CN110372579B - 1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone and preparation method and application thereof - Google Patents

1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone and preparation method and application thereof Download PDF

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CN110372579B
CN110372579B CN201910633037.0A CN201910633037A CN110372579B CN 110372579 B CN110372579 B CN 110372579B CN 201910633037 A CN201910633037 A CN 201910633037A CN 110372579 B CN110372579 B CN 110372579B
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CN110372579A (en
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周中振
汤侣
徐江平
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Southern Medical University
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

The invention relates to 1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone, the molecular structure of which is shown as the following general formula: in the general formula, R 1 Is hydrogen or methoxy, R 2 Is hydrogen or methoxy, R 3 Is hydrogen or methoxy, ar is phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl or 3,4,5-trimethoxyphenyl. The compound can be obtained by the aldehyde ketone condensation reaction between 6-aryl pyridine-2-formaldehyde and substituted acetophenone. The 1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone has good anti-tumor activity on human intestinal cancer cells, human lung cancer cells and human glioma cells.

Description

1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone and preparation method and application thereof
Technical Field
The invention relates to an acrylketone compound, in particular to an aryl-containing acrylketone compound which shows good inhibitory activity on human intestinal cancer cells, human lung cancer cells and human glioma cells and can effectively inhibit tubulin aggregation.
Background
Malignant tumor is one of serious diseases threatening human life and health, and has become the second leading cause of death worldwide. According to 2015 World Health Organization (WHO) data statistics, 880 million people/year are lost lives. The morbidity and mortality of tumors in china is high: 286 people have cancer in an average of every 10 million people; 181 people died due to cancer. Since 2010, malignant tumor exceeds cardiovascular and cerebrovascular diseases, becomes the first cause of death of Chinese population, seriously threatens the life and health of people, and brings heavy disease burden to society. Therefore, the research of novel antitumor drugs is very important.
Microtubules are polar hollow tubular structures formed by 13 fibrils formed by connecting alpha, beta-tubulin dimers head and tail in parallel and expanding [ Nature,2004,428 (6979): 198-202]. The length of which can be adjusted by the polymerization-depolymerization process as required for a particular cell function. Tubulin plays an important role in cell growth, morphology maintenance, signal transduction, cell proliferation and mitosis. Thus, disrupting the normal function of microtubules provides an entry point for anti-tumor therapeutic strategies that target tubulin. The tubulin binding sites that have been demonstrated in current studies fall into two categories: 1) Tubulin depolymerization target (such as vinblastine binding site, colchicine binding site and Laulimide binding site); 2) A tubulin stabilizing binding site (e.g., an epothilone binding site with a paclitaxel binding site).
Acting on tubulin colchicine site inhibitor (CBSIs) has antimitotic ability, and can effectively act on tumor vascular endothelial cells, destroy tumor neovessels, block blood supply of tumor regions, and finally cause tumor necrosis. For example, tubulin depolymerizing agents, such as combretastatin IV (CA-4) disodium phosphate (CA-4P, 1), etc., can disrupt the tubulin backbone structure of cells and alter endothelial cell morphology, leading to tumor vessel occlusion [3]. Its appearance phenomenon is that firstly the tumor cells in the central part of the tumor are killed, then the apoptosis action begins to expand, deprives the tumor nutrient substances, and then the membrane bottom layer is exposed, bleeds and coagulates, i.e. the tumor necrosis [4]. In addition, the colchicine site cavity volume is small, and the structure of the corresponding inhibitor is simple, so that the research of CBSIs is concerned. Over the last decade a number of CBSI-based engineered tubulin inhibitors have been discovered and tested clinically, such as combretastatin (CA-4, CA-4P (phase II), CA-1P (phase I) and AVE8062 (phase III)). However, cis CA-4 readily isomerizes to form a heat stable trans isomer, thereby completely losing cytotoxicity. To avoid trans-isomerization, replacement of the double bond with acrylketone is a good option. In view of the above, in order to continuously search for a tubulin inhibitor with a novel and stable structure, the invention uses acrylketone to replace a double-bond bridging group, and designs and synthesizes 1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone with a novel structure. The derivatives are not reported in documents, show good inhibitory activity on human intestinal cancer cells and human glioma cells, and can effectively inhibit tubulin aggregation.
Disclosure of Invention
In order to solve the above problems, the present invention provides a 1-aryl-3- (6-arylpyridin-2-yl) -propenone, which shows good inhibitory activity against human intestinal cancer cells, human lung cancer cells and human glioma cells.
1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone, the molecular structure of which is shown as the following formula (I):
Figure GDA0002178506130000021
in the formula, R 1 Is hydrogen or methoxy; r 2 Is hydrogen or methoxy; r 3 Is hydrogen or methoxy, ar is phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl or 3,4,5-trimethoxyphenyl.
The preferable scheme of the 1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone compound is as follows:
when R is 1 Is hydrogen, R 2 Is hydrogen, R 3 When Ar is p-methoxyphenyl, the compound is 1- (4-methoxy-phenyl) -3- (6-phenyl-pyridin-2-yl) -propenone;
when R is 1 Is hydrogen, R 2 Is hydrogen, R 3 When Ar is 3,4-dimethoxyphenyl, the compound is 1- (3,4-dimethoxy-phenyl) -3- (6-phenyl-pyridin-2-yl) -propenone;
when R is 1 Is hydrogen, R 2 Is hydrogen, R 3 When Ar is 3,4,5-trimethoxyphenyl, the compound is 3- (6-phenyl-pyridin-2-yl) -1- (3,4,5-trimethoxy-phenyl) -propenone;
when R is 1 Is hydrogen, R 2 Is methoxy, R 3 When Ar is 4-methoxyphenyl, the compound is 1- (4-methoxy-phenyl) -3- [6- (4-methoxy-phenyl) -pyridin-2-yl]-acrylketone;
when R is 1 Is hydrogen, R 2 Is methoxy, R 3 When Ar is 3,4-dimethoxyphenyl, the compound is 1- (3,4-dimethoxyphenyl-phenyl) -3- [6- (4-methoxy-phenyl) -pyridin-2-yl]-acrylketone;
when R is 1 Is hydrogen, R 2 Is methoxy, R 3 When Ar is 3,4,5-trimethoxyphenyl, the compound is 3- [6- (4-methoxy-phenyl) -pyridin-2-yl]-1- (3,4,5-trimethoxy-phenyl) -propenone;
when R is 1 Is hydrogen, R 2 Is methoxy, R 3 When Ar is 4-methoxyphenyl, the compound is 3- [6- (3,4-dimethoxy-phenyl) -pyridin-2-yl]-1- (4-methoxy-phenyl) -propenone;
when R is 1 Is hydrogen, R 2 Is methoxy, R 3 When Ar is 3,4-dimethoxyphenyl, the compound is 1- (3,4-dimethoxy-phenyl) -3- [6- (3,4-dimethoxy-phenyl) -pyridin-2-yl]-acrylketone;
when R is 1 Is hydrogen, R 2 Is methoxy, R 3 When Ar is 3,4,5-trimethoxyphenyl, the compound is 3- [6- (3,4-dimethoxy-phenyl) -pyridin-2-yl]-1- (3,4,5-trimethoxy-phenyl) -propenone;
when R is 1 Is methoxy, R 2 Is hydrogen, R 3 When Ar is 4-methoxyphenyl, the compound is 3- [6- (3,5-dimethoxy-phenyl) -pyridin-2-yl]-1- (4-methoxy-phenyl) -propenone;
when R is 1 Is methoxy, R 2 Is hydrogen, R 3 When Ar is 3,4-dimethoxyphenyl, the compound is 1- (3,4-dimethoxy-phenyl) -3- [6- (3,5-dimethoxy-phenyl) -pyridin-2-yl]-acrylketone;
when R is 1 Is methoxy, R 2 Is hydrogen, R 3 When Ar is 3,4,5-trimethoxyphenyl, the compound is 3- [6- (3,5-dimethoxy-phenyl) -pyridin-2-yl]-1- (3,4,5-trimethoxy-phenyl) -propenone;
when R is 1 Is methoxy, R 2 Is methoxy, R 3 When Ar is 4-methoxyphenyl, is methoxy, the compound is 1- (4-methoxy-phenyl) -3- [6- (3,4,5-trimethoxy-phenyl) -pyridin-2-yl]-acrylketone;
when R is 1 Is methoxy, R 2 Is methoxy, R 3 When Ar is 3,4-dimethoxy, the compound is 1- (3,4-dimethoxy-phenyl) -3- [6- (3,4,5-trimethoxy-phenyl) -pyridin-2-yl]-acrylketone;
when R is 1 Is methoxy, R 2 Is methoxy, R 3 When Ar is 3,4,5-triphenyl, the compound is 1- (3,4,5-trimethoxy-phenyl) -3- [6- (3,4,5-trimethoxy-phenyl) -pyridin-2-yl]-acrylketone.
The 1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone compound is prepared by a conventional method, and is preferably prepared by performing an aldehyde ketone condensation reaction on 6-aryl pyridine-2-formaldehyde and substituted acetophenone. The reaction formula of the above preparation method is shown as the following formula (II):
Figure GDA0002178506130000031
in the above formula (II), R 1 Is hydrogen or methoxy; r 2 Is hydrogen or methoxy; r 3 Is hydrogen or methoxy, ar is phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl or 3,4,5-trimethoxyphenyl.
The 1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone can induce the cell cycle of HT-29 cells to be blocked in a G2/M stage, can also inhibit tubulin aggregation, has obvious anti-tumor effect, and particularly shows good inhibitory activity on human intestinal cancer cells, human lung cancer and human glioma cells, so that the 1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone can be used for preparing medicines for treating intestinal cancer, lung cancer or glioma.
Drawings
FIG. 1 is a graph showing the kinetic results of the enzyme inhibitory activity of a portion of the compounds on tubulin (graph of absorbance as a function of time).
FIG. 2 cell cycle diagram of the effect of compound PP13 on the HT-29 cell cycle.
Detailed Description
Example 1 (Synthesis of PP 01)
The compound synthesized by the embodiment is 1- (4-methoxyphenyl) -3- (6-phenylpyridin-2-yl) -acrylketone, and the synthesis method of the compound comprises the following steps (1) and (2):
(1) Synthesis of 6-phenylpyridine carboxaldehyde: 6-bromopyridine-2-carbaldehyde (1 mmol), phenylboronic acid (1 mmol) and K are sequentially added into a 15mL pressure-resistant reaction tube 2 CO 3 (150mg, 1.09mmol) with Pd (PPh) as a catalyst 3 ) 4 (46mg, 0.04mmol) was sealed with a rubber stopper, followed by evacuation under reduced pressure and then filling with argon, and this was repeated three times. Then, after placing a balloon filled with argon gas on a closed rubber stopper of the reaction flask, the mixed solvent (DME/EtOH/H) was injected with a syringe 2 O = 7. Then, the whole apparatus was placed in a magnetic stirrer at 80 ℃ and the reaction was stirred with heating for 10 hours, then cooled to room temperature, 50mL of water was added, extraction was performed with ethyl acetate (2X 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the resulting solid was subjected to silica gel column chromatography (V) Petroleum ether ：V Acetic acid ethyl ester = 20). The spectrum data are as follows: 1 H NMR(400MHz,CDCl 3 )δ10.19(s,1H),8.16–8.07(m,2H),8.00–7.88(m,3H),7.59–7.45(m,3H). 13 C NMR(101MHz,CDCl 3 )δ193.70,157.79,152.53,137.88,137.79,129.60,128.85,126.93,124.43,119.68.
(2) Synthesis of PPA2: p-methoxyacetophenone (1.64 mmol) and 8mg of lithium hydroxide monohydrate (0.19 mmol) were charged in a 25mL round-bottomed flask followed by 1mL of anhydrous ethanol. After the mixture was stirred at room temperature for 10min, arylpyridylaldehyde (1 mmol) was added and reacted at room temperature for 1h. The progress of the reaction was monitored by Thin Layer Chromatography (TLC). After completion of the reaction, the solvent was removed under reduced pressure by means of a rotary evaporator, 50mL of water was added, extraction was performed with chloroform (3X 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed to obtain a solid silica gel column chromatography (V) Petroleum ether ：V Ethyl acetate = 25).
The spectrogram data are as follows: 1 H NMR(400MHz,CDCl 3 )δ3.90(s,3H),6.99-7.03(m,2H),7.44(d,J＝7.6Hz,1H),7.48(d,J＝8Hz,1H),7.46-7.49(m,1H),7.51-7.55(m,2H),7.75(d,J＝7.6Hz,1H),7.81-7.86(m,2H),8.10(s,1H),8.11-8.13(m,2H),8.14-8.15(m,1H),8.27(d,J＝15.2Hz,1H). 13 C NMR(100Hz,CDCl 3 )δ188.9,157.4,153.5,153.0,149.3,142.1,138.8,137.6,131.1,129.3,128.7,127.1,125.6,123.6,121.1,110.7,110.0,56.0.HRMS(ESI)calcd for C 21 H 18 NO 2 [M+H] + :376.1669,found:376.1655.
from the above data, it can be known that the synthesized compound is 1- (4-methoxyphenyl) -3- (6-phenylpyridin-2-yl) -propenone, and the chemical structure of the compound is
Figure GDA0002178506130000041
The chemical reaction formula of the method in the steps (1) and (2) is as follows:
Figure GDA0002178506130000051
example 2 (Synthesis of PP 02)
The compound synthesized in this example was 1- (3,4-dimethoxyphenyl) -3- (6-phenylpyridin-2-yl) -propenone, which was synthesized as described in example 1 starting from phenylboronic acid, 6-bromopyridine-2-carbaldehyde and 3,4-dimethoxyacetophenone.
The obtained white solid is identified by mass spectrum and nuclear magnetic resonance spectrum, and the spectrum data is as follows: 1 H NMR(400MHz,CDCl 3 )δ3.99(s,6H),6.98(d,J＝8.4Hz,1H),7.45-7.50(m,2H),7.53-7.55(m,2H),7.69(d,J＝2.0Hz,1H),7.77(d,J＝7.6Hz,1H),7.82-7.87(m,2H),8.11(dd,J＝1.6,8.4Hz,1H),8.32(d,J＝15.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ157.4,153.5,153.0,149.3,142.1,138.8,137.6,131.1,129.3,128.7,127.1,125.6,123.6,121.1,110.0,56.0.HRMS(ESI)calcd for C 22 H 20 NO 3 [M+H] + :346.1438,found:346.1440.
from the above data, it can be known that the synthesized compound is 1- (3,4-dimethoxyphenyl) -3- (6-phenylpyridin-2-yl) -propenone, and the chemical structure of the compound is
Figure GDA0002178506130000052
Example 3 (Synthesis of PP 03)
The compound synthesized in this example was 3- (6-phenylpyridin-2-yl) -1- (3,4,5-trimethoxyphenyl) -propenone, which was synthesized as described in example 1 using phenylboronic acid, 6-bromopyridine-2-carbaldehyde and 3,4,5-trimethoxyacetophenone as starting materials (Isolated yield = 48%).
The obtained white solid is identified by mass spectrum and nuclear magnetic resonance spectrum, and the spectrum data is as follows: 1 H NMR(400MHz,CDCl 3 )δ3.95(s,3H),3.98(s,6H),7.41(s,2H),7.49-7.53(m,4H),7.78(d,J＝8.0Hz,1H),7.84(d,J＝15.2Hz,1H),7.90(t,J＝8.0Hz,1H),8.09(dd,J＝1.6,8.4Hz,1H),8.37(d,J＝15.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ189.6,157.4,153.1,152.7,142.7,138.7,137.8,133.3,129.4,128.8,127.7,127.1,125.9,123.7,121.4,106.4,61.0,56.4.HRMS(ESI)calcd for C 23 H 22 NO 4 [M+H] + :376.1543,found:376.1545.
from the above data, it can be known that the synthesized compound is 3- (6-phenylpyridin-2-yl) -1- (3,4,5-trimethoxyphenyl) -propenone, and the chemical structure of the compound is
Figure GDA0002178506130000061
Example 4 (Synthesis of PP 04)
The compound synthesized in this example is 1- (4-methoxyphenyl) -3- [ 6-p-methoxyphenylpyridin-2-yl]The synthesis method of the compound is to synthesize 6- (p-methoxyphenyl) pyridylaldehyde first and then synthesize a target compound; the synthesis method of 6- (p-methoxyphenyl) pyridylaldehyde is the same as that in example 1 (Isolated yield = 78%), and the spectrum data thereof is as follows: 1 H-NMR(400MHz,CDCl 3 )δ3.89(s,3H),7.04(d,J＝8.4Hz,2H),7.85-7.87(m,3H),8.07(d,J＝8.4Hz,2H),10.16(s,1H). 13 C-NMR(100MHz,CDCl 3 )δ194.0,160.9,157.5,152.5,137.5,128.2,123.6,119.0,114.2,55.3.
the target compound was synthesized as described in example 1 (Isolated yield = 22%) using 6- (p-methoxyphenyl) pyridylaldehyde and p-methoxyacetophenone as starting materials. The obtained white solid is identified by mass spectrum and nuclear magnetic resonance spectrum, and the spectrum data is as follows: 1 H NMR(400MHz,CDCl 3 )δ3.89(s,3H),3.90(s,3H),7.00(s,1H),7.05(dd,J＝8.8,13.6Hz,1H),7.06(s,1H),7.38(d,J＝7.2Hz,1H),7.69(d,J＝7.6Hz,1H),7.77-7.84(m,2H),8.06-8.10(m,2H),8.13(d,J＝8.8Hz,2H),8.25(d,J＝15.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ189.1,163.5,160.7,157.0,152.8,142.4,137.5,131.5,131.0,128.4,125.6,123.0,114.1,113.8,55.4.HRMS(ESI)calcd for C 22 H 20 NO 3 [M+H] + :346.1436,found:346.1436.
from the above data, it can be seen that the synthesized compound is 1- (4-methoxyphenyl) -3- [ 6-p-methoxyphenylpyridin-2-yl]-propenone having the chemical structure
Figure GDA0002178506130000062
Example 5 Synthesis of PP05
The compound synthesized in this example was 1- (3,4-dimethoxyphenyl) -3- [ 6-p-methoxyphenylpyridin-2-yl ] -propenone, which was synthesized as described in example 1 (Isolated yield = 91%) starting from 6- (p-methoxyphenyl) pyridylaldehyde and p-methoxyacetophenone.
Identifying the obtained white solid by adopting mass spectrum and nuclear magnetic resonance spectrum, wherein the spectrogram data is as follows: 1 H NMR(400MHz,CDCl 3 )δ3.89(d,J＝1.6Hz,3H),3.98(dd,J＝1.2,3.2Hz,6H),6.97(dd,J＝1.6,8.4Hz,1H),7.04(dd,J＝1.6,8.8Hz,2H),7.37(dd,J＝3.6,7.6Hz,2H),7.68-7.70(m,2H),7.76-7.83(m,2H),8.06-8.09(m,2H),8.25(dd,J＝3.6,15.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ188.9,160.8,157.0,153.4,152.8,149.3,142.3,137.5,131.4,131.2,128.4,125.5,123.6,123.0,120.4,110.8,110.0,56.0,55.3.HRMS(ESI)calcd for C 23 H 22 NO 4 [M+H] + :376.1543,found:376.1545.
from the above data, it can be seen that the synthesized compound is 1- (3,4-dimethoxyphenyl) -3- [ 6-p-methoxyphenylpyridin-2-yl]-propenone having the chemical structure
Figure GDA0002178506130000071
Example 6 (Synthesis of PP 06)
The compound synthesized in this example was 3- [6- (4-methoxy-phenyl) -pyridin-2-yl ] -1- (3,4,5-trimethoxy-phenyl) -propenone, which was synthesized as described in example 1 (Isolated yield = 26%) starting from 6- (p-methoxyphenyl) pyridylaldehyde and 3,4,5-trimethoxyacetophenone.
The obtained white solid is identified by mass spectrum and nuclear magnetic resonance spectrum, and the spectrum data is as follows: 1 H NMR(400MHz,CDCl 3 )δ3.89(s,3H),3.96((d,J＝8Hz,9H),7.03(dd,J＝2.0,8.8Hz,2H),7.36-7.38(m,3H),7.70(d,J＝7.6Hz,1H),7.75-7.78(m,1H),7.82(d,J＝10.4Hz,1H),8.05-8.08(m,2H),8.16(d,J＝15.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ189.7,157.1,153.1,152.6,142.7,133.3,128.4,123.1,120.6,114.1,106.4,61.0,56.4,55.4.HRMS(ESI)calcd for C 24 H 2 4NO 5 [M+H] + :406.1649,found:406.1650.
from the above data, it can be seen that the synthesized compound is 3- [6- (4-methoxy-phenyl) -pyridin-2-yl]-1- (3,4,5-trimethoxy-phenyl) -propenone, the chemical structure of the compound is
Figure GDA0002178506130000072
Example 7 (Synthesis of PP 07)
The compound synthesized in this example was 3- [6- (3,4-dimethoxy-phenyl) -pyridin-2-yl]The synthesis method of the compound is also that 6- (3,4-dimethoxyphenyl) pyridine formaldehyde is firstly synthesized, and then the target compound is synthesized; wherein 6- (3,4-dimethoxyphenyl) pyridylaldehyde is synthesized as in example 1 (Isolated yield = 68%) for the following spectral data: 1 H-NMR(400MHz,CDCl 3 )δ3.97(s,3H),4.03(s,3H),7.00(d,J＝8.4Hz,1H),7.62(d,J＝8.4Hz,1H),7.77(s,1H),7.86-7.94(m,3H),10.19(s,1H). 13 C-NMR(100MHz,CDCl 3 )δ193.7,157.4,152.4,150.5,149.4,137.7,130.7,123.8,119.1,111.1,109.9,55.9,55.9.
the target compound was synthesized from 6- (3,4-dimethoxyphenyl) pyridylaldehyde and p-methoxyacetophenone as raw materials (Isolated yield = 51%) as described in example 1 to obtain PP07. Identifying the obtained white solid by adopting mass spectrum and nuclear magnetic resonance spectrum, wherein the spectrogram data is as follows:
spectral data of PP 07: 1 H NMR(400MHz,CDCl 3 )δ3.90(s,3H),3.96(s,3H),4.05(s,3H),7.01(d,J＝8.4Hz,3H),7.48-7.52(m,1H),7.63(d,J＝7.6Hz,1H),7.74(d,J＝6.0Hz,1H),7.78(s,IH),7.82-7.87(m,1H),7.92(d,J＝15.2Hz,1H),8.13(d,J＝8.4Hz,2H),8.21(d,J＝15.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ55.5,113.9,131.2,149.3,150.3,152.8,153.4,157.0,188.9.HRMS(ESI)calcd for C 23 H 22 NO 4 [M+H] + :376.1543,found:376.1545.
from the above data, it can be seen that the compound synthesized is 3- [6- (3,4-dimethoxy-phenyl) -pyridin-2-yl]-1- (4-methoxy-phenyl) -propenone having the chemical structure
Figure GDA0002178506130000081
Example 8 (synthesis of PP 08):
the compound synthesized in this example was 1- (3,4-dimethoxy-phenyl) -3- [6- (3,4-dimethoxy-phenyl) -pyridin-2-yl]-acrylketone, synthesized as described in example 1 (Isolated yield = 33%) starting from 6- (3,4-dimethoxyphenyl) pyridylaldehyde and 3,4-dimethoxyacetophenone, to give PP08. The obtained white solid is identified by mass spectrum and nuclear magnetic resonance spectrum, and the spectrum data is as follows: 1 H NMR(400MHz,CDCl 3 )δ3.98(m,9H),4.04(s,3H),6.95(d,J＝8Hz,1H),7.00(q,J＝8.4Hz,1H),7.42(d,J＝8Hz,1H),7.62(d,J＝7.2Hz,1H),7.65(dd,J＝2.0,8.4Hz,1H),7.70(d,J＝1.6Hz,1H),7.73(d,J＝8.0Hz,1H),7.79-7.82(m,3H),7.87(dd,J＝2.0,15.6Hz,1H),8.25(d,J＝15.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ142.4,137.5,131.8,131.2,125.5,123.4,122.9,120.6,119.8,111.1,110.8,110.1,56.0.HRMS(ESI)calcd for C 24 H 24 NO 5 [M+H] + :406.1649,found:406.1653.
from the above data, it can be seen that the compound synthesized is 1- (3,4-dimethoxy-phenyl) -3- [6- (3,4-dimethoxy-phenyl) -pyridin-2-yl]-propenone
Figure GDA0002178506130000091
Example 9 (synthesis of PP 09):
the compound synthesized in this example was 3- [6- (3,4-dimethoxy-phenyl) -pyridin-2-yl]-1- (3,4,5-trimethoxy-phenyl) -propenone, which was synthesized as described in example 1 (Isolated yield = 47%) starting from 6- (3,4-dimethoxyphenyl) pyridylaldehyde and 3,4,5-trimethoxyacetophenone to give PP09. The obtained white solid is identified by mass spectrum and nuclear magnetic resonance spectrum, and the spectrum data is as follows: 1 H NMR(400MHz,CDCl 3 )δ3.8(s,12H),4.01(s,3H),6.99(d,J＝8.4Hz,1H),7.37(s,2H),7.41(d,J＝7.6Hz,1H),7.61(dd,J＝1.6,8.4Hz,1H),7.72(d,J＝7.6Hz,1H),7.77-7.85(m,3H),8.18(d,J＝15.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ189.5,157.0,153.1,149.2,142.7,133.2,123.1,120.8,119.8,111.1,110.1,106.3,61.0,56.1,56.5.HRMS(ESI)calcd for C 25 H 26 NO 6 [M+H] + :436.1755,found:436.1767.
from the above data, it can be seen that the compound synthesized is 3- [6- (3,4-dimethoxy-phenyl) -pyridin-2-yl]-1- (3,4,5-trimethoxy-phenyl) -propenone, the chemical structure of the compound is
Figure GDA0002178506130000092
Example 10 (synthesis of PP 10):
the compound synthesized in this example was 3- [6- (3,5-dimethoxy-phenyl) -pyridin-2-yl]-1- (4-methoxy-phenyl) -propenone,the synthesis method of the compound also comprises the steps of firstly synthesizing 6- (3,5-dimethoxyphenyl) pyridine formaldehyde and then synthesizing a target compound; the synthesis method of 6- (3,5-dimethoxyphenyl) pyridine formaldehyde is the same as that of example 1 (Isolated yield = 71%), and the spectrum data thereof is as follows: 1 H-NMR(400MHz,DMSO-d 6 )δ3.85(s,6H),6.65(t,J＝2.4Hz,1H),7.35(d,J＝4Hz,2H),7.90(dd,J＝0.4,7.6Hz,1H),8.13(t,J＝7.6Hz,1H),8.31(dd,J＝0.4,7.6Hz),10.07(s,1H). 13 C-NMR(100MHz,CDCl 3 )δ193.8,161.2,157.5,152.5,140.0,137.7,124.5,119.9,105.0,101.6,55.4.
the target compound was synthesized as described in example 1 using 6- (3,5-dimethoxyphenyl) pyridylaldehyde and p-methoxyacetophenone as starting materials (Isolated yield = 76%).
Spectral data of PP 10: 1 H NMR(400MHz,DMSO-d 6 )δ3.85(s,6H),3.87(s,6H),6.62(t,J＝2.4Hz,1H),7.12(d,J＝8.8Hz,2H),7.34(d,J＝2.4Hz,2H),7.74(d,J＝15.6Hz,1H),7.89(d,J＝7.2Hz,1H),7.97(t,J＝7.2Hz,1H),8.01(d,J＝7.6Hz,1H),8.13(d,J＝8.8Hz,2H),8.22(d,J＝15.6Hz,1H). 13 C NMR(100MHz,DMSO-d 6 )δ188.2,163.8,161.3,156.3,153.1,142.8,138.6,130.7,126.0,121.9,114.6,105.2,101.7,56.0,55.8.HRMS(ESI)calcd for C 23 H 22 NO 4 [M+H] + :376.1543,found:376.1541.
from the above data, it can be seen that the compound synthesized is 3- [6- (3,5-dimethoxy-phenyl) -pyridin-2-yl]-1- (4-methoxy-phenyl) -propenone having the chemical structure
Figure GDA0002178506130000101
Example 11 (synthesis of PP 11):
the compound synthesized in this example was 1- (3,4-dimethoxy-phenyl) -3- [6- (3,5-dimethoxy-phenyl) -pyridin-2-yl]-propenone, which was synthesized as described in example 1 starting from 6- (3,5-dimethoxyphenyl) pyridinecarboxaldehyde and 3,4-dimethoxyacetophenone (Isolated yield = 76%). Identifying the obtained white solid by mass spectrum and nuclear magnetic resonance spectrumThe data are as follows: 1 H NMR(400MHz,DMSO-d 6 )δ3.86(s,6H),3.88(s,3H),3.89(s,3H),6.63(t,J＝2.0Hz,1H),7.15(d,J＝8.4Hz,2H),7.36(d,J＝2.0Hz,2H),7.62(d,J＝1.6Hz,1H),7.76(d,J＝15.2Hz,1H),7.87(dd,J＝1.6,8.0Hz,1H),7.91(d,J＝7.2Hz,1H),7.98(t,J＝7.2Hz,1H),8.0(d,J＝7.6Hz,1H),8.26(d,J＝16Hz,1H). 13 C NMR(100MHz,DMSO-d 6 )δ188.0,161.3,153.2,153.9,153.1,149.3,142.7,140.7,138.6,130.7,125.8,123.9,121.8,111.4,111.0,105.2,101.7,79.6,56.2,55.8.HRMS(ESI)calcd for C 24 H 24 NO 5 [M+H] + :406.1649,found:406.1654.
from the above data, it can be seen that the compound synthesized is 1- (3,4-dimethoxy-phenyl) -3- [6- (3,5-dimethoxy-phenyl) -pyridin-2-yl]-propenone
Figure GDA0002178506130000102
Example 12 (synthesis of PP 12):
the compound synthesized in this example was 3- [6- (3,5-dimethoxy-phenyl) -pyridin-2-yl]-1- (3,4,5-trimethoxy-phenyl) -propenone, which was synthesized as described in example 1 (Isolated yield = 38%) starting from 6- (3,5-dimethoxyphenyl) pyridylaldehyde and 3,4,5-trimethoxyacetophenone. The obtained white solid is identified by mass spectrum and nuclear magnetic resonance spectrum, and the spectrum data is as follows: 1 H NMR(400MHz,DMSO-d 6 )δ3.79(s,3H),3.86(s,6H),(s,6H),6.62(t,J＝2.0Hz,1H),7.39(d,J＝2.0Hz,2H),7.44(s,2H),7.79(d,J＝15.2Hz,1H),7.93(d,J＝7.6Hz,1H),7.99(t,J＝8.0Hz,1H),7.85(d,J＝7.6Hz,1H),8.27(d,J＝15.2Hz,1H). 13 C NMR(100MHz,DMSO-d 6 )δ188.6,161.3,156.1,153.4,152.9,143.4,142.6,140.6,138.1,133.1,125.8,124.1,121.9,106.6,105.1,102.0,60.6,56.5,55.7.HRMS(ESI)calcd for C 25 H 26 NO 6 [M+H] + :436.1755,found:436.1757.
from the above data, it can be seen that the synthetic compound is 3- [6- (3,5-dimethoxy-phenyl) -pyridin-2-yl]-1- (3,4,5-trimethoxy-phenyl) -propenone having the chemical structure
Figure GDA0002178506130000111
Example 13 (synthesis of PP 13):
the compound synthesized in this example was 1- (4-methoxy-phenyl) -3- [6- (3,4,5-trimethoxy-phenyl) -pyridin-2-yl]The synthesis method of the compound is to synthesize 6- (3,4,5-trimethoxyphenyl) pyridine formaldehyde and then synthesize a target compound; the synthesis method of 6- (3,4,5-trimethoxyphenyl) pyridine formaldehyde is the same as that in example 1 (Isolated yield = 78%). The spectrogram data is as follows: 1 H-NMR(400MHz,CDCl 3 )δ3.94(s,3H),4.00(s,6H),7.34(s,2H),7.91-7.99(m,3H),10.24(s,1H). 13 C-NMR(100MHz,CDCl 3 )δ193.8,157.5,153.6,152.5,137.7,133.6,124.2,119.5,104.3,60.9,56.2.
the target compound was synthesized as described in example 1 using 6- (3,4,5-trimethoxyphenyl) pyridinecarboxaldehyde and p-methoxyacetophenone as starting materials (Isolated yield = 44%). The obtained white solid is identified by mass spectrum and nuclear magnetic resonance spectrum, and the spectrum data is as follows:
1 H NMR(400MHz,CDCl 3 )δ3.96(d,J＝12Hz,6H),4.00(s,6H),6.99(d,J＝8.8Hz,2H),7.34(s,2H),7.44(d,J＝7.2Hz,1H),7.69(d,J＝8.0Hz,1H),7.77-7.83(m,2H),8.10(d,J＝8.8Hz,2H),8.17(d,J＝15.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ189.0,163.6,157.1,153.5,153.0,142.3,139.4,137.5,130.9,125.9,123.1,120.9,113.9,104.5,60.9,55.3.HRMS(ESI)calcd for C 24 H 24 NO 5 [M+H] + :406.1649,found:406.1653.
from the above data, it can be seen that the compound synthesized is 1- (4-methoxy-phenyl) -3- [6- (3,4,5-trimethoxy-phenyl) -pyridin-2-yl]-propenone having the chemical structure
Figure GDA0002178506130000121
Example 14 (synthesis of PP 14):
the compound synthesized in this example was 1- (3,4-dimethoxy-phenyl) -3- [6- (3,4,5-trimethoxy-phenyl) -pyridin-2-yl]Propenone, which was synthesized as described in example 1 (Isolated yield = 60%) starting from 6- (3,4,5-trimethoxyphenyl) pyridinecarboxaldehyde and 3,4-dimethoxyacetophenone to yield PP14. The obtained white solid is identified by mass spectrum and nuclear magnetic resonance spectrum, and the spectrum data is as follows: 1 H NMR(400MHz,CDCl 3 )δ3.92(s,3H),3.98(d,J＝2Hz,12H),6.96(d,J＝8.4Hz,2H),7.34(s,2H),7.46(d,J＝7.2Hz,1H),7.69(s,1H),7.71(d,J＝7.6Hz,1H),7.78-7.87(m,3H),8.18(d,J＝15.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ188.8,157.1,153.5,153.0,149.3,142.1,137.7,131.0,128.7,125.8,123.4,123.2,121.0,111.8,110.0,104.6,68.1,60.9,56.1.HRMS(ESI)calcd for C 25 H 26 NO 6 [M+H] + :436.1755,found:436.1757.
from the above data, it can be seen that the compound synthesized is 1- (3,4-dimethoxy-phenyl) -3- [6- (3,4,5-trimethoxy-phenyl) -pyridin-2-yl]-propenone having the chemical structure
Figure GDA0002178506130000122
Example 15 (synthesis of PP 15):
the compound synthesized in this example was 1- (3,4,5-trimethoxy-phenyl) -3- [6- (3,4,5-trimethoxy-phenyl) -pyridin-2-yl]Propenone, which was synthesized as described in example 1 (Isolated yield = 51%) starting from 6- (3,4,5-trimethoxyphenyl) pyridinecarboxaldehyde and 3,4,5-trimethoxyacetophenone to yield PP14. The obtained white solid is identified by mass spectrum and nuclear magnetic resonance spectrum, and the spectrum data is as follows: 1 H NMR(400MHz,CDCl 3 )δ3.95(t,J＝12Hz,18H),7.35(d,J＝6.8Hz,4H),7.45(d,J＝7.2Hz,1H),7.74(d,J＝7.6Hz,1H),7.83-7.88(m,2H),,8.17(d,J＝15.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ189.3,157.1,153.5,153.2,152.7,142.8,139.6,137.8,133.2,125.8,123.4,121.3,106.3,104.6,61.0,56.3.HRMS(ESI)calcd for C 26 H 28 NO 7 [M+H] + :466.1860,found:466.1860.
from the above data, it can be seen that the compound synthesized is 1- (3,4,5-trimethoxy-phenyl) -3- [6- (3,4,5-trimethoxy-phenyl) -pyridin-2-yl]-propenone having the chemical structure
Figure GDA0002178506130000131
Example 16 evaluation of Activity of (1-aryl-3- (6-Arylpyridin-2-yl) -propenone)
1. Tumor cell proliferation inhibitory activity;
the relevant experimental materials including fetal bovine serum, RPMI-1640 cell culture medium, DMEM cell culture medium, PBS phosphate buffer solution and Penicilin-Streptomycin Liquid double antibody are all products of GIBCO company; DMSO for activity testing was purchased from SIGMA, USA; HTS Transwell-96 orifice plate and cell culture bottle are CORNING products; microporous membrane filters are commercially available from Millipore, USA. The instrument used in the experiment was a multifunctional microplate reader (BioTek, USA); cell culture chambers (Thermo corporation, usa); super clean bench (Suzhou, china, clean-up facilities); pipettors (Gilson corporation, usa).
Preparation of MTT: taking 200mg of MTT powder, adding PBS solution to prepare 5mg/mL MTT solution, namely fixing the volume to 40mL, filtering and sterilizing by using a microporous filter membrane, then storing in a refrigerator at the temperature of-20 ℃, unfreezing in the refrigerator at the temperature of 4 ℃ before use, and storing in a dark place.
Cell culture: human colon cancer cell HT-29, human non-small cell lung cancer cell A549 and human glioma cell U251 are from the cell bank of Chinese academy of sciences (Shanghai, china). The cells were cultured with RPMI 1640 containing 10% FBS and 1% antibiotics (100 International units/mL penicillin and streptomycin 100 mg/mL) at 37 ℃ with 5% CO 2 Culturing in an incubator.
Test of the inhibitory activity of the target compounds on tumor cells: for each experiment, compound-treated group, positive control group (colchicine group), blank control (whole culture medium only, with cells) were set up to exclude the effect of culture medium and MTT reagent on the experimental results and T 0 Group (whole medium only, with cells added). Cells in logarithmic growth phase were seeded in 96-well cell culture plates at a volume of 200. Mu.L/well, 37 ℃ and 5% CO 2 Culture boxAfter internal culture for 12h, the control group was treated according to the control group treatment method (the positive control group was selected to have a concentration of IC of colchicine on the cells 50 Value, blank control was replaced with whole medium), compound treatment groups were treated with different concentrations of target compound, with 6 duplicate wells for each drug concentration. T is 0 Group 20. Mu.L MTT per well, 5% CO at 37 ℃% 2 After incubation in an incubator for 4h, plate T 0 Sucking out the liquid in 6 multiple wells, adding 150 μ L DMSO, mixing, sucking 135 μ L liquid, adding into another clean 96-well plate, and detecting OD value as T value with 570nm wavelength in enzyme labeling instrument (Synergy HT, bioTek, USA) 0 The value is obtained. The drug-treated plates were treated at 37 ℃ with 5% CO 2 After 48 hours incubation in an incubator, 20. Mu.L of MTT was added to each well, mixed well, and the content of CO was 5% at 37 ℃% 2 After incubation in the incubator for 4h, the OD was measured with a microplate reader (Synergy HT, bioTek, USA) at a wavelength of 570 nm. Averaging 6 replicate wells for each treatment and control group, each subtracting T from the value obtained 0 Value comparison to obtain GI 50 The value is obtained. The relative cytostatic rate of human cancer cells after compound treatment was calculated according to the following formula: cell growth inhibition rate = (experimental drug group OD value-T) 0 Value/blank control OD value-T 0 Value) × 100%. The above experiment was repeated 3 times and the average was taken.
Results of the experiment
The MTT method is adopted to preliminarily evaluate the antiproliferative activity of the 1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone on different tumor cells (human colon cancer cells HT-29, human non-small cell lung cancer cells A549 and human glioma cells U251) (Table 1). As shown in Table 1, 7 1-aryl-3- (6-aryl-pyridin-2-yl) -propenones (PP 1-3, PP05, PP07, PP08 and PP 13) showed good inhibitory activity against human glioma cell U251 (0.34)<GI 50 <1.84. Mu.M). The 5 aryl pyridine derivatives PP01, PP02, PP05, PP07 and PP13 show good inhibitory activity to all tested tumor cells (0.34)<GI 50 <4.6. Mu.M). Wherein, the inhibitory activity of the compounds PP05, PP08 and PP09 on human glioma cell U251 reaches nanomolar level (0.78 μ M,0.34 μ M and 0.73 μ M). The compound PP06 shows selective inhibition on human non-small cell lung cancer cell A549Preparation Activity (GI) 50 ＝2.67±0.13μM)。
TABLE 1 antitumor Activity (GI) 50 ，μM) a
Figure GDA0002178506130000141
a Is the average of all data from three independent experiments; b colchicine with code number Col; c Combretastatin-A4 with the code number CA4.
2. Evaluation of inhibitory Activity on tubulin
The experimental scheme is as follows: firstly, an in-vitro screening method and a model for inhibiting the activity of tubulin are established, colchicine and CA-4 are used as contrast drugs, and the half inhibition rate IC on the model is 50 Value, result and IC reported in various literatures 50 The values are similar, which indicates that the screening model is successfully constructed. The compound samples were dissolved in DMSO to prepare 5. Mu.M stock solutions, and then the compounds were added to the screening system.
The experimental steps are as follows: experiments were divided into drug-treated groups (containing 10mM of compound, paclitaxel and colchicine, respectively, in 50mL G-PEM buffer), and a DMSO control group (0.1% DMSO) was established for each experiment to exclude the effect of the solvent DMSO on the experiments. The procedure was performed according to the instructions provided by the kit manufacturing company. Dissolving tubulin with the purity of more than 99% in a G-PEM buffer solution to obtain a tubulin solution with the concentration of 4 mg/mL. Each test drug was dissolved in 100. Mu. L G-PEM buffer and added to a 96-well cell culture plate. Then adding the prepared tubulin solution into a 96-well cell culture plate, mixing and hooking each 10 mu L of the solution in each well, and measuring the absorbance value (the wavelength of the measured light is 367 nm) by using an enzyme-labeling instrument once per minute for 1h. The absorbance values measured represent the level of tubulin in the reaction in the polymerized state. The inhibitory activity of the compounds of the present invention on tubulin is shown in figure 1 below.
The experimental results are as follows: as can be seen from FIG. 1, 1-aryl-3- (6-arylpyridin-2-yl) -propenone PP05, PP07, PP08, PP13 and PP15 showed some inhibitory activity on tubulin aggregation. Among them, PP13 has the strongest inhibitory action on tubulin aggregation, and is equivalent to colchicine.
3. Cell cycle experiments
The experimental scheme is as follows: tubulin depolymerants can arrest the tumor cell cycle in the G2/M phase, leading to cell cycle disorders up to apoptosis. Based on the activity screening and tubulin inhibitory activity results, we tested the effect of PP13 (PPEA) on the HT-29 cell cycle of human colon cancer cells at different concentrations.
The experimental steps are as follows: experiments are divided into drug treatment groups (culture media respectively contain several high-activity compounds with different concentrations), and a blank control group and a positive control group are set. The human colon cancer cells in logarithmic growth phase were seeded in 6-well plates of 2X 106 cells per well, treated with the drug, and subjected to a treatment containing 5% CO 2 And incubating for 48h in a constant-temperature incubator at 37 ℃. Collecting cells, centrifuging at 2000rpm for 5min, removing supernatant, washing cell precipitate with PBS for 2 times, slowly dripping 0.5mL of precooled 70% ethanol into the cell precipitate after centrifugation, mixing, and storing at 4 deg.C overnight for use. On the day of the experiment, the prepared cell suspension was centrifuged at 2000rpm for 5min, the supernatant was removed, 500. Mu.L of PI staining solution (RNase A: PI volume ratio 1:9) was added, the mixture was incubated for at least half an hour in the dark, and the cell suspension was filtered through a 200 mesh screen and sucked into a flow tube to be ready for use. The flow cytometer detects cell cycle distribution, and then software analysis is used to obtain relevant flow experimental data, and the result is shown in fig. 2.
The experimental results are as follows: as can be seen from FIG. 2, PP13 has a weak cycle-arresting effect on HT-29 cells of human colon cancer, and arrests them in G2/M phase in a concentration-dependent manner. For example, the ratio of G2/M cells (8.76% and 10.34%) of human colon cancer cells HT-29 after 48h of high concentration PP13 (1.25. Mu.M and 2.5. Mu.M) treatment was higher than that of the blank control group (6.53%).

Claims (3)

1. A1-aryl-3- (6-aryl pyridine-2-yl) -acrylketone has a molecular structure shown as the following formula (I):
Figure 345604DEST_PATH_IMAGE001
（I）；
the method is characterized in that:
when R is 1 Is hydrogen, R 2 Is methoxy, R 3 When Ar is 3,4-dimethoxyphenyl, the compound is 1- (3,4-dimethoxy-phenyl) -3- [6- (4-methoxy-phenyl) -pyridin-2-yl]-acrylketone;
when R is 1 Is hydrogen, R 2 Is methoxy, R 3 When Ar is 4-methoxyphenyl, the compound is 3- [6- (3,4-dimethoxy-phenyl) -pyridin-2-yl]-1- (4-methoxy-phenyl) -propenone;
when R is 1 Is hydrogen, R 2 Is methoxy, R 3 When Ar is 3,4-dimethoxyphenyl, the compound is 1- (3,4-dimethoxy-phenyl) -3- [6- (3,4-dimethoxy-phenyl) -pyridin-2-yl]-acrylketone;
when R is 1 Is methoxy, R 2 Is methoxy, R 3 When Ar is 4-methoxyphenyl, the compound is 1- (4-methoxy-phenyl) -3- [6- (3,4,5-trimethoxy-phenyl) -pyridin-2-yl]-acrylketone;
when R is 1 Is methoxy, R 2 Is methoxy, R 3 When Ar is 3,4,5-triphenyl, the compound is 1- (3,4,5-trimethoxy-phenyl) -3- [6- (3,4,5-trimethoxy-phenyl) -pyridin-2-yl]-acrylketone.
2. A process for the preparation of 1-aryl-3- (6-arylpyridin-2-yl) -propenone according to claim 1, comprising the step of subjecting 6-arylpyridine-2-carbaldehyde to an aldehyde ketone condensation reaction with a substituted acetophenone, to obtain a compound according to claim 1, according to the following formula (II):
Figure 718816DEST_PATH_IMAGE002
（II）
in the above formula (II), R 1 Is hydrogen or methoxy, R 2 Is hydrogen or methoxy, R 3 Is hydrogen orA methoxy group, ar is 4-methoxyphenyl, 3,4-dimethoxyphenyl or 3,4,5-trimethoxyphenyl.
3. Use of 1-aryl-3- (6-arylpyridin-2-yl) -propenone according to claim 1 in the manufacture of a medicament for the treatment of intestinal cancer, lung cancer or glioma.
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