CN116143693A - 2-methylquinoline derivative with anti-tumor activity and synthesis method and application thereof - Google Patents

2-methylquinoline derivative with anti-tumor activity and synthesis method and application thereof Download PDF

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CN116143693A
CN116143693A CN202310136177.3A CN202310136177A CN116143693A CN 116143693 A CN116143693 A CN 116143693A CN 202310136177 A CN202310136177 A CN 202310136177A CN 116143693 A CN116143693 A CN 116143693A
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孙建博
王坤
王莹
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China Pharmaceutical University
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Abstract

The invention belongs to the field of biological medicine, and discloses a 2-methylquinoline derivative with a structure shown as a formula I, wherein R is selectedShown as follows
Figure DDA0004085660410000011
Substituted phenyl,
Figure DDA0004085660410000012
n=an integer of 1 to 5, R 1 Selected from C 1 ‑C 3 Alkyl, halogen substituted C 1 ‑C 3 Alkyl, C 1 ‑C 3 Alkoxy, halogen substituted C 1 ‑C 3 Alkoxy, 3, 4-methylenedioxy, phenyl, -NR 3 R 4 ；R 3 、R 4 Are respectively and independently selected from H, C 1 ‑C 3 An alkyl group; but substituted phenyl groups do not include p-methoxyphenyl, 3-amino-4-methoxyphenyl; x is selected from C, N, R 2 Selected from H, C 1 ‑C 3 Alkyl, but not simultaneously X, is selected from C, R 2 Selected from H. The 2-methylquinoline derivative has better anti-tumor activity, and has weaker toxicity to normal cells than to cancer cells, and the invention discloses application of the 2-methylquinoline derivative in preparing anti-tumor drugs.

Description

2-methylquinoline derivative with anti-tumor activity and synthesis method and application thereof
The application is a divisional application with the application number 2020105839155, and the title of the application is 2-methylquinoline derivative with anti-tumor activity, and a synthetic method and application thereof is filed in 6/24/2020.
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a 2-methylquinoline derivative with anti-tumor activity, and a synthesis method and application thereof.
Background
Cancer is a major disease affecting human health and longevity, and has become one of the global important public health problems. According to the global cancer report, 1810 ten thousand cancer cases are expected to be newly increased in 2018 worldwide, the number of deaths reaches 960 ten thousand, and the global cancer burden is further increased. Among women, the most commonly afflicted cancer in women is breast cancer, and is also the leading cause of death in women from cancer. The incidence of breast cancer (24.2%, i.e. 24.2% of total cases in women) and mortality (15.0%, i.e. about 15.0% of all cancer deaths in women) are highest.
Tubulin inhibitors represented by paclitaxel are one of the most effective antitumor drugs, but conventional tubulin inhibitors are often interfered by rapidly developing tumor multidrug resistance, which is also a troublesome problem facing clinical treatment. In recent years, some natural small molecular microtubulin inhibitors not only have the characteristics of high activity, low toxicity, good bioavailability and the like, but also are often not substrates of multi-drug resistant pumps, so that the natural small molecular microtubulin inhibitors are also effective on multi-drug resistant tumor cells. The structure modification research of the small molecular compounds has become one of important ways for searching high-efficiency multi-drug resistant protein inhibitors so as to improve the chemotherapy effect of breast cancer.
In recent years, the antitumor effect of quinoline compounds has attracted attention. Many researchers refer to the structural features of the known tubulin inhibitor CA-4 to synthesize compounds with good anti-tumor activity.
Disclosure of Invention
Through computer modeling, the inventors speculate that the structural basis for quinoline compounds to bind to microtubules and inhibit microtubule polymerization may be: 1) Quinoline alkaloid skeleton, this skeleton structure may be relatively coincident with the lumen of microtubule target; 2) Quinoline compounds have N atoms, mercapto groups in microtubules are donors of hydrogen bonds, acceptors of the hydrogen bonds of the N atoms and are easy to combine, and the characteristic structures can be one of chemical structural bases for combining the quinoline compounds with the microtubules and inhibiting microtubule polymerization.
The invention aims to provide a 2-methylquinoline derivative shown in a formula I:
Figure BDA0004085660390000011
wherein R is selected from the group consisting of
Figure BDA0004085660390000021
Substituted phenyl,/->
Figure BDA0004085660390000022
n=an integer of 1 to 5, R 1 Selected from C 1 -C 3 Alkyl, halogen substituted C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halogen substituted C 1 -C 3 Alkoxy, 3, 4-methylenedioxy, phenyl, -NR 3 R 4 ；R 3 、R 4 Are respectively and independently selected from H, C 1 -C 3 An alkyl group; but substituted phenyl groups do not include p-methoxyphenyl, 3-amino-4-methoxyphenyl;
x is selected from C, N, R 2 Selected from H, C 1 -C 3 Alkyl, but not simultaneously X, is selected from C, R 2 Selected from H.
Preferably, n=an integer from 1 to 3, R 1 Selected from C 1 -C 3 Alkyl, halogen substituted C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, 3, 4-methylenedioxy, phenyl, -NR 3 R 4 ；R 3 、R 4 Independently selected from C 1 -C 3 An alkyl group; but substituted phenyl groups do not include p-methoxyphenyl, 3-amino-4-methoxyphenyl;
x is selected from C, N, R 2 Selected from H, methyl, but not both X is selected from C, R 2 Selected from H.
More preferably, n=1, 2, r 1 Selected from C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, 3, 4-methylenedioxy, phenyl, -NR 3 R 4 ；R 3 、R 4 Independently selected from C 1 -C 3 An alkyl group; however, substituted phenyl groups do not include p-methoxyphenyl, 3-amino-4-methoxyphenyl. When n=1, R 1 Preferably para-substitution; when n=2, R 1 Para and meta substitution is preferred;
x is selected from C, N, R 2 Selected from H, methyl, but not both X is selected from C, R 2 Selected from H.
The halogen in the invention is F, cl, br, I.
Specifically, the 2-methylquinoline derivative is selected from the following components:
Figure BDA0004085660390000023
Figure BDA0004085660390000031
the corresponding chemical names are:
n, 2-dimethyl-N- (3, 4, 5-trimethoxyphenyl) quinolin-4-amine;
n, 2-dimethyl-N- (3, 4-dimethoxyphenyl) quinolin-4-amine;
n, 2-dimethyl-N- (4-methylphenyl) quinolin-4-amine;
n, 2-dimethyl-N- (3, 4-methylenedioxyphenyl) quinolin-4-amine;
n, 2-dimethyl-N- (4-trifluoromethylphenyl) quinolin-4-amine;
n, 2-dimethyl-N- (4-biphenyl) quinolin-4-amine;
n, 2-dimethyl-N- (4-dimethylaminophenyl) quinolin-4-amine;
n, 2-dimethyl-N- (4-diethylaminophenyl) quinolin-4-amine;
n, 2-dimethyl-N- (1-methyl-7-N-heteroindol-5-yl) quinolin-4-amine;
n, 2-dimethyl-N- (1, 2-dimethylindol-5-yl) quinolin-4-amine.
The invention also aims to provide a synthesis method of the 2-methylquinoline derivative shown in the formula I, wherein the reaction formula is as follows:
Figure BDA0004085660390000032
the method comprises the following steps:
step (1), substitution reaction: with 2-methyl-4-chloroquinoline and substituted anilines (R-NH) 2 ) Adding concentrated hydrochloric acid as raw material to regulate reaction bodyThe pH of the system is 5-7, and the reaction is carried out for 2-4 hours at 75-85 ℃ to obtain an intermediate shown in a formula II;
step (2), methylation reaction: taking an intermediate shown in a formula II and sodium hydrogen and methyl iodide as raw materials, taking N, N-Dimethylformamide (DMF) as a reaction solvent, firstly reacting for 0.5-1 h under the ice bath condition, and then reacting for 1-2 h at normal temperature; extracting the reaction solution with water and dichloromethane, suspending the organic phase, and purifying by column chromatography to obtain 2-methylquinoline derivatives shown in formula I; wherein the molar ratio of the intermediate of formula ii, sodium hydrogen and methyl iodide=1:3:3.
In the step (1), the molar ratio of the 2-methyl-4-chloroquinoline to the substituted aniline is 1:1-1.2, preferably 1:1.
The reaction solvent is isopropyl alcohol (IPA), a mixed solvent of ethanol and water, a mixed solvent of tetrahydrofuran and water, and the like. The inventor finds that the intermediate can be separated out in isopropanol, so that the intermediate is more conveniently and efficiently obtained, therefore, the reaction solvent is preferably isopropanol, and after the reaction is finished, the reaction solution is cooled for crystallization, filtered and dried, thus obtaining the intermediate shown in the formula II.
In the step (2), the molar ratio of the intermediate shown in the formula II, sodium hydrogen and methyl iodide is 1:3-4:3-4, preferably 1:3:3.
After the reaction is finished, extracting the reaction solution with water and dichloromethane, suspending an organic phase, adopting a silica gel column chromatography, and purifying by using petroleum ether and ethyl acetate=1:1V/V as eluent to obtain the 2-methylquinoline derivative shown in the formula I.
The inventor verifies through experiments that the 2-methylquinoline derivatives have better anti-tumor activity, and have weaker toxicity to normal cells than to cancer cells, wherein the compounds I-9 and I-10 have obvious inhibition level to HepG2 tumor cell lines, and have smaller toxicity, and are expected to become anti-cancer drugs with research prospects through further research. Therefore, another object of the invention is to provide the application of the 2-methylquinoline derivatives in preparing antitumor drugs.
Preferably, the tumor is liver cancer.
The invention has the beneficial effects that:
the 2-methylquinoline derivative has the advantages of cheap and easily obtained raw materials, low toxicity of the used reagent, mild reaction conditions in the preparation method, convenient post-treatment and capability of enriching a large amount. Pharmacological experiments show that the 2-methylquinoline derivatives have good anti-tumor activity and are expected to be developed into anti-tumor drugs.
Detailed Description
To further illustrate the invention, a series of examples are set forth below. These examples are illustrative and should not be construed as limiting the invention.
Example 1
Preparation of N, 2-dimethyl-N- (3, 4, 5-trimethoxyphenyl) quinolin-4-amine (Compound I-1)
2-methyl-4-chloroquinoline (100 mg, 0.560 mmol) and 3,4, 5-trimethoxyaniline (103 mg, 0.560 mmol) were dissolved in isopropanol, concentrated hydrochloric acid was added to adjust pH to 6, and the mixture was heated to reflux for 2h (complete reaction of starting materials was detected by TLC). The reaction solution is cooled for crystallization, filtered and dried to obtain 117mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 26mg of sodium hydrogen and 67 μl of methyl iodide were added to the solution, followed by reaction for 1 hour in an ice bath, then reaction at room temperature, extraction of the reaction solution with water and methylene chloride, suspension of the organic phase, and purification by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1v/V) gave 91mg of the final product N, 2-dimethyl-N- (3, 4, 5-trimethoxyphenyl) quinolin-4-amine in 48% yield.
Figure BDA0004085660390000051
ESI-MS：337.16[M-H] - .
1 H-NMR(300MHz,DMSO-d 6 ,TMS),δ H :2.75(3H,s),3.47(3H,s),3.7(6H,s),3.83(3H,s),6.14(2H,s),7.01(1H,s),7.32(1H,t),7.61(1H,t),7.68(1H,d),8.03(1H,d).
Example 2
Preparation of N, 2-dimethyl-N- (3, 4-dimethoxyphenyl) quinolin-4-amine (Compound I-2)
2-methyl-4-chloroquinoline (100 mg, 0.560 mmol) and 3, 4-dimethoxyaniline (86 mg, 0.560 mmol) were dissolved in isopropanol, concentrated hydrochloric acid was added to adjust pH to 6, and the mixture was heated to reflux for 2h (complete reaction of starting material by TLC). The reaction solution is cooled for crystallization, filtered and dried to obtain 120mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 29mg of sodium hydrogen and 76 μl of methyl iodide were added to the solution, reacted for 1 hour in an ice bath, then reacted for 1 hour at normal temperature, the reaction solution was extracted with water and methylene chloride, the organic phase was suspended, and the final product N, 2-dimethyl-N- (3, 4-dimethoxyphenyl) quinolin-4-amine 94mg was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1V/V) in 54% yield.
Figure BDA0004085660390000052
ESI-MS：307.15[M-H] - .
1 H-NMR(300MHz,DMSO-d 6 ,TMS),δ H :2.61(3H,s),3.39(3H,s),3.65(3H,s),3.69(3H,s),
6.31(1H,d),6.77(2H,m),7.06(1H,s),7.19(1H,m),7.52(2H,m),7.81(1H,dd).
Example 3
Preparation of N, 2-dimethyl-N- (4-methylphenyl) quinolin-4-amine (Compound I-3)
2-methyl-4-chloroquinoline (100 mg, 0.560 mmol) and 3, 4-dimethoxyaniline (60 mg, 0.560 mmol) were dissolved in isopropanol, concentrated hydrochloric acid was added to adjust pH to 6, and the mixture was heated to reflux for 2h (TLC detection of complete reaction of starting material). The reaction solution is cooled for crystallization, filtered and dried to obtain 105mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 31mg of sodium hydrogen and 79 μl of methyl iodide were added to the solution, reacted for 1 hour in an ice bath, then reacted for 1 hour at normal temperature, the reaction solution was extracted with water and methylene chloride, the organic phase was suspended, and the final product N, 2-dimethyl-N- (4-methylphenyl) quinolin-4-amine 89mg was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1V/V) in 60% yield.
Figure BDA0004085660390000061
ESI-MS：261.15[M-H] - .
1 H-NMR(300MHz,DMSO-d 6 ,TMS),δ H :2.21(3H,s),2.61(3H,s),3.38(3H,s),6.76(2H,dd),7.02(2H,dd),7.12(1H,s),7.21(1H,m),7.53(2H,m),7.84(1H,dd).
Example 4
Preparation of N, 2-dimethyl-N- (3, 4-methylenedioxyphenyl) quinolin-4-amine (Compound I-4)
2-methyl-4-chloroquinoline (100 mg, 0.560 mmol) and 3, 4-dimethoxyaniline (77 mg, 0.560 mmol) were dissolved in isopropanol, concentrated hydrochloric acid was added to adjust pH to 6, and the mixture was heated to reflux for 2h (TLC detection of complete reaction of starting material). The reaction solution is cooled for crystallization, filtered and dried to obtain 110mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 28mg of sodium hydrogen and 74 μl of methyl iodide were added to the solution, reacted for 1 hour in an ice bath, then reacted for 1 hour at normal temperature, the reaction solution was extracted with water and methylene chloride, the organic phase was suspended, and the final product N, 2-dimethyl-N- (3, 4-methylenedioxyphenyl) quinolin-4-amine 81mg was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1V/V) in 49% yield.
Figure BDA0004085660390000062
ESI-MS：291.12[M-H] - .
1 H-NMR(300MHz,DMSO-d 6 ,TMS),δ H :2.61(3H,s),3.35(3H,s),5.98(2H,s),6.29(1H,dd),6.68(1H,d),6.75(1H,d),7.08(1H,s),7.24(1H,m),7.54(2H,m),7.83(1H,dd).
Example 5
Preparation of N, 2-dimethyl-N- (4-trifluoromethylphenyl) quinolin-4-amine (Compound I-5)
2-methyl-4-chloroquinoline (100 mg, 0.560 mmol) and 3, 4-dimethoxyaniline (91 mg, 0.560 mmol) were dissolved in isopropanol, and concentrated hydrochloric acid was added to adjust pH to 6, and heated under reflux for 2h (TLC detection of complete reaction of starting materials). The reaction solution is cooled for crystallization, filtered and dried to obtain 137mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 33mg of sodium hydrogen and 84 μl of methyl iodide were added to the solution, reacted for 1 hour in an ice bath, then reacted for 1 hour at normal temperature, the reaction solution was extracted with water and methylene chloride, the organic phase was suspended, and the final product N, 2-dimethyl-N- (4-trifluoromethylphenyl) quinolin-4-amine 121mg was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1V/V) in 68% yield.
Figure BDA0004085660390000071
ESI-MS：315.12[M-H] - .
1 H-NMR(300MHz,DMSO-d 6 ,TMS),δ H :2.66(3H,s),3.30(3H,s),6.77(2H,d),7.39(1H,s),7.46(3H,m),7.62(1H,d),7.70(1H,m),7.98(1H,d).
Example 6
Preparation of N, 2-dimethyl-N- (4-biphenylyl) quinolin-4-amine (Compound I-6)
2-methyl-4-chloroquinoline (100 mg, 0.560 mmol) and 3, 4-dimethoxyaniline (96 mg, 0.560 mmol) were dissolved in isopropanol, and concentrated hydrochloric acid was added to adjust pH to 6, and heated under reflux for 2h (complete reaction of starting material as detected by TLC). The reaction solution was cooled and crystallized, and filtered to obtain 140mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 33mg of sodium hydrogen and 84 μl of methyl iodide were added to the solution, reacted for 1 hour in an ice bath, then reacted for 1 hour at normal temperature, the reaction solution was extracted with water and methylene chloride, the organic phase was suspended, and the final product N, 2-dimethyl-N- (4-biphenyl) quinolin-4-amine 103mg was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1V/V) in 56% yield.
Figure BDA0004085660390000072
ESI-MS：323.16[M-H] - .
1 H-NMR(300MHz,DMSO-d 6 ,TMS),δ H :2.65(3H,s),3.47(3H,s),6.88(2H,d),7.37(5H,m),7.59(6H,m),7.92(1H,d).
Example 7
Preparation of N, 2-dimethyl-N- (4-dimethylaminophenyl) quinolin-4-amine (Compound I-7)
2-methyl-4-chloroquinoline (100 mg, 0.560 mmol) and 3, 4-dimethoxyaniline (77 mg, 0.560 mmol) were dissolved in isopropanol, concentrated hydrochloric acid was added to adjust pH to 6, and the mixture was heated to reflux for 2h (TLC detection of complete reaction of starting material). The reaction solution is cooled for crystallization, filtered and dried to obtain 102mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 26mg of sodium hydrogen and 69 μl of methyl iodide were added to the solution, reacted for 1 hour in an ice bath, then reacted for 1 hour at normal temperature, the reaction solution was extracted with water and methylene chloride, the organic phase was suspended, and the final product N, 2-dimethyl-N- (4-dimethylaminophenyl) quinolin-4-amine 64mg was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1V/V) in 39% yield.
Figure BDA0004085660390000081
ESI-MS：290.17[M-H] - .
1 H-NMR(300MHz,DMSO-d 6 ,TMS),δ H :2.60(3H,s),2.84(6H,s),3.32(3H,s),6.65(2H,d),6.86(2H,d),6.98(1H,s),7.12(1H,t),7.48(2H,m),7.77(1H,d).
Example 8
Preparation of N, 2-dimethyl-N- (4-diethylaminophenyl) quinolin-4-amine (Compound I-8)
2-methyl-4-chloroquinoline (100 mg, 0.560 mmol) and 4-diethylaminoaniline (93 mg, 0.560 mmol) were dissolved in isopropanol, and concentrated hydrochloric acid was added to adjust pH to 6, followed by heat refluxing for 2 hours (complete reaction of starting materials as detected by TLC). The reaction solution was cooled and crystallized, and filtered to obtain 138mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 33mg of sodium hydrogen and 84 μl of methyl iodide were added to the solution, reacted for 1 hour in an ice bath, then reacted for 1 hour at normal temperature, the reaction solution was extracted with water and methylene chloride, the organic phase was suspended, and the final product N, 2-dimethyl-N- (4-diethylaminophenyl) quinolin-4-amine 43mg was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1V/V) in 24% yield.
Figure BDA0004085660390000082
ESI-MS：318.20[M-H] - .
1H-NMR(300MHz,DMSO-d 6 ,TMS),δppm1.05(6H,t),2.60(3H,s),3.29(7H,m),6.59(2H,m),6.84(2H,m),7.12(1H,m),7.49(2H,m),7.77(1H,d).
Example 9
Preparation of N, 2-dimethyl-N- (1-methyl-7-N-heteroindol-5-yl) quinolin-4-amine (Compound I-9)
2-methyl-4-chloroquinoline (100 mg, 0.560 mmol) and 5-amino-7-N heteroindole (75 mg, 0.560 mmol) were dissolved in isopropanol, added with concentrated hydrochloric acid to adjust pH to 6, and heated to reflux for 2h (TLC detection of complete reaction of starting material). The reaction solution was cooled and crystallized, and then filtered to obtain 132mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 35mg of sodium hydrogen and 90 μl of methyl iodide were added to the solution, reacted for 1 hour in an ice bath, then reacted for 1 hour at normal temperature, the reaction solution was extracted with water and methylene chloride, the organic phase was suspended, and the final product N, 29mg of 2-dimethyl-N- (1-methyl-7-N-heteroindol-5-yl) quinolin-4-amine was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1V/V) to give a yield of 17%.
Figure BDA0004085660390000091
ESI-MS：301.15[M-H] - .
1H-NMR(300MHz,DMSO-d 6 ,TMS),δppm:2.74(3H,s),3.51(3H,s),3.89(3H,s),6.32(1H,d),6.95(1H,s),7.12(1H,t),7.18(1H,d),7.51(2H,m),7.59(1H,d),7.96(1H,d),8.20(1H,d).
Example 10
Preparation of N, 2-dimethyl-N- (1, 2-dimethylindol-5-yl) quinolin-4-amine (Compound I-10)
2-methyl-4-chloroquinoline (100 mg, 0.560 mmol) and 2-methyl-5-aminoindole (83 mg,
0.565 mmol) was dissolved in isopropanol, and concentrated hydrochloric acid was added to adjust the pH to 6, and the mixture was heated to reflux for 2h (TLC detection of complete reaction of starting material). The reaction solution was cooled and crystallized, and 127mg of intermediate was obtained by suction filtration. The intermediate was dissolved in N, N-dimethylformamide, 32mg of sodium hydrogen and 82 μl of methyl iodide were added to the solution, reacted for 1 hour in an ice bath, then reacted for 1 hour at normal temperature, the reaction solution was extracted with water and methylene chloride, the organic phase was suspended, and the final product N, 2-dimethyl-N- (1, 2-dimethylindol-5-yl) quinolin-4-amine 28mg was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1V/V) in 16% yield.
Figure BDA0004085660390000092
ESI-MS：314.17[M-H] - .
1H-NMR(300MHz,DMSO-d 6 ,TMS),δppm:2.35(3H,s),2.62(3H,s),3.40(3H,s),3.62(3H,s),6.07(1H,s),6.84(1H,dd),7.02(3H,m),7.28(1H,m),7.43(2H,dd),7.75(1H,m).
Example 11
Pharmacological experiments of 2-methylquinoline derivatives
The anti-tumor activity test is carried out on the 2-methylquinoline derivatives by adopting a tetramethyl-azosin colorimetric method (MTT method), and combretastatin (CA-4) is selected as a positive control drug.
Instrument: ultra clean bench (SW-CJ-1 FD, AIRTECH, sujingtai), constant temperature CO 2 Incubator (3111, thermo, U.S.), inverted biological microscope (IX 71, OLYMPUS, japan), enzyme-linked immunosorbent assay (Model 680, BIO-RAD, U.S.), plate shaker (Kylin-bell lab Instruments), autoclave (YXO.SG41.280, shanghai Hua line), centrifuge (SIGMA).
Reagent: DMEM medium (GIBCO), fetal bovine serum (GIBCO), trypsin (SIGMA), DMSO (SIGMA).
Cell lines: human hepatoma cell line HepG2 and human normal hepatoma cell line L-02 (all supplied by Jiangsu Kaiki Biotechnology Co., ltd.).
The method comprises the following steps: resuscitating the frozen cell strain with DMEM medium, and placing in CO at 37deg.C 2 Culturing in incubator, changing liquid once every day, and spreading when it is in good state in exponential growth phase. 1mL of 0.25% trypsin digestion solution was added to digestObserving cell state under microscope for 1-2min, sucking digestive juice when the adherent cells become round and shrink, adding 1-2mL DMEM medium containing 10% foetal calf serum to make cell suspension, counting cells, and making cell count according to 5×10 per well 4 The amount of the cell suspension required was calculated from the number of individual cells and the total number of wells, the cell suspension was inoculated on a 96-well plate, 100. Mu.L/well, the periphery was sealed with PBS, and the mixture was placed in CO at a constant temperature of 37 ℃ 2 Culturing in an incubator for 24 hours.
Test drugs and positive control combretastatin (CA-4) were prepared in DMEM medium to a final concentration of 1. Mu.M/well, and DMSO was used as a blank (DMSO was diluted with medium) and incubated for 3 duplicate wells per drug for 48 hours. MTT reagent (5 mg/mL in PBS) was added to the 96-well plate, 10. Mu.L/well, and incubation was continued for 4h. The medium in the plate was aspirated, 100. Mu.L of DMSO was added to each well, and the plate was shaken for 10min to dissolve the crystals. And detecting the absorbance value of each hole at the wavelength of 570nm by using an enzyme-linked immunosorbent assay instrument, and calculating the cell inhibition rate. The average value of the 3 primary screening results is the final inhibition rate, and the compound with the primary screening inhibition rate being more than 50% is subjected to concentration gradient screening (5-time dilution) to calculate the IC of the tested medicament 50 Values (graphpad software calculation), 3 replicates were the final IC for the tested compounds 50 Values.
Cell inhibition ratio = [ (blank OD value-dosing OD value)/blank OD value ] ×100%
Results: the 2-methylquinoline derivatives have an inhibition effect on the human liver cancer cell line HepG2, but the inhibition rate of the tested compounds I-1 and I-5 is less than 50 percent (1 mu M concentration, the inhibition rate of the compound I-1 on the HepG2 is 10 percent, and the inhibition rate of the compound I-5 on the HepG2 is 16 percent), thus the IC of the compounds I-2, I-3, I-4, I-6, I-7, I-8, I-9 and I-10 is tested 50 。
TABLE 1 inhibition of HepG2 cell lines by test compounds
Figure BDA0004085660390000101
As can be seen from Table 1, the compounds I-2, I-3, I-4, I-6, I-7, I-8, I-9, I-10 were fine for HepG2The cells have obvious inhibition effect, wherein the compounds I-9 and I-10 have optimal activity, and IC 50 The values were 0.0025.+ -. 0.0001, 0.0021.+ -. 0.0001. Mu.M, respectively.
TABLE 2 inhibition of L-02 cell lines by test compounds
Figure BDA0004085660390000111
As is clear from Table 2, 2-methylquinoline derivatives were less toxic to human normal liver cell line L-02 than to cancer cells, and among them, compound I-2 showed the best selectivity to liver cancer cells, and its SI value (SI value=IC 50 L-02/IC 50 HepG 2) is 80.
In conclusion, the 2-methylquinoline derivatives have a strong inhibition effect on the human lung cancer cell strain HepG 2. IC for HepG2 cell lines with optimal Compound I-10 Activity 50 The value was 0.0021.+ -. 0.0001. Mu.M. IC for HepG2 with best selectivity of Compound I-2 50 IC with a value of 0.027.+ -. 0.005. Mu.M for L-02 50 The value is 2.172+/-0.680 mu M, the SI value is 80, and the preparation is expected to become a new anti-tumor drug and deserves intensive research.

Claims (9)

1. 2-methylquinoline derivatives represented by formula I:
Figure FDA0004085660370000011
wherein R is selected from the group consisting of
Figure FDA0004085660370000012
Substituted phenyl,/->
Figure FDA0004085660370000013
n＝1、2，R 1 Selected from C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, -NR 3 R 4 ；R 3 、R 4 Independent of each otherSelected from C 1 -C 3 An alkyl group; but substituted phenyl groups do not include p-methoxyphenyl; x is selected from CH, R 2 Selected from methyl groups.
2. The 2-methylquinoline derivative according to claim 1, wherein the 2-methylquinoline derivative is selected from the group consisting of:
n, 2-dimethyl-N- (3, 4-dimethoxyphenyl) quinolin-4-amine;
n, 2-dimethyl-N- (4-methylphenyl) quinolin-4-amine;
n, 2-dimethyl-N- (4-dimethylaminophenyl) quinolin-4-amine;
n, 2-dimethyl-N- (4-diethylaminophenyl) quinolin-4-amine;
n, 2-dimethyl-N- (1, 2-dimethylindol-5-yl) quinolin-4-amine.
3. The method for synthesizing the 2-methylquinoline derivative according to claim 1, which is characterized by comprising the following steps:
step (1), substitution reaction: 2-methyl-4-chloroquinoline and R-NH as shown in formula 2 The substituted aniline is taken as a raw material, concentrated hydrochloric acid is added to adjust the pH value of a reaction system to 5-7, and the reaction is carried out for 2-4 hours at 75-85 ℃ to obtain an intermediate shown in a formula II;
Figure FDA0004085660370000014
step (2), methylation reaction: the intermediate shown in the formula II and sodium hydrogen and methyl iodide are used as raw materials, N-dimethylformamide is used as a reaction solvent, the reaction is carried out for 0.5 to 1 hour under the ice bath condition, and then the reaction is carried out for 1 to 2 hours at normal temperature, so that the 2-methylquinoline derivative shown in the formula I is obtained.
4. The method for synthesizing 2-methylquinoline derivatives according to claim 3, wherein in the step (1), the molar ratio of the 2-methyl-4-chloroquinoline to the substituted aniline is 1:1-1.2.
5. The method for synthesizing 2-methylquinoline derivatives according to claim 3, wherein in the step (1), the reaction solvent is a mixed solvent of isopropanol, ethanol and water, or a mixed solvent of tetrahydrofuran and water.
6. The method of synthesizing a 2-methylquinoline derivative according to claim 5, wherein in the step (1), the reaction solvent is isopropanol.
7. The method for synthesizing 2-methylquinoline derivatives according to claim 3, wherein in the step (2), the molar ratio of the intermediate represented by the formula II, sodium hydrogen and methyl iodide is 1:3 to 4:3 to 4.
8. The method for synthesizing 2-methylquinoline derivatives according to claim 3, wherein in the step (2), the reaction solution is extracted with water and methylene dichloride, the organic phase is suspended, and the 2-methylquinoline derivatives shown in the formula I are obtained by purifying by adopting a silica gel column chromatography method with petroleum ether: ethyl acetate=1:1V/V as eluent.
9. The use of 2-methylquinoline derivatives according to claim 1 in the preparation of a medicament for the treatment of tumors.
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