CN115417860B - Quinazoline derivative with anti-tumor activity and synthesis method and application thereof - Google Patents
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Abstract
The application belongs to the field of biological medicine, and discloses quinazoline derivatives shown as follows. The quinazoline derivative has better anti-tumor activity, smaller toxicity to normal cells and better selectivity, and also discloses application of the quinazoline derivative in preparation of anti-tumor drugs.
Description
The application relates to quinazoline derivatives with anti-tumor activity, a synthesis method and application thereof and a divisional application with application number 2020107653004, which are filed 8/3/2020.
Technical Field
The application belongs to the field of pharmaceutical chemistry, and relates to a quinazoline 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 anti-tumor effect of quinazoline 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 the quinazoline compounds to bind to microtubules and inhibit microtubule polymerization may be: 1) A quinazoline alkaloid skeleton, which is likely to be more coincident with the lumen of a microtubule target; 2) The quinazoline compound has 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 are probably one of chemical structural bases of the quinazoline compound combined with the microtubules and inhibiting microtubule polymerization.
The application aims to provide quinazoline derivatives shown in a formula I:
wherein R is 1 Selected from F, cl, br, C C1-C3 alkyl or C1-C3 alkoxy, R 2 Selected from H, C C1-C3 alkyl or C1-C3 alkoxy, X is selected from C, N; but does not include R 1 ＝CH 3 、R 2 ＝H、X＝C，R 1 ＝Cl、R 2 ＝H、X＝C。
Preferably, R 1 Selected from Cl, CH 3 ，R 2 Selected from H, CH 3 X is selected from C, N; but does not include R 1 ＝CH 3 、R 2 ＝H、X＝C，R 1 ＝Cl、R 2 ＝H、X＝C。
Specifically, the quinazoline derivatives are selected from the following:
the corresponding chemical names are:
2-chloro-N-methyl-N- (1, 2-dimethylindol-5-yl) quinazolin-4-amine;
n, 2-dimethyl-N- (1-methyl-7-azaindol-5-yl) quinazolin-4-amine;
n, 2-dimethyl-N- (1, 2-dimethylindol-5-yl) quinazolin-4-amine.
The application also aims to provide a synthesis method of quinazoline derivatives shown in a formula I, wherein the reaction formula is as follows:
wherein R is selected fromR 1 、R 2 As before.
Specifically, the synthesis method of the quinazoline derivative comprises the following steps:
step (1), substitution reaction: compounds of formula III and of formula R-NH 2 The secondary amine is used as a raw material, the pH value of a reaction system is regulated to be 5-7 by concentrated hydrochloric acid, 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; the reaction solution is extracted by water and dichloromethane, the organic phase is suspended and purified by a silica gel column chromatography to obtain the quinazoline derivative shown in the formula I.
In the step (1), the molar ratio of the compound represented by the formula III to the secondary amine is 1:1 to 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.
Specifically, the compound represented by formula III may be selected from 2-methyl-4-chloroquinazoline and 2, 4-dichloroquinazoline.
Specifically, the secondary amine may be selected from 5-amino-7-azaindole, 5-amino-2-methylindole.
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.
The silica gel column chromatography uses petroleum ether and ethyl acetate=10:1v/V as eluent.
The inventor verifies through experiments that the quinazoline derivative has better anti-tumor activity, has obvious inhibition level on HepG2 tumor cell lines, has smaller toxicity on normal cells, has better selectivity, and is expected to become an anticancer drug with research prospect through further research. Therefore, another object of the application is to provide the application of the quinazoline derivatives in preparing antitumor drugs.
Preferably, the tumor is liver cancer.
The application has the beneficial effects that:
the quinazoline derivative has the advantages of cheap and easily obtained raw materials, low toxicity of the used reagents, mild reaction conditions, convenient post-treatment and capability of enriching a large amount. Pharmacological experiments show that the quinazoline derivative has good anti-tumor activity and is expected to be developed into an anti-tumor drug.
Detailed Description
To further illustrate the application, a series of examples are set forth below. These examples are illustrative and should not be construed as limiting the application.
Example 1
Preparation of 2-chloro-N-methyl-N- (1, 2-dimethylindol-5-yl) quinazolin-4-amine (Compound I-1)
2, 4-dichloroquinazoline (100 mg,0.505 mmol) and 2-methyl-5-aminoindole (74 mg,0.505 mmol) were dissolved in isopropanol, concentrated hydrochloric acid was added to adjust pH to 6, and heated to reflux for 2h (TLC detection of complete reaction starting material). The reaction solution is cooled for crystallization, filtered and dried to obtain 140mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 33mg of sodium hydrogen and 85 μl of methyl iodide were added to the solution, followed by reaction under ice bath for 1 hour, then reaction at room temperature for 1 hour, the reaction solution was extracted with water and methylene chloride, and the organic phase was suspended, and 49mg of 2-chloro-N-methyl-N- (1, 2-dimethylindol-5-yl) quinazolin-4-amine (compound I-1) was obtained in 27% yield by silica gel column chromatography using petroleum ether: ethyl acetate=10:1v/V as eluent.
ESI-MS：361.13[M-H] - .
1H-NMR(300MHz,DMSO-d6,TMS),δppm:2.41(3H,s),3.56(3H,s),3.71(3H,s),6.23(1H,s),6.73(1H,d),6.95(1H,m),7.06(1H,m),7.42(1H,d),7.50(1H,d),7.59(2H,m).
Example 2
Preparation of N, 2-dimethyl-N- (1-methyl-7-azaindol-5-yl) quinazolin-4-amine (Compound I-2)
2-methyl-4-chloroquinazoline (100 mg,0.562 mmol) and 5-amino-7-azaindole (75 mg,0.562 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 was detected by TLC). The reaction solution is cooled for crystallization, filtered and dried to obtain 145mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 38mg of sodium hydrogen and 99 μl of methyl iodide were added to the solution, followed by reaction under ice bath for 1 hour, then reaction at room temperature for 1 hour, the reaction solution was extracted with water and dichloromethane, and the organic phase was suspended, and N, 2-dimethyl-N- (1-methyl-7-azaindol-5-yl) quinazolin-4-amine (compound I-2) was obtained in a yield of 24% by silica gel column chromatography using petroleum ether: ethyl acetate=10:1v/V as eluent.
ESI-MS：302.15[M-H] - .
1H-NMR(300MHz,DMSO-d6,TMS),δppm:2.61(3H,s),3.58(3H,s),3.84(3H,s),6.45(1H,d),6.86(1H,d),6.96(1H,m),7.55(1H,m),7.60(1H,d),7.66(1H,d),7.92(1H,d),8.17(1H,d).
Example 3
Preparation of N, 2-dimethyl-N- (1, 2-dimethylindol-5-yl) quinazolin-4-amine (Compound I-3)
2-methyl-4-chloroquinazoline (100 mg,0.562 mmol) and 2-methyl-5-aminoindole (74 mg,0.562 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 was detected by TLC). The reaction solution is cooled for crystallization, filtered and dried to obtain 154mg of intermediate. The intermediate was dissolved in N, N-dimethylformamide, 38mg of sodium hydrogen and 100 μl of methyl iodide were added to the solution, followed by reaction under ice bath for 1 hour, then reaction at room temperature for 1 hour, the reaction solution was extracted with water and methylene chloride, and the organic phase was suspended and dried by silica gel column chromatography with petroleum ether: ethyl acetate=10:1V/V as eluent to give N, 2-dimethyl-N- (1, 2-dimethylindol-5-yl) quinazolin-4-amine (compound I-3) 51mg in 29% yield.
ESI-MS：315.17[M-H] - .
1H-NMR(300MHz,DMSO-d6,TMS),δppm:2.41(3H,s),2.59(3H,s),3.55(3H,s),3.69(3H,s),6.19(1H,s),6.87(2H,m),6.97(1H,d),7.30(1H,d),7.49(2H,m),7.61(1H,d).
Example 4
Pharmacological experiments on quinazoline derivatives
The anti-tumor activity test is carried out on the quinazoline 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, USA),Inverted biological microscope (IX 71, OLYMPUS, japan), enzyme-linked immunosorbent assay (Model 680, BIO-RAD, USA), plate shaker (Kylin-bell lab Instruments), autoclave (YXO.SG41.280, shanghai Hua Lin), 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 exponential growth phase and in good state. Adding 1mL of 0.25% trypsin digestion solution, digesting for 1-2min, observing cell state under microscope, sucking out digestion solution when the adherent cells become round and shrink, adding 1-2mL of DMEM medium containing 10% fetal bovine serum to make cell suspension, counting cells, and keeping the cell count at 5×10 per well 3 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 (compounds I-1, I-2, I-3) and positive control combretastatin (CA-4) were prepared in DMEM medium to a final concentration of 1. Mu.M/well, and each drug was incubated for 48 hours in 3 duplicate wells with DMSO as a blank (DMSO diluted in medium). 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%
Initial results showed that at a concentration of 1 μm, the test compounds had greater than 50% inhibition of HepG2 cells, so the test compounds were fine-screened.
TABLE 1 inhibition of HepG2 cell lines by test compounds
As shown in Table 1, the quinazoline derivatives have obvious inhibition effect on HepG2 cells, wherein the compound I-3 has optimal activity and IC 50 The value was 1.0.+ -. 0.1nM.
TABLE 2 inhibition of L-02 cell lines by test compounds
As can be seen from Table 2, the quinazoline derivatives of the present application have toxicity to human normal liver cell line L-02 which is weaker than that to cancer cells, wherein the compound I-1 has the best selectivity to liver cancer cells, and its SI value (SI value=IC 50 L-02/IC 50 HepG 2) was 5.4.
In conclusion, the quinazoline derivative has a strong inhibition effect on the human liver cancer cell strain HepG2, the inhibition effect on tumor cells is superior to that of a positive control drug CA-4, the activity of the compound I-3 is optimal, and the compound I-3 is used for IC of the HepG2 cell strain 50 The value was 1.0.+ -. 0.1nM. IC for HepG2 with best selectivity of Compound I-1 50 IC for L-02 with a value of 1.2+ -0.1 nM 50 The value is 6.5+/-0.1 nM, the SI value is 5.4, and the preparation is expected to become a new anti-tumor drug and deserves intensive research.
Claims (10)
1. Quinazoline derivatives as shown below:
2. the method for synthesizing quinazoline derivatives according to claim 1, wherein the reaction formula is as follows:
wherein R is selected fromR 1 =cl or CH 3 ，R 2 ＝CH 3 、X＝CH。
3. The method for synthesizing quinazoline derivatives according to claim 2, comprising the following steps: a step of
Step (1), substitution reaction: compounds of formula III and of formula R-NH 2 The secondary amine is used as a raw material, the pH value of a reaction system is regulated to be 5-7 by concentrated hydrochloric acid, 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 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; the reaction solution is extracted by water and dichloromethane, the organic phase is suspended and purified by a silica gel column chromatography to obtain the quinazoline derivative shown in the formula I.
4. The method for synthesizing quinazoline derivatives according to claim 3, wherein in the step (1), the molar ratio of the compound represented by formula III to the secondary amine is 1:1 to 1.2.
5. The method for synthesizing quinazoline 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 for synthesizing a quinazoline derivative according to claim 5, wherein in the step (1), the reaction solvent is isopropyl alcohol.
7. The method for synthesizing quinazoline derivatives according to claim 3, wherein in the step (2), the molar ratio of the intermediate shown in the formula II to sodium hydrogen to methyl iodide is 1:3-4:3-4.
8. The method for synthesizing quinazoline derivatives according to claim 7, wherein in the step (2), the molar ratio of the intermediate shown in the formula II to sodium hydrogen to methyl iodide is 1:3:3.
9. The method for synthesizing quinazoline derivatives according to claim 3, wherein the silica gel column chromatography uses petroleum ether/ethyl acetate=10:1v/V as eluent.
10. The use of quinazoline derivatives as claimed in claim 1 in the manufacture of a medicament for the treatment of liver cancer.
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