CN111494381B - Application of alkenyl quinoline compound in preparation of antitumor drugs - Google Patents

Abstract

The invention discloses application of an alkenyl quinoline compound in preparation of antitumor drugs. The structure of the alkenyl quinoline compound is shown as a formula (I); wherein R is ¹ Is hydrogen, C _1‑6 Alkyl, substituted C _1‑6 Alkyl, C _5‑6 Aryl, substituted C _5‑6 Aromatic groups or C _9‑10 A fused bicyclic aromatic group; r is R ² Is C _1‑6 Alkyl, substituted C _1‑6 Alkyl, C _5‑6 Aryl, substituted C _5‑6 Aromatic groups or C _9‑10 Fused bicyclic aromatic groups. The alkenyl quinoline compound provided by the invention has a certain inhibition effect on breast cancer, colon cancer and liver cancer cells, wherein the inhibition effect on liver cancer cells is particularly obvious and even obviously superior to that of a positive control medicament, and 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 resisting tumors.

Description

Application of alkenyl quinoline compounds in the preparation of antitumor drugs

technical field

The invention relates to the technical field of medicine, and more specifically, relates to the application of alkenyl quinoline compounds in the preparation of antitumor drugs.

Background technique

Cancer has become a disease that seriously endangers human health, and it is also the second largest killer after cardiovascular disease. At present, clinical anticancer drugs mainly include alkylating agents, antimetabolite drugs, antitumor antibiotics, antitumor herbal medicines and immunotherapy drugs, etc., but many anticancer drugs have obvious toxic side effects on normal organisms, such as mutagenicity, genetic Toxicity, etc., so the study of anticancer drugs has become a hot topic today. At present, the structures of anti-tumor drugs are complex and diverse, and compounds with different structures show excellent anti-tumor activities. Finding effective and less toxic anti-tumor drugs has become a hot spot in the development of new anti-tumor drugs.

Alkenyl quinoline compounds have a wide range of biological activities and are important functional structures of many bioactive macromolecules and natural products. For example, montelukast sodium, a leukotriene receptor antagonist clinically used in the treatment of asthma. The reported biological activities mainly include anti-Alzheimer's disease, anti-fungal and anti-parasitic (Bioorganic & Medicinal Chemistry Letters 28 (2018) 1011-1019; European Journal of Medicinal Chemistry 89 (2015) 349-361; European Journal of Medicinal Chemistry 130 (2017) 139–153; Bioorganic & Medicinal Chemistry 20 (2012) 6960–6968), and its antitumor activity has not been reported yet.

Contents of the invention

The object of the present invention is to provide the application of alkenyl quinoline compound in the preparation of antitumor drugs. At present, alkenyl quinolines are mostly used in the treatment of asthma, anti-Alzheimer's disease, anti-fungal and anti-parasite, etc. The present invention discloses its application in anti-tumor, which belongs to the new application of alkenyl quinoline compounds.

Another object of the present invention is to provide the use of the isomer or pharmaceutically acceptable salt of the alkenyl quinoline compound in the preparation of antitumor drugs.

Above-mentioned purpose of the present invention is achieved by following scheme:

The application of alkenyl quinoline compound in the preparation of antitumor drugs, the structure of said alkenyl quinoline compound is shown in formula (I):

Wherein R ¹ is hydrogen, C _1-6 alkyl, C _5-6 aryl or C _9-10 condensed bicyclic aryl;

R ² is C _1-6 alkyl, C _5-6 aryl or C _9-10 condensed bicyclic aromatic;

One or more hydrogens in the C _1-6 alkyl or C _5-6 aryl can be independently substituted by substituents, and the substituents are selected from the following groups: halogen, perhalogenated C _1-2 alkane group, halogenated C _1-4 alkyl, hydroxyl, C _1-6 straight or branched alkoxy, C _1-6 cycloalkoxy, nitro, cyano, amino, C _1-6 monoalkyl Amino, C _1-6 dialkylamino, C _5-8 monocycloalkylamino, C _5-6 monoheterocyclylamino, C _5-6 monoarylamino, C _1-6 alkylamido, C _5-6 aryl amido, aminocarbonyl, C _1-6 monoalkylaminocarbonyl, C _1-6 dialkylaminocarbonyl, C _1-6 alkyl acyl, C _5-8 aryl acyl, aminosulfone , C _1-6 monoalkylaminosulfone group, C _1-6 dialkylaminosulfone group, C _5-8 arylaminosulfone group, C _1-6 alkylsulfonylamino group, carboxyl group, straight chain or branched chain Alkyl, C _5-8 cycloalkyl, C _5-8 substituted cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, aryl C _1-3 alkyl, C _5-6 aryl , C _5-6 substituted aryl, C _5-6 polysubstituted arylamino, C _5-6 condensed bicyclic aryl, C _5-6 heterocyclic, C _5-6 aromatic heterocyclic, C _{9- 10} condensed bicyclic aromatic groups or C _5-6 condensed bicyclic aromatic heterocyclic groups.

The inventor researched and disclosed a simple and efficient synthesis method of alkenyl quinoline compounds in 2019. The synthesis method has the advantages of easy control of the reaction, simple reaction conditions, cheap and easy-to-obtain raw materials, and easy industrialization. The application value of alkenyl quinoline compounds. Prior to this, the application of alkenyl quinoline compounds was mostly used for anti-Alzheimer's disease, anti-parasite, anti-fungal, etc. The inventor unexpectedly found that the alkenyl quinoline compounds prepared by this method have good anti-tumor It has a certain inhibitory effect on breast cancer, colon cancer and liver cancer cells, among which the inhibitory effect on liver cancer cells is particularly obvious, even significantly better than the positive control drug, and can be prepared as an anti-tumor drug for application. Great application prospects.

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, the R ¹ is H, C _1～4 alkyl or phenyl; one or more hydrogens in the phenyl can be independently substituted by substituents, and the substituents are selected from the following groups: halogen , hydroxyl, cyano, halogenated C _1-4 alkyl, C _1-4 alkoxy, C _1-4 halogenated alkoxy or C _1-6 amido.

More preferably, said R ¹ is H, methyl, ethyl or phenyl.

Preferably, the R ² is C _1-4 alkyl, phenyl or heteroatom-containing four-membered ring or five-membered ring;

Wherein one or more hydrogens in C _1-4 alkyl or phenyl can be independently replaced by substituents, the substituents are selected from the following groups: halogen, hydroxyl, cyano, halogenated C _1-4 alkyl , C _1-4 alkoxy, C _1-4 haloalkoxy or C _1-6 amido.

More preferably, the R ² is 2-thiophene, 4-pyridine or phenyl; one or more hydrogens in the phenyl can be independently replaced by substituents, the substituents are selected from the following groups: halogen , hydroxy, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, formamido or acetamido.

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

At the same time, the present invention also protects the application of the isomer or pharmaceutically acceptable salt of the alkenyl quinoline compound in the preparation of antitumor drugs.

Preferably, the dosage form of the antitumor drug is capsule, tablet, pill, granule, electuary, injection or spray.

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

S1. Accurately weigh substituted or unsubstituted 2-methylquinoline (5mmol), aldehyde (5mmol), acetic acid (1mmol), 1,3-dimethylbarbituric acid (1mmol) into a clean round bottom flask Add 20ml of water and a stirrer to the Erlenmeyer flask, and reflux at 100°C for 24h;

S2. After the reaction is finished (detect the reaction with TLC), after cooling, add an appropriate amount of methylene chloride to _extract the reaction solution, take the methylene chloride layer, and repeatedly extract three times; then add an appropriate amount of _Na2SO4 to the obtained methylene chloride layer Carry out drying, then concentrate under reduced pressure distillation;

S3. Carrying out column chromatography sequentially using a mixed solvent of mobile phase petroleum ether:ethyl acetate (2-30):1 in different proportions as the eluent to obtain the proposed target product.

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

The alkenyl quinoline compound of the present invention shows a certain inhibitory effect on breast cancer, colon cancer and liver cancer cells, and the inhibitory effect on liver cancer cells is particularly obvious, even significantly better than the positive control drug, and can be prepared as an anti-cancer drug. Application of tumor drugs;

At the same time, the preparation method of the alkenyl quinoline compound is simple and efficient, the raw materials are easy to obtain, industrial production can be realized, and it has great application value in anti-tumor.

Detailed ways

The present invention will be further described in detail below in conjunction with specific embodiments, which are only used to explain the present invention, and are not intended to limit the scope of the present invention. The test methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used are commercially available reagents and materials unless otherwise specified.

The preparation route diagram of alkenyl quinoline compound described in the following examples is as follows:

The specific steps are as follows:

S1. Accurately weigh ^R substituted 2-methylquinoline (5mmol), aldehyde (5mmol), acetic acid (1mmol), 1,3-dimethylbarbituric acid (1mmol) into a clean round bottom flask Add 20ml of water and a stirrer to the Erlenmeyer flask, and reflux at 100°C for 24h;

S2. After the reaction is finished (detect the reaction with TLC), after cooling, add an appropriate amount of methylene chloride to _extract the reaction solution, take the methylene chloride layer, and repeatedly extract three times; then add an appropriate amount of _Na2SO4 to the obtained methylene chloride layer Carry out drying, then concentrate under reduced pressure distillation;

S3. Carrying out column chromatography sequentially using a mixed solvent of mobile phase petroleum ether:ethyl acetate (2-30):1 in different proportions as the eluent to obtain the proposed target product.

Example 1

(E)-2-(3-Hydroxy-4-methoxystyryl)-quinoline: 87% yield, ¹ H NMR (400MHz, CDCl ₃ ) δ8.11 (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). ¹³ C NMR( 100MHz, CDCl ₃ ) δ156.2, 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: 76% yield, ¹ H NMR (400MHz, CDCl ₃ ) δ8.19(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). ¹³ C NMR(101MHz,CDCl ₃ )δ154.7,148.1 , 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-fluorostyryl)-quinoline: 75% yield, ¹ H NMR (400MHz, CDCl ₃ ) δ8.11–8.08(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). ¹³ C NMR(100MHz,CDCl ₃ )δ161.6(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 = 22.7 Hz), 14.6 (d, J = 3.4 Hz).

Example 4

(E)-2-(3,4,5-trimethoxystyryl)-quinoline: 70% yield, ¹ H NMR (400MHz, CDCl ₃ ) δ8.09 (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). ¹³ C NMR (100MHz, CDCl ₃ ) δ155.8, 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-(pyridinevinyl)-quinoline: 49% yield, ¹ H NMR (400MHz, CDCl ₃ ) δ8.60 (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). ¹³ C NMR(100MHz,CDCl ₃ )δ154.6,150.2,148.1,143.7, 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-Carboxamidostyryl)-quinoline, 83% yield, ¹ H NMR (400MHz, CDCl ₃ ) δ8.08 (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,CDCl ₃ )δ168.4,156.0,148.2,138.3,136.4,133.8,132.5,129.8,129.0,128.0,127.5,127.3,126.1,119.9,119.2,2 4.6.

Example 7

(E)-2-(4-trifluoromethylstyryl)-quinoline: 94% yield, ¹ H NMR (400MHz, CDCl ₃ ) δ8.10 (d, J=8.5Hz, 2H), 7.77– 7.66(m,5H),7.63–7.60(m,3H),7.54–7.42(m,2H). ¹³ C NMR(101MHz,CDCl ₃ )δ155.1,148.1,139.9,136.5,132.6,131.2,130.2,129.9, 129.2, 127.5, 127.5, 127.2, 126.5, 125.7 (q, J=3.8Hz), 122.8, 119.4.

Example 8

(E)-2-(Thienyl vinyl)-quinoline: 82% yield, ¹ H NMR (400MHz, CDCl ₃ ) δ8.08 (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). ¹³ C NMR (100MHz, CDCl ₃ ) δ155.4, 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 present invention utilizes the MTT experiment to prove the effect of the compound on the proliferation activity of tumor cells.

Experimental results show that the compound of the invention has obvious inhibitory effect on tumor cells and can be used for treating cancer. The specific test method is as follows:

1. The purpose and principle of the experiment

Experimental purpose: MTT method was used to determine the inhibitory effect of the series of compounds in this patent on the proliferation activity of different types of tumor cells.

Experimental principle: The full name of MTT is 3-(4,5)-dimethylthiazo(-z-y1)-3,5-di-phenyltetrazolium romide, and the Chinese chemical name is 3-(4,5-dimethylthiazol-2)-2 , 5-diphenyltetrazolium bromide, trade name: thiazolium blue, is a yellow dye. The MTT colorimetric method used in this patent is a method for detecting cell survival and growth. Its principle is that succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple crystalline formazan, and Deposits in cells, a function that dead cells lack. Dimethyl sulfoxide (DMSO) can dissolve formazan in living cells, and the absorbance value (OD value) at 570nm can be detected with an enzyme-linked immunosorbent detector, and the number of living cells can be reflected according to the absorbance value. Within a certain range, OD The smaller the value, the weaker the cell activity and the better the effect of the drug on inhibiting proliferation.

2. Basic information of reagents

3. Reagent preparation

1. DMEM complete medium

Complete medium containing 10% fetal bovine serum was prepared for use.

2. MTT solution configuration

Dissolve 250mg of MTT powder in a 50mL centrifuge tube, add 50mL of PBS solution, wrap it in tinfoil to avoid light, shake it fully to dissolve it completely, then use a microporous filter membrane with a pore size of 0.22μm to filter and sterilize and aliquot, in- Store in the dark at 20°C.

3. Compound Configuration

Accurately weigh a certain amount of compound, dissolve it in DMSO solution, and prepare a 100mM stock solution, and dilute to 0.05μM, 0.5μM, 5μM, 10μM, 30μM, 50μM working solution with complete medium before use.

4. Experimental process

(1) Cells in the logarithmic growth phase were taken, digested with trypsin, adjusted the cell number concentration to 5.0×10 ⁴ /mL, and inoculated into a 96-well plate at 100 μL/well. Incubate overnight in a 37 °C, 5% _CO2 cell incubator.

(2) After the cells adhered to the wall, the original medium was discarded, and different concentrations of the test compound and positive control drug 5-fluorouracil (5-Fu) were added. The compound concentrations were 0.05 μM, 0.5 μM, 5 μM, 10 μM, and 30 μM, respectively. 50 μM, and three parallel wells were set up for each concentration. After adding the drug, the culture plate was placed in a 37°C, 5% CO ₂ cell incubator to continue culturing for 48h.

(3) Discard the old solution in the well, add 100 μL MTT working solution (5 mg/mL) to each well, and incubate in the incubator for 4 hours.

(4) The medium was discarded, and 100 μL of DDMSO was added to each well, and the formazan crystals were fully dissolved by shaking for 15 minutes.

(5) Measure the absorbance value at 570 nm with an enzyme-linked immunosorbent assay.

(6) Calculate the cell growth inhibition rate according to the following formula:

Inhibition rate=[(As-Ab)/(Ac-Ab)]×100%

As: Absorbance of experimental wells (including cells, MTT, compounds)

Ac: Absorbance of control wells (with cells, MTT, no compound)

Ab: Absorbance of blank wells (without cells and compounds, with MTT)

According to the inhibitory rate of the drug on cell proliferation at different doses, the half inhibitory concentration (IC ₅₀ ) of the compound was calculated by GraphPad Prism 8 software. The experiment was repeated 3 times, and the results were average ± standard deviation. The activity results of the compounds are shown in Table 1.

The tumor inhibitory effect of table 1 compound

According to the above in vitro experimental results, compounds 1, 2, 3, 4 and 5 have stronger inhibitory effects on the proliferation of liver cancer cells than 5-Fu, especially compound 2 has a significant inhibitory effect on the proliferation of liver cancer cells, and its inhibitory activity is about It is 22 times that of 5-Fu; the inhibitory ability of compound 4 to colon cancer cell proliferation is stronger than that of 5-Fu.

From the above results, it can be seen that the compound protected by the present invention has good anti-tumor effect, and this type of compound can be synthesized by the synthetic method of the present invention, which is efficient, simple, atom-economical, and can realize product structure diversity and complexity. It is easy to realize industrialization and has wide application value.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than limit the protection scope of the present invention. For those of ordinary skill in the art, on the basis of the above descriptions and ideas, they can also make There is no need to and cannot exhaustively list all the implementation manners for other changes or changes in different forms. All modifications, equivalent replacements and improvements made within the spirit and principles of the present invention shall be included within the protection scope of the claims of the present invention.

Claims (2)

1. The application of the alkenyl quinoline compound in preparing the antitumor drugs is characterized in that the alkenyl quinoline compound has the following structure:

；

the antitumor drug is an anti-liver cancer drug.

2. The use according to claim 1, wherein the anti-tumor medicament is in the form of a capsule, tablet, pill, granule, injection or spray.