CN111494381A

CN111494381A - Application of alkenyl quinoline compound in preparation of antitumor drugs

Info

Publication number: CN111494381A
Application number: CN202010367197.8A
Authority: CN
Inventors: 吴婷; 唐晓冬; 梁恩; 石杰
Original assignee: Southern Medical University
Current assignee: Southern Medical University
Priority date: 2020-04-30
Filing date: 2020-04-30
Publication date: 2020-08-07
Anticipated expiration: 2040-04-30
Also published as: CN111494381B

Abstract

The invention discloses an application of an alkenyl quinoline compound in preparing an anti-tumor medicament. The structure of the alkenyl quinoline compound is shown as a formula (I); wherein R is¹Is hydrogen, C_1‑6Alkyl, substituted C_1‑6Alkyl radical, C_5‑6Aryl, substituted C_5‑6Aryl or C_9‑10A fused bicyclic aromatic group; r²Is C_1‑6Alkyl, substituted C_1‑6Alkyl radical, C_5‑6Aryl, substituted C_5‑6Aryl or C_9‑10A fused bicyclic aromatic group. The alkenyl quinoline compound has certain inhibition effect on breast cancer, colon cancer and liver cancer cells, has particularly obvious inhibition effect on the liver cancer cells, is even remarkably superior to a positive control medicament, and can be prepared into an anti-tumor medicamentApplying the substance; meanwhile, the preparation method of the alkenyl quinoline compound is simple and efficient, raw materials are easy to obtain, industrial production can be realized, and the alkenyl quinoline compound has great application value in tumor resistance.

Description

Application of alkenyl quinoline compound in preparation of antitumor drugs

Technical Field

The invention relates to the technical field of medicines, in particular to application of an alkenyl quinoline compound in preparing an anti-tumor medicine.

Background

Cancer has become a serious health hazard to humans, and is currently second only to cardiovascular disease. At present, clinical antitumor drugs mainly comprise alkylating agents, antimetabolites, antitumor antibiotics, antitumor botanical drugs, immunotherapy drugs and the like, but many antitumor drugs have obvious toxic and side effects on normal organisms, such as mutagenesis, genetic toxicity and the like, so that research on antitumor drugs has become a popular topic at present. The existing antitumor drugs have complex and various structures, and compounds with different structures show excellent antitumor activity. The search for effective antitumor drugs with small toxic and side effects has become a hot spot in the current research and development of new antitumor drugs.

The biological activities also reported mainly include anti-Alzheimer's disease, anti-fungi and anti-parasites (Bioorganic & Medicinal Chemistry L ets 28(2018) 1011-.

Disclosure of Invention

The invention aims to provide application of an alkenyl quinoline compound in preparation of an anti-tumor medicament. At present, alkenyl quinoline is mostly applied to the aspects of treating asthma, resisting Alzheimer's disease, resisting fungi, resisting parasites and the like, the invention discloses application of the alkenyl quinoline in resisting tumors, and belongs to new application of alkenyl quinoline compounds.

The invention also aims to provide the application of the isomer or the pharmaceutically acceptable salt of the alkenyl quinoline compound in preparing the antitumor drugs.

The above object of the present invention is achieved by the following scheme:

the application of the alkenyl quinoline compound in preparing the antitumor drugs is shown in the formula (I):

wherein R is¹Is hydrogen, C_1-6Alkyl radical, C_5-6Aryl or C_9-10A fused bicyclic aromatic group;

R²is C_1-6Alkyl radical, C_5-6Aryl or C_9-10A fused bicyclic aromatic group;

said C is_1-6Alkyl or C_5-6One or more hydrogens of the aromatic group may be independently substituted with a substituent selected from the group consisting of: halogen, perhalogenated C_1-2Alkyl, halo C_1-4Alkyl, hydroxy, C_1-6Straight or branched alkoxy, C_1-6Cycloalkoxy, nitro, cyano, amino, C_1-6Monoalkylamino group, C_1-6Dialkylamino radical, C_5-8Monocycloalkylamino radical, C_5-6Monoheterocyclylamino, C_5-6Monoarylamino group, C_1-6Alkylamido radical, C_5-6Arylamido, aminocarbonyl, C_1-6Monoalkylaminocarbonyl radical, C_1-6Dialkylaminocarbonyl group, C_1-6Alkyl acyl radical, C_5-8Aryl acyl, aminosulfonyl, C_1-6Monoalkylaminosulfonyl radical, C_1-6Dialkyl amino sulfone group, C_5-8Aryl aminosulfonyl radical, C_1-6Alkylsulfonylamino, carboxyl, straight or branched alkyl, C_5-8Cycloalkyl radical, C_5-8Substituted cycloalkyl, C_2-4Alkenyl radical, C_2-4Alkynyl, aryl C_1-3Alkyl radical, C_5-6Aryl radical, C_5-6Substituted aromatic radical, C_5-6Polysubstituted arylamino, C_5-6Fused bicyclic aromatic radical, C_5-6Heterocyclic group, C_5-6Aromatic heterocyclic group, C_9-10Fused bicyclic aromatic radical or C_5-6Fused bicyclic aromatic heterocyclic group.

The inventor researches and discloses a simple and efficient synthesis method of an alkenyl quinoline compound in 2019, the synthesis method has the advantages of easily controllable reaction, simple reaction conditions, cheap and easily available raw materials, easiness in realizing industrialization and the like, and the application value of the alkenyl quinoline compound is greatly developed. Before the application, the alkenyl quinoline compound is mostly used for resisting Alzheimer's disease, parasites, fungi and the like, and the inventor unexpectedly finds that the alkenyl quinoline compound prepared by the method has good antitumor activity, shows a certain inhibition effect on breast cancer, colon cancer, liver cancer cells and the like, has a particularly obvious inhibition effect on the liver cancer cells, is even remarkably superior to a positive control medicament, can be prepared into an antitumor medicament for application, and has a great application prospect.

Preferably, the anti-tumor drug is an anti-breast cancer drug, an anti-colon cancer drug and/or an anti-liver cancer drug.

Preferably, the anti-tumor drug is an anti-liver cancer drug.

Preferably, said R is¹Is H, C_1～4Alkyl or phenyl; one or more hydrogens of the phenyl group may be independently substituted with a substituent selected from the group consisting of: halogen, hydroxy, cyano, halogeno C_1～4Alkyl radical, C_1～4Alkoxy radical, C_1～4Haloalkoxy or C_1-6An amide group.

More preferably, said R¹Is H, methyl, ethyl or phenyl.

Preferably, said R is²Is C_1～4Alkyl, phenyl or a heteroatom containing four or five membered ring;

wherein C is_1～4One or more hydrogens of the alkyl or phenyl group may be independently substituted with a substituent selected from the group consisting of: halogen, hydroxy, cyano, halogeno C_1～4Alkyl radical, C_1～4Alkoxy radical, C_1～4Haloalkoxy or C_1-6An amide group.

More preferably, said R²Is 2-thiophene, 4-pyridine or phenyl; one or more hydrogens of the phenyl group may be independently substituted with a substituent selected from the group consisting of: halogen, hydroxy, cyano, methyl, ethylMethoxy, ethoxy, trifluoromethyl, trifluoroethyl, carboxamido or acetylamino.

Preferably, the structure of the alkenylquinoline compound is shown in one of the following structures:

the invention also protects the application of the isomer or pharmaceutically acceptable salt of the alkenyl quinoline compound in preparing antitumor drugs.

Preferably, the dosage form of the anti-tumor medicine is capsules, tablets, pills, granules, injection or spray.

The preparation method of the alkenyl quinoline compound is simple, and the preparation process is as follows:

s1, accurately weighing substituted or unsubstituted 2-methylquinoline (5mmol), aldehyde (5mmol), acetic acid (1mmol) and 1, 3-dimethyl barbituric acid (1mmol) and adding the weighed materials into a clean round-bottom flask; adding 20ml of water and a stirrer into the conical flask, and carrying out reflux reaction at 100 ℃ for 24 hours;

s2, after the reaction is finished (the reaction is detected by T L C), cooling, adding a proper amount of dichloromethane to extract reaction liquid, taking a dichloromethane layer, repeatedly extracting for three times, adding a proper amount of Na into the obtained dichloromethane layer₂SO₄Drying, and then distilling and concentrating under reduced pressure;

s3, sequentially mixing the following mobile phase petroleum ether: and (3) performing column chromatography by using a mixed solvent of ethyl acetate (2-30) and 1 as an eluent to obtain a target product to be synthesized.

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

the alkenyl quinoline compound has certain inhibition effect on breast cancer, colon cancer and liver cancer cells, wherein the inhibition effect on the liver cancer cells is particularly obvious and even remarkably superior to that of a positive control medicament, and the alkenyl quinoline compound can be prepared into an anti-tumor medicament for application;

meanwhile, the preparation method of the alkenyl quinoline compound is simple and efficient, raw materials are easy to obtain, industrial production can be realized, and the alkenyl quinoline compound has great application value in tumor resistance.

Detailed Description

The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.

The preparation scheme for alkenylquinoline compounds described in the following examples is shown below:

the specific steps are as follows:

s1, accurately weighing R¹Substituted 2-methylquinoline (5mmol), aldehyde (5mmol), acetic acid (1mmol), 1, 3-dimethyl barbituric acid (1mmol) were added to a clean round bottom flask; adding 20ml of water and a stirrer into the conical flask, and carrying out reflux reaction at 100 ℃ for 24 hours;

Example 1

(E) -2- (3-hydroxy-4-methoxystyryl) -quinoline: the yield of the reaction solution is 87 percent yield,¹H NMR(400MHz,CDCl₃)8.11(d,J＝8.5Hz,2H),7.78(d,J＝8.0Hz,1H),7.71(t,J＝7.2Hz,1H),7.62(dd,J＝19.3,12.4Hz,2H),7.50(t,J＝7.4Hz,1H),7.30(d,J＝9.5Hz,2H),7.14(dd,J＝8.3,1.7Hz,1H),6.87(d,J＝8.3Hz,1H),3.91(s,3H).¹³C NMR(100MHz,CDCl₃)156.2,148.0,147.4,145.9,136.4,134.4,130.1,129.7,128.8,127.4,127.2,127.0,126.0,120.3,119.1,112.8,110.7,55.9。

example 2

(E) -2- (4-cyanostyryl) -quinoline: the yield of the crystal is 76 percent of yield,¹H NMR(400MHz,CDCl₃)8.19(d,J＝8.5Hz,1H),8.12(d,J＝8.5Hz,1H),7.83(d,J＝8.1Hz,1H),7.79–7.65(m,7H),7.58–7.46(m,2H).¹³C NMR(101MHz,CDCl₃)154.7,148.1,140.9,136.7,132.5,132.2,132.2,130.0,129.3,127.6,127.5,126.7,119.6,118.8,111.6。

example 3

(E) -2- (3-methyl-4-fluorophenylvinyl) -quinoline: the yield of the crystal is 75 percent of yield,¹H NMR(400MHz,CDCl₃)8.11–8.08(m,2H),7.76(d,J＝8.1Hz,1H),7.75–7.67(m,1H),7.65–7.59(m,2H),7.53–7.39(m,3H),7.30(d,J＝16.3Hz,1H),7.02(t,J＝8.9Hz,1H).2.31(s,3H).¹³C NMR(100MHz,CDCl₃)161.6(d,J＝246Hz),155.8,148.1,136.4,133.5,132.3(d,J＝3.7Hz),130.3(d,J＝5.4Hz),129.8,129.0,128.3,127.5,127.3,126.3(d,J＝8.1Hz),126.1,125.2(d,J＝17.7Hz),119.1,115.4(d,J＝22.7Hz),14.6(d,J＝3.4Hz)。

example 4

(E) -2- (3,4, 5-trimethoxystyryl) -quinoline: the yield of the high-molecular-weight polyethylene glycol is 70 percent,¹H NMR(400MHz,CDCl₃)8.09(dd,J＝18.7,8.5Hz,2H),7.77(d,J＝8.0Hz,1H),7.73–7.65(m,2H),7.58(d,J＝16.3Hz,1H),7.48(t,J＝7.5Hz,1H),7.33(d,J＝16.3Hz,1H),6.87(s,2H),3.91(s,6H),3.89(s,3H).¹³C NMR(100MHz,CDCl₃)155.8,153.4,148.1,138.7,136.4,134.4,132.1,129.8,129.0,128.4,127.5,127.3,126.2,118.8,104.3,60.9,56.1。

example 5

(E) -2- (pyridinylvinyl) -quinoline: the yield of the reaction solution is 49 percent yield,¹H NMR(400MHz,CDCl₃)8.60(dd,J＝4.0,2.2Hz,2H),8.16–8.06(m,2H),7.80–7.68(m,2H),7.63–7.49(m,4H),7.43(d,J＝6.0Hz,2H).¹³C NMR(100MHz,CDCl₃)154.6,150.2,148.1,143.7,136.6,133.2,131.4,129.9,129.3,127.6,127.5,126.7,121.3,119.5。

example 6

(E) -2- (4-carboxamido styryl) -quinoline, 83% yield,¹H NMR(400MHz,CDCl₃)8.08(dd,J＝14.0,8.6Hz,2H),7.77(d,J＝8.1Hz,1H),7.72–7.67(m,1H),7.66–7.54(m,6H),7.52–7.45(m,1H),7.32(d,J＝16.3Hz,1H),2.18(s,3H).¹³C NMR(100MHz,CDCl₃)168.4,156.0,148.2,138.3,136.4,133.8,132.5,129.8,129.0,128.0,127.5,127.3,126.1,119.9,119.2,24.6。

example 7

(E) -2- (4-trifluoromethylstyryl) -quinoline: the yield of the crystal is 94 percent of yield,¹H NMR(400MHz,CDCl₃)8.10(d,J＝8.5Hz,2H),7.77–7.66(m,5H),7.63–7.60(m,3H),7.54–7.42(m,2H).¹³C NMR(101MHz,CDCl₃)155.1,148.1,139.9,136.5,132.6,131.2,130.2,129.9,129.2,127.5,127.5,127.2,126.5,125.7(q,J＝3.8Hz),122.8,119.4。

example 8

(E) -2- (thienylvinyl) -quinoline: the yield of the product is 82 percent of yield,¹H NMR(400MHz,CDCl₃)8.08(dd,J＝14.9,8.6Hz,2H),7.88–7.83(m,1H),7.77–7.68(m,2H),7.54(d,J＝8.6Hz,1H),7.51–7.46(m,1H),7.30(d,J＝5.7Hz,1H),7.26–7.19(m,2H),7.06(dd,J＝5.0,3.6Hz,1H).¹³C NMR(100MHz,CDCl₃)155.4,148.1,142.0,136.2,129.6,129.0,128.1,128.0,127.7,127.4,127.2,127.1,126.0,125.9,119.2。

result detection

The invention utilizes MTT experiment to prove the influence of the compound on the proliferation activity of tumor cells.

The experimental result shows that the compound has obvious effect of inhibiting tumor cells and can be used for treating cancers. The specific test method is as follows:

first, experimental purpose and principle

Purpose of the experiment: MTT method is adopted to determine the inhibition effect of the series of compounds in the patent on the proliferation activity of different types of tumor cells.

The experimental principle is as follows: MTT is named 3- (4, 5) -dimethylthiahia azo (-z-y1) -3, 5-di-phenylyttrazolimide, and the chemical name of Chinese is 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazole bromide, the trade name is: thiazole blue, a yellow dye. The MTT colorimetry employed in this patent is a method for detecting survival and growth of cells, and its principle is that succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-violet crystalline formazan and deposit it in cells, while dead cells lack this function. Dimethyl sulfoxide (DMSO) can dissolve formazan in living cells, an enzyme linked immunosorbent assay detector is used for detecting an absorbance value (OD value) at 570nm, the quantity of the living cells can be reflected according to the absorbance value, and in a certain range, the smaller the OD value is, the weaker the cell activity is, and the better the proliferation inhibition effect of the drug is.

Second, basic information of reagent

Third, reagent preparation

DMEM complete Medium

Preparing a complete culture medium containing 10% fetal bovine serum for later use.

Preparation of MTT solution

Dissolving 250mg of MTT powder in a centrifuge tube with the thickness of 50m L, adding 50m L PBS solution, wrapping the mixture with tinfoil paper in the dark, fully shaking the mixture to ensure that the mixture is completely dissolved, then filtering the mixture by using a microporous filter membrane with the aperture of 0.22 mu m for sterilization, subpackaging the mixture, and storing the mixture in the dark at the temperature of-20 ℃.

3. Compound configuration

A certain mass of compound is precisely weighed, dissolved in DMSO solution to prepare 100mM mother liquor, and diluted to working solution of 0.05. mu.M, 0.5. mu.M, 5. mu.M, 10. mu.M, 30. mu.M and 50. mu.M with complete culture medium before use.

Fourth, the experimental process

(1) Collecting cells in logarithmic growth phase, digesting with pancreatin, and adjusting cell number concentration to 5.0 × 10⁴M L, 100 μ L/well into 96-well plates, 5% CO at 37 ℃₂The cells were cultured in a cell incubator overnight.

(2) After the cells are attached to the wall, the original culture medium is discarded, and the test compound and the positive control drug 5-fluorouracil (5-Fu) with different concentrations are added, wherein the compound concentrations are respectively 0.05 mu M, 0.5 mu M, 5 mu M, 10 mu M, 30 mu M and 50 mu M, and each concentration is provided with 3 parallel holes. Adding medicine, placing the culture plate at 37 deg.C and 5% CO₂The cell culture box is continued to culture for 48 h.

(3) The old solution in the wells was discarded, and 100. mu. L MTT working solution (5mg/m L) was added to each well and incubated for 4h in an incubator.

(4) The medium was discarded, 100. mu. L DMSO was added to each well, and formazan crystals were sufficiently dissolved by shaking for 15 min.

(5) The absorbance at 570nm was measured using an enzyme linked immunosorbent assay.

(6) The cell growth inhibition rate was calculated according to the following formula:

the inhibition rate was 100% (As-Ab)/(Ac-Ab) ] × 100%

As: absorbance of assay well (cell, MTT, Compound)

Ac: absorbance of control wells (cell, MTT, no Compound)

Ab: absorbance of blank wells (cell and Compound free, MTT containing)

Half maximal Inhibitory Concentration (IC) of compounds was calculated by GraphPad Prism 8 software based on the inhibition rate of drug on cell proliferation at different doses₅₀). The experiment was repeated 3 times in total and the results were averaged ± standard deviation. The activity results of the compounds are shown in table 1.

Tumor inhibiting effects of the compounds of Table 1

According to the results of the in vitro experiments, the inhibition effects of the compounds 1, 2, 3,4 and 5 on the proliferation activity of the liver cancer cells are all stronger than that of 5-Fu, especially the compound 2 has a remarkable inhibition effect on the proliferation of the liver cancer cells, and the inhibition activity is about 22 times of that of 5-Fu; the inhibition ability of the compound 4 on the proliferation of colon cancer cells is stronger than that of 5-Fu.

From the results, the compound protected by the invention has good anti-tumor effect, and the compound can be synthesized by the synthesis method of the invention with high efficiency, simplicity, convenience, atom economy, product structure diversity and complexity, is easy to realize industrialization and has wide application value.

It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. The application of the alkenyl quinoline compound in preparing the antitumor drugs is characterized in that the structure of the alkenyl quinoline compound is shown as the formula (I):

R²is C_1-6Alkyl radical, C_5-6Aryl or C_9-10A fused bicyclic aromatic group;

2. The use of the alkenylquinoline compound of claim 1 for the preparation of an antitumor agent, wherein the antitumor agent is an anti-breast cancer agent, an anti-colon cancer agent and/or an anti-liver cancer agent.

3. The use of the alkenylquinoline compound of claim 1 for the preparation of an antitumor agent, wherein the antitumor agent is an anti-liver cancer agent.

4. The use of the alkenyl quinoline compound of claim 1, wherein R is selected from the group consisting of¹Is H, C_1～4Alkyl or phenyl; one or more hydrogens of the phenyl group may be independently substituted with a substituent selected from the group consisting of: halogen, hydroxy, cyano, halogeno C_1～4Alkyl radical, C_1～4Alkoxy radical, C_1～4Haloalkoxy or C_1-6An amide group.

5. The use of the alkenyl quinoline compound of claim 4, wherein R is selected from the group consisting of¹Is H, methyl, ethyl or phenyl.

6. The use of the alkenyl quinoline compound of claim 1, wherein R is selected from the group consisting of²Is C_1～4Alkyl, phenyl or a heteroatom containing four or five membered ring;

7. Use of the alkenylquinoline compound according to claim 6 for the preparation of an antitumor agentCharacterized in that R is²Is 2-thiophene, 4-pyridine or phenyl; one or more hydrogens of the phenyl group may be independently substituted with a substituent selected from the group consisting of: halogen, hydroxy, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, carboxamido or acetylamino.

8. The use of an alkenyl quinoline compound as claimed in claim 1 in the manufacture of a medicament for use as an antineoplastic agent, wherein the alkenyl quinoline compound has a structure represented by one of the following structures:

9. use of an isomer or a pharmaceutically acceptable salt of the alkenylquinoline compound of claim 1 for the preparation of an antitumor agent.

10. The use according to claim 1 or 9, wherein the antitumor drug is in the form of capsule, tablet, pill, granule, injection or spray.