mainly comprises an epidermal growth factor receptor inhibitor, an angiogenesis inhibitor, a cell cycle inhibitor, an apoptosis promoter, a matrix metalloproteinase inhibitor and the like.

The applicant finds that the anti-tumor drug 3- (1, 3-benzodioxol-5-yl) -5- (4-methylbenzene) -5H- [1,3] benzodiazepine [4,5-g ] pyrazolo [4,3-c ] quinoline found in earlier studies by the applicant has a very obvious growth inhibition effect on lung cancer cells, but has no inhibition effect on breast cancer and gastric cancer (201810015107.1), so that the development of a broad-spectrum anti-cancer drug is a long-term development direction in the field.

Disclosure of Invention

The invention aims to provide a quinoline derivative VCTb9, wherein the structural formula of VCTb9 is as follows:

the invention also aims to provide application of the quinoline derivative VCTb5 in preparing anti-cancer drugs.

In order to achieve the purpose, the invention adopts the following technical measures:

quinoline derivative VCTb9 with molecular formula C₃₁H₃₈N₃O₄Br, moleculeAmount 595.20, structural formula:

the R is tridecyl bromide; the specific structural formula of VCTb9 is as follows:

the application of quinoline VCTb9 in preparing anticancer drugs, wherein the anticancer drugs include but are not limited to anti-lung cancer drugs, anti-breast cancer drugs and anti-gastric cancer drugs.

Compared with the prior art, the invention has the following advantages:

in the antitumor activity experiment of the quinoline derivative, the structural compound has high antitumor cell growth effect and small toxic and side effect on normal cells, and VCTb9 is a new compound with small side effect and antitumor activity.

Drawings

FIG. 1 is a synthetic scheme of quinoline derivatives VCTb5 and VCTb 9.

FIG. 2 is a schematic diagram showing the inhibitory effect of compound VCTb5 at different concentrations on human lung cancer cell A549, breast cancer cell MDA231-LM2 and human gastric cancer cell MGC-803.

FIG. 3 is a schematic diagram showing the inhibitory effect of compound VCTb9 at different concentrations on human lung cancer cell A549, breast cancer cell MDA231-LM2 and human gastric cancer cell MGC-803.

FIG. 4 is a schematic diagram showing the inhibitory effect of compound VCTb10 at different concentrations on human lung cancer cell A549, breast cancer cell MDA231-LM2 and human gastric cancer cell MGC-803.

Detailed Description

In order that the invention may be better understood, the invention will now be further described with reference to specific examples. The technical scheme of the invention is a conventional scheme in the field unless specifically stated; the reagents or materials are commercially available.

Example 1:

preparation of quinoline derivatives VCTb5 and VCTb 9:

(1) synthesis of VCTb 5:

1) synthesis of Compound 2:

in a two-necked flask, sodium hydroxide (28mmol) and 2.42mL (20mmol) of diethyl carbonate were added to 20mL of anhydrous THF, and the mixture was heated at 70 ℃ under an argon atmosphere. 1.642g of compound 1 was dissolved in 10 ml of dry tetrahydrofuran and added dropwise to the reaction system, followed by refluxing for 8 hours. After cooling, 25mL of 10% acetic acid was added, and the mixture was stirred for 15 minutes. The mixture was extracted three times with ethyl acetate. After this time, the mixture was dried, filtered and purified by column chromatography (PE/EA 25: 1). Colorless oily particles are obtained, and the structure of the compound 2 in the figure 1 is determined through nuclear magnetic resonance detection, namely triethyl orthoformate, the yield of the compound 2 in the step is 1.78g, and the yield is 72%;

the compound 1 is

2) Synthesis of Compound 3:

1.78g of purified triethyl orthoformate and 4.98mL of acetic anhydride were refluxed at 140 ℃ for 12h, and the completion of the reaction was checked by TLC. After cooling, the reaction mixture was quenched with 30ml of distilled water. Extracting twice with ethyl acetate; with anhydrous Na₂SO₄The organic phase was dried. The solvent was evaporated to dryness and the product was taken to the next step without further purification. The product was obtained as a pale yellow oil, which was confirmed to have the structure of compound 3 in FIG. 1 by NMR, and the yield of compound 3 in this step was 2.10g, 95%.

3) Synthesis of Compound 4:

1.0g of Compound 3 was dissolved in 15mL of isopropanol. 281.5g of 3,4- (methyldioxy) aniline was added to the solution, and the reaction was monitored for completion by stirring and thin layer chromatography every 30 minutes. The solvent was evaporated to dryness under reduced pressure and the residue was purified by column chromatography using PE/EA (10:1) as eluent. A yellow solid was obtained, the E/Z isomer (ratio 60:40)), which was confirmed by nmr to be the structure of compound 4 in fig. 1, with a yield of 640 mg of compound 4 in this step, yield: 60 percent.

4) Synthesis of Compound 5:

1.0g of Compound 4 was added to diphenyl ether (15ml) and refluxed at 260 ℃ for 6 hours. After cooling, the reaction mixture was diluted with 50mL of petroleum ether and stirred for 1 hour to precipitate the product. Washing crude oil with petroleum ether for several times to remove diphenyl ether to obtain compound 5, detecting by nuclear magnetic resonance to determine the structure of compound 5 in figure 1, i.e. quinolone, and directly using in the next step; in this step, the yield of compound 5 was 330 mg, yield: 38 percent.

5) Synthesis of Compound 6

Adding anhydrous DMF and 60% sodium hydroxide solution into a 100mL round-bottom flask according to the volume ratio of 1:1.2, and stirring at room temperature; then adding the compound 5 and aralkyl bromine into a round-bottom flask according to the molar ratio of 1:1.2, stirring for 5-8h at 75-80 ℃, concentrating the solvent under reduced pressure, dissolving the residue in ethyl acetate, filtering to remove precipitates, concentrating an organic layer under reduced pressure, separating and purifying by column chromatography with PE/EA/MeOH (2:1:0.2) as an eluent to obtain a compound 6, and detecting by nuclear magnetic resonance to obtain the structure of the compound 6 in the figure 1;

6) synthesis of compound VCTb 5:

the solution of hydrazine hydrate 85% and compound 6 are dissolved in 25mL of glacial acetic acid according to the molar ratio of hydrazine hydrate to compound 6 of 5:1, and heated under reflux at 80 ℃ for 8 h. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure, extracted with dichloromethane, the organic phases were combined and washed with anhydrous Na₂SO₄Drying, and separating and purifying by column chromatography with DCM/MeOH as eluent to obtain compound VCTb5 with the following structural formula:

(2) synthesis of VCTb 9:

1) synthesis of compound 7:

adding anhydrous DMF and 60% sodium hydroxide solution into a 100mL round-bottom flask according to the volume ratio of 1:1.2, stirring at room temperature, then adding compound 5 and alkyl bromide into the round-bottom flask according to the molar ratio of 1:1.2, stirring at 75-80 ℃ for 5-8h, concentrating the solvent under reduced pressure, dissolving the residue in ethyl acetate, filtering to remove the precipitate, concentrating the organic layer under reduced pressure, separating and purifying by column chromatography with PE/EA/MeOH (2:1:0.2) as an eluent to obtain compound 7, and detecting by nuclear magnetic resonance to obtain the structure of the compound 7 in the figure 1;

2) synthesis of compound VCTb 9:

the solution of hydrazine hydrate 85% and compound 7 are dissolved in 25mL of glacial acetic acid according to the molar ratio of hydrazine hydrate to compound 7 of 5:1 and heated under reflux at 80 ℃ for 8 h. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure, extracted with dichloromethane, the organic phases were combined and washed with anhydrous Na₂SO₄Drying, and separating and purifying by column chromatography with DCM/MeOH as eluent to obtain compound VCTb9 with the following structural formula:

example 2:

the application of quinoline derivatives VCT b5 and VCT b9 in preparing anticancer drugs:

this example contrasts with the effect of VCT b10 in inhibiting tumors, where VCT b10 is

Quinoline derivatives in which R in (1) is butyltriphenylphosphonium bromide:

the structural formula of VCT b10 is:

(1) the inhibition effect of quinoline derivatives VCT b5, VCT b9 and VCT b10 on human lung cancer cell A549, breast cancer cell MDA231-LM2 and human stomach cancer cell MGC-803:

culturing human lung cancer cell A549, breast cancer cell MDA231-LM2 and human gastric cancer cell MGC-803 at 200 μ L/well and 5000 fine particlesCell density of cells seeded in 96-well plates at 37 ℃ 5% CO₂After culturing in an incubator for 24 hours until the cells are completely attached to the wall, 200. mu.L of DMEM diluted to a final concentration of 0.0625X 10 was added to each 96-well plate^-6、0.125×10^-6、0.25×10^-6、0.5×10^-6、1×10^-6、2×10^-6、4×10^-6、8×10^-6、16×10^-6、32×10^-6mol/L quinoline derivatives (VCT b5, VCT b9 or VCT b10) at 37 ℃ with 5% CO₂After culturing for 48 hours in an incubator, detecting the growth condition of the cells by a CCK-8 method;

the results are shown in FIGS. 2-4:

tables 1-3 show the growth inhibition of VCTb5 on human lung cancer cell A549, breast cancer cell MDA231-LM2 and human gastric cancer cell MGC-803; IC of VCT b5 inhibition of Lung cancer A549 cells₅₀2.013uM, IC of inhibitory effect on breast cancer cells MDA231-LM2₅₀2.370uM, IC as an inhibitory effect on MGC-803 of gastric cancer cells₅₀＝1.86uM。

Tables 4-6 show the growth inhibition of VCTb9 on human lung cancer cell A549, breast cancer cell MDA231-LM2 and human gastric cancer cell MGC-803, and the IC of VCT b9 on the inhibition of lung cancer cell A549₅₀IC of inhibition of breast cancer cells MDA231-LM2 by 2.701uM₅₀1.680uM, IC is the inhibition of human gastric cancer cell MGC-803₅₀＝2.29uM。

Tables 7-9 show the growth inhibition of VCTb10 on human lung cancer cell A549, breast cancer cell MDA231-LM2 and human gastric cancer cell MGC-803, the growth inhibition of VCT b10 on lung cancer cell A549, breast cancer cell MDA231-LM2 and gastric cancer cell MGC-803, and the inhibition of VCT b10 on lung cancer cell A549₅₀IC > 30uM, inhibition of breast cancer cells MDA231-LM2₅₀More than 30uM, and the inhibition effect on gastric cancer cell MGC-803 is IC₅₀＞30uM。

TABLE 1 inhibition ratio of VCTb5 on A549 cells at different concentrations

TABLE 2 inhibition of LM2 cells by VCTb5 at various concentrations

TABLE 3 inhibition rate of MGC-803 cells by VCTb5 at different concentrations

TABLE 4 inhibition of A549 cells by VCTb9 at various concentrations

TABLE 5 inhibition of LM2 cells by VCTb9 at various concentrations

TABLE 6 inhibition of MGC-803 cells by VCTb9 at various concentrations

TABLE 7 inhibition ratio of VCTb10 on A549 cells at different concentrations

TABLE 8 inhibition of LM2 cells by VCTb10 at various concentrations

TABLE 9 inhibition of LM2 cells by VCTb10 at various concentrations

Claims

1. A quinoline derivative, wherein the structural formula of the quinoline derivative is as follows:

2. the use of a quinoline derivative according to claim 1 in the manufacture of a medicament for inhibiting the growth of a cancer cell, said cancer cell being a breast cancer cell or a gastric cancer cell.