CN116375672A - Coumarin acrolein derivative, preparation method thereof and application thereof in preparation of antitumor drugs - Google Patents

Coumarin acrolein derivative, preparation method thereof and application thereof in preparation of antitumor drugs Download PDF

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CN116375672A
CN116375672A CN202310144127.XA CN202310144127A CN116375672A CN 116375672 A CN116375672 A CN 116375672A CN 202310144127 A CN202310144127 A CN 202310144127A CN 116375672 A CN116375672 A CN 116375672A
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coumarin
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acrolein
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季红
张超
吕倩倩
陈乐贤
梁嘉杰
林嘉慧
肖瑛
陈瑞瑶
张芷菱
洪悦
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Guangzhou Medical University
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Abstract

The invention discloses coumarin acrolein derivatives, a preparation method thereof and application thereof in preparing antitumor drugs. The structural formula of the coumarin acrolein derivative is shown in the formula (I); the coumarin acrolein derivative is prepared from 3-acetylcoumarin and POCl containing different substituents 3 And DMF through Vilsmeier-Haack-Arnold reaction. The coumarin acrolein derivative has outstanding antitumor effect, has excellent antiproliferative activity on non-small cell lung cancer A549, oral epithelial cancer KB, cervical cancer Hela and breast cancer MCF-7, and can inhibit tumor migrationInvasion and induction of tumor cell apoptosis, and has wide application space in preparing antitumor drugs.
Figure DDA0004088510360000011

Description

Coumarin acrolein derivative, preparation method thereof and application thereof in preparation of antitumor drugs
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to coumarin acrolein derivatives, a preparation method thereof and application thereof in preparation of antitumor drugs.
Background
The influence of many factors such as the change of global climate environment and the change of life patterns of people, etc., makes cancers inferior to cardiovascular diseases and becomes a main cause of death of human beings. Statistics of World Health Organization (WHO) 2020 show that approximately 1400 tens of thousands of new cancer cases and 900 tens of thousands of cancer death cases occur annually worldwide. By 2040 years, cancer deaths would be expected to increase to about 2840 ten thousand. Cancer has become one of the biggest health challenges facing people in all countries of the world. At present, modes of cancer treatment mainly comprise chemotherapy, radiotherapy, surgical excision and the like, and although the treatment means show effects of various degrees, the prognosis of treatment of many cancer patients is not ideal and the survival rate after treatment is still low due to the lack of effective early diagnosis standards and specific medicines for prevention and treatment. Most of the existing antitumor drugs have the problems of low selectivity, large toxic and side effects, easy drug resistance and the like. Therefore, research and development of novel antitumor drugs has been a significant topic of meaning in research of novel drugs at home and abroad.
Many naturally occurring or synthetic coumarin compounds have outstanding antitumor activity. Based on the development potential and value of coumarin compounds in tumor treatment, the inventor of the invention performs research works such as designing and synthesizing coumarin antitumor drugs, and discovers various coumarin derivatives with outstanding antitumor activity.
Disclosure of Invention
The invention aims to provide coumarin acrolein derivatives with definite activity, low toxicity and good anti-tumor effect.
The first object of the present invention is to provide a coumarin acrolein derivative or a pharmaceutically acceptable salt thereof, which has the structural formula shown in formula (I):
Figure BDA0004088510340000021
wherein R is 1 Selected from hydrogen, hydroxy, alkoxy, halogen or amino; r is R 2 Selected from hydrogen, hydroxy, alkyl or halogen atoms.
Preferably, the alkyl group is methyl; the amino group is diethyl amine.
Preferably, the halogen atom is a bromine atom.
A second object of the present invention is to provide a process for preparing the coumarin acrolein derivatives from 3-acetylcoumarin and POCl containing different substituents 3 And DMF through Vilsmeier-Haack-Arnold reaction.
Preferably, the 3-acetylcoumarin containing different substituents is shown as a formula (II) or a formula (III):
Figure BDA0004088510340000022
preferably, the specific steps of the method are as follows: POCl was added to the ice-water bath 3 Dissolving in DMF, adding under stirring the mixture of formula (II)The DMF solution of Compound 2 was reacted at 60℃for 5 hours. After the reaction is completed, the compounds 5a-g are obtained after extraction and purification, and the structural formula is shown as the formula (IV):
Figure BDA0004088510340000031
preferably, the specific steps of the method are as follows: POCl was added to the ice-water bath 3 Dissolving in DMF, adding DMF solution of compound 4 shown in formula (III) under stirring, and stirring at 60-70deg.C for reacting for 5 hr. After the reaction is completed, the compounds 6a-g are obtained through extraction and purification, and the structural formula is shown as a formula (V):
Figure BDA0004088510340000032
the third object of the invention is to provide the application of the coumarin acrolein derivative or the pharmaceutical salt thereof in preparing antitumor drugs.
Preferably, the antitumor drug is a drug for resisting non-small cell lung cancer, oral epithelial cancer, cervical cancer or breast cancer.
A fourth object of the present invention is to provide an antitumor drug comprising an effective amount of the above coumarin acrolein derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
The invention has the advantages that:
the coumarin acrolein derivative has outstanding anti-tumor effect, has excellent anti-proliferation activity on non-small cell lung cancer A549, oral epithelial cancer KB, cervical cancer Hela and breast cancer MCF-7, and can inhibit migration and invasion of tumors and induce apoptosis of tumor cells. In particular, compound 6e has the strongest antiproliferative activity on KB cells (IC 50 =0.39 μm), can significantly inhibit proliferation, migration, invasion of KB cells, and can induce apoptosis thereof. The coumarin acrolein derivative has wide application space in preparing antitumor drugs.
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FIG. 1 is a synthesis of intermediates 2a-g and 4a-gRoute wherein (i) is Pieridine, C 2 H 5 OH, rt. (ii) is K 2 CO 3 ,DMF,N 2 ,rt.
FIG. 2 is a scheme showing the synthesis of coumarin acrolein derivatives 5a-g and 6a-g, wherein (i) is POCl 3 ,DMF,60-70℃.
FIG. 3 is that Compound 6e inhibits KB cell migration.
FIG. 4 is that Compound 6e inhibits KB cell invasion.
Figure 5 is the induction of KB apoptosis by compound 6 e.
Detailed Description
The following examples are further illustrative of the invention and are not intended to be limiting thereof.
Examples:
the synthesis part comprises the following steps:
the synthetic route is as follows:
1. the synthetic routes for intermediates 2a-g and 4a-g are as follows, as shown in FIG. 1;
Figure BDA0004088510340000051
reagents and conditions (i) Piperidine, C 2 H 5 OH,rt.(ii)K 2 CO 3 ,DMF,N 2 ,rt.
2. The synthetic routes for coumarin acrolein derivatives 5a-g and 6a-g are shown below, and are shown in FIG. 2:
Figure BDA0004088510340000061
reagents and conditions (i) POCl 3 ,DMF,60-70℃。
(1) Synthesis of Compound 2:
Figure BDA0004088510340000062
salicylaldehyde 1 (7.0 mmol) and ethyl acetoacetate (0.89 mL,7.0 mmol) containing different substituents were dissolved in eachIn absolute ethanol (20 mL), a catalytic amount of piperidine (0.1 mL) was slowly added dropwise, the reaction was stirred at room temperature for 0.5-2h, petroleum ether-ethyl acetate (2:1) was used as developing agent, and the reaction process was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, deionized water (20 mL) was added thereto for dilution, and ethyl acetate (20 mL. Times.3) was used for extraction, and the obtained organic layer was taken up with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain the compounds 2a-g. The technical route is shown in figure 1.
2a： 1 H-NMR(400MHz,CDCl 3 )δ8.51(s,1H),7.65(ddd,J＝7.3,4.2,2.6Hz,2H),7.38–7.32(m,2H),2.73(s,3H). 13 C NMR(100MHz,CDCl 3 )δ195.64,159.37,155.45,147.61,134.53,130.36,125.11,124.64,118.38,116.82,30.69.
2b： 1 H-NMR(400MHz,DMSO-d 6 )δ8.40(s,1H),7.55(d,J＝8.8Hz,1H),6.54(dd,J＝8.8,2.1Hz,1H),6.34(d,J＝1.9Hz,1H),2.49(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.21,171.55,160.01,158.70,147.17,132.54,117.39,114.12,108.52,102.24,30.12.
2c： 1 H-NMR(400MHz,CDCl 3 )δ8.43(s,1H),7.39(d,J＝9.0Hz,1H),6.61(dd,J＝9.0,2.5Hz,1H),6.46(d,J＝2.5Hz,1H),3.45(q,J＝7.2Hz,4H),2.68(s,3H),1.24(t,J＝7.2Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ195.88,161.01,158.86,153.12,148.00,132.02,116.18,109.96,108.26,96.66,45.26(2C),30.74,12.55(2C).
2d： 1 H-NMR(400MHz,CDCl 3 )δ8.46(d,J＝3.9Hz,1H),7.56(s,1H),7.49(m,2H),2.71(d,J＝3.7Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ195.24,158.66,155.48,146.88,131.13,129.13,128.74,124.58,120.19,117.25,30.68.
2e： 1 H-NMR(400MHz,DMSO-d 6 )δ9.91(s,1H),8.55(s,1H),7.29(d,J＝9.0Hz,1H),7.22(d,J＝3.0Hz,1H),7.15(dd,J＝8.8,2.9Hz,1H),2.56(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ195.40,158.76,154.06,148.09,147.10,124.43,122.80,118.71,117.09,114.21,30.16.
2f： 1 H-NMR(400MHz,CDCl 3 )δ8.29(s,1H),7.29(dd,J＝8.3,2.1Hz,1H),7.26(s,1H),7.10(d,J＝8.3Hz,1H),2.56(s,3H),2.26(s,3H). 13 C NMR(100MHz,CDCl 3 )δ195.78,159.58,153.58,147.64,135.74,134.93,129.91,124.36,118.07,116.47,30.71,20.80.
2g： 1 H-NMR(400MHz,CDCl 3 )δ8.39(s,1H),7.76(d,J＝2.2Hz,1H),7.71(dd,J＝8.7,2.3Hz,1H),7.24(d,J＝1.7Hz,1H),2.70(s,3H). 13 C NMR(100MHz,CDCl 3 )δ195.24,158.73,154.21,146.20,137.21,132.34,125.51,119.84,118.58,117.68,30.72.
(2) Synthesis of Compound 4:
Figure BDA0004088510340000081
compound 2b (204.2 mg,1.0 mmol) and K were combined under nitrogen 2 CO 3 (165.8 mg,1.2 mmol) was added to anhydrous DMF (6 mL), and after stirring for several minutes, alkyl bromide 3 (1.4 mmol) was added dropwise and reacted at room temperature for 16-20 hours. The reaction was monitored by TLC using petroleum ether-ethyl acetate (4:1) as the developing solvent. After the reaction was completed, it was diluted with deionized water (10 mL) to precipitate a solid, which was filtered, washed with deionized water, and dried to obtain compounds 4a-g. The technical route is shown in figure 1.
4a： 1 H-NMR(400 MHz,CDCl 3 )δ8.50(d,J＝3.8 Hz,1H),7.55(dd,J＝8.6,3.7 Hz,1H),6.90(d,J＝8.5 Hz,1H),6.83(s,1H),3.92(d,J＝3.8 Hz,3H),2.71(d,J＝3.7 Hz,3H). 13 C NMR(100 MHz,CDCl 3 )δ195.65,165.38,159.86,157.90,147.93,131.62,120.73,114.00,112.14,100.38,56.16,30.71.
4b： 1 H-NMR(400 MHz,CDCl 3 )δ8.50(d,J＝3.6 Hz,1H),7.54(dd,J＝8.7,3.6 Hz,1H),6.88(dt,J＝8.7,3.0 Hz,1H),6.80(d,J＝2.7 Hz,1H),4.13(tt,J＝7.3,3.4 Hz,2H),2.71(d,J＝3.8Hz,3H),1.48(td,J＝6.8,3.6 Hz,3H). 13 C NMR(100 MHz,CDCl 3 )δ195.69,164.83,159.95,157.92,147.99,131.61,120.55,114.34,111.99,100.78,64.70,30.72,14.58.
4c： 1 H-NMR(400 MHz,CDCl 3 )δ8.48(s,1H),7.52(d,J＝8.7 Hz,1H),6.88(dd,J＝8.7,2.6Hz,1H),6.80(d,J＝2.4 Hz,1H),4.00(t,J＝6.5 Hz,2H),2.69(s,3H),1.85(h,J＝7.2 Hz,2H),1.05(t,J＝7.4 Hz,3H). 13 C NMR(100 MHz,CDCl 3 )δ195.75,165.05,160.00,157.95,148.05,131.60,120.50,114.40,111.97,100.80,70.56,30.76,22.37,10.54.
4d： 1 H-NMR(400 MHz,CDCl 3 )δ8.49(s,1H),7.52(d,J＝8.7 Hz,1H),6.85(dd,J＝8.7,2.3 Hz,1H),6.79(d,J＝2.4 Hz,1H),4.65(p,J＝6.0 Hz,1H),2.70(s,3H),1.39(d,J＝6.2 Hz,6H). 13 C NMR(100 MHz,CDCl 3 )δ195.75,163.97,160.03,157.99,148.04,131.70,120.36,115.06,111.79,101.53,71.37,30.75,21.85(2C).
4e： 1 H-NMR(400 MHz,DMSO-d 6 )δ8.64(s,1H),7.88(d,J＝8.8 Hz,1H),7.49(d,J＝8.5Hz,2H),7.44–7.34(m,3H),7.15(d,J＝2.3 Hz,1H),7.09(dd,J＝8.7,2.4 Hz,1H),5.26(s,2H),2.56(s,3H). 13 C NMR(100 MHz,CDCl 3 )δ195.64,164.40,159.85,157.79,147.87,135.38,131.66,128.97(2C),128.72,127.68(2C),120.89,114.59,112.33,101.45,70.93,30.72.
4f： 1 H-NMR(400MHz,CDCl 3 )δ8.51(s,1H),8.29(d,J＝8.7Hz,2H),7.61(dd,J＝12.0,8.5Hz,3H),6.99(dd,J＝8.8,2.3Hz,1H),6.88(d,J＝2.3Hz,1H),5.27(s,2H),2.70(s,3H). 13 CNMR(100MHz,CDCl 3 )195.58,165.95,159.65,150.25,147.73,142.73,137.65,131.91,127.93(2C),124.23(2C),114.32,112.79,109.16,101.47,69.42,30.75.
4g： 1 H-NMR(400MHz,CDCl 3 )δ8.49(s,1H),7.59(s,1H),7.56(d,J＝8.7Hz,1H),7.50(d,J＝7.7Hz,1H),7.35(d,J＝7.8Hz,1H),7.29(d,J＝7.8Hz,1H),6.97(dd,J＝8.7,2.3Hz,1H),6.87(d,J＝2.3Hz,1H),5.13(s,2H),2.70(s,3H). 13 C NMR(100MHz,CDCl 3 )δ195.62,163.97,159.78,157.75,147.82,137.68,131.79(2C),130.54(2C),126.06,123.06,121.11,114.48,112.54,101.42,69.91,30.73.
(3) Synthesis of Compound 5:
Figure BDA0004088510340000101
POCl was added to the ice-water bath 3 (0.1 mL,1.1 mmol) was dissolved in DMF (5 mL), a solution of compound 2 (1.0 mmol) in DMF (2 mL) was added with stirring, and the reaction was carried out at 60℃for 5 hours. After the completion of the reaction, the reaction solution was treated and purified to obtain compounds 5a to g. The technical route is shown in figure 2.
5a: after the reaction was completed, the mixture was cooled to room temperature, diluted with deionized water (4 mL) to precipitate a yellow solid, and the solid obtained by filtration was recrystallized from ethanol to give Compound 5a. 1 H-NMR(400MHz,DMSO-d 6 )δ10.19(d,J＝6.8Hz,1H),8.85(s,1H),7.99(dd,J＝7.8,1.7Hz,1H),7.74-7.80(m,1H),7.45-7.51(m,2H),7.42(d,J＝6.8Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ192.10,157.40,153.85,144.98,143.32,134.40,129.59,129.33,125.36,121.93,118.45,116.72.
5b: after the completion of the reaction, the reaction mixture was cooled to room temperature, saturated aqueous sodium chloride (10 mL) was added, the mixture was extracted with ethyl acetate (20 mL. Times.3), and the aqueous layer was allowed to stand overnight to precipitate a yellow solid, which was then filtered, washed with deionized water and dried to give Compound 5b. 1 H-NMR(400MHz,DMSO-d 6 )δ11.57(s,1H),10.16(ddd,J＝6.9,2.0,1.0Hz,1H),8.78(s,1H),7.83(d,J＝8.7Hz,1H),7.42(d,J＝6.9Hz,1H),6.97(d,J＝8.6Hz,1H),6.88(s,1H). 13 C NMR(100MHz,DMSO-d 6 )δ192.13,164.20,157.50,155.73,146.32,144.61,132.22,126.61,115.73,114.48,111.24,101.68.
5c: after completion of the reaction, the reaction mixture was cooled to room temperature, saturated aqueous sodium chloride (10 mL) was added, the mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic layer was subjected to anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain orange crude product. The crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) and recrystallized from ethyl acetate to give yellow powder 5c. 1 H-NMR(400MHz,CDCl 3 )δ10.27(d,J＝6.9Hz,1H),8.37(s,1H),7.67(d,J＝6.9Hz,1H),7.39(d,J＝8.9Hz,1H),6.64(dd,J＝9.0,2.5Hz,1H),6.47(d,J＝2.3Hz,1H),3.46(d,J＝7.2Hz,4H),1.24(d,J＝7.1Hz,6H). 13 C NMR(100MHz,DMSO-d 6 )δ192.63,158.56,157.00,152.90,145.49,145.03,131.14,126.20,113.00,110.10,108.48,96.57,45.31(2C),12.58(2C).
5d: after the reaction was completed, it was cooled to room temperature, and sodium acetate (400.0 mg) and deionized water (0.80 mL) were added thereto, followed by stirring for 5 hours. Subsequently 5% Na was added 2 CO 3 The pH value of the aqueous solution is regulated to 7-8, yellow solid matters are separated out, and the yellow powder 5d is obtained after filtering, washing by deionized water and drying. 1 H-NMR(400MHz,DMSO-d 6 )δ10.18(ddd,J＝6.8,3.0,1.6Hz,1H),8.84(d,J＝2.2Hz,1H),7.91–7.94(m,1H),7.85(q,J＝2.0Hz,1H),7.66(ddt,J＝6.4,3.8,1.7Hz,1H),7.41(m,1H). 13 C NMR(100MHz,DMSO-d 6 )δ192.05,156.62,153.51,145.04,143.46,131.58,128.35,128.30,127.50,121.50,119.09,117.72.
5e: after the completion of the reaction, the mixture was cooled to room temperature, and sodium acetate (400.0 mg) and deionized water (0.80 mL) were added thereto, followed by stirring for 5 hours. Saturated aqueous sodium chloride (10 mL) was then added and extracted with ethyl acetate (20 mL. Times.3). The organic layer was treated with anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure gave an orange crude product. The crude product was separated by column chromatography on silica gel (dichloromethane: methanol=100:1) to give an orange powder 5e. 1 H-NMR(400MHz,DMSO-d 6 )δ10.17(d,J＝6.8Hz,1H),9.96(s,1H),8.75(s,1H),7.41(d,J＝6.8Hz,1H),7.33(d,J＝9.0Hz,1H),7.26(d,J＝2.8Hz,1H),7.17(dd,J＝8.9,2.7Hz,1H). 13 C NMR(100MHz,DMSO-d 6 )δ192.10,157.31,154.21,146.80,145.75,143.97,128.15,122.79,121.19,118.93,116.99,113.71.
5f: after the reaction was completed, the mixture was cooled to room temperature, diluted with deionized water (4 mL), and a yellow solid was precipitated, filtered, washed with deionized water, and the obtained solid was recrystallized from methylene chloride to obtain yellow powder 5f. 1 H-NMR(400MHz,CDCl 3 )δ10.28(d,J＝6.7Hz,1H),8.45(s,1H),7.67(d,J＝6.6Hz,1H),7.43(m,2H),7.23(d,J＝3.3Hz,1H),2.42(s,3H). 13 C NMR(100MHz,CDCl 3 )δ192.13,157.59,152.04,145.01,143.51,135.59,135.22,129.21,129.17,121.67,118.20,116.40,20.88.
5g: after the reaction is finished, the mixture is cooled to room temperature, diluted by deionized water (4 mL) and separated out greenAfter filtration and washing with deionized water, the solid obtained was purified by silica gel column chromatography (dichloromethane: methanol=100:1) to obtain 5g of yellow powder. 1 H-NMR(400MHz,CDCl 3 )δ10.27(d,J＝6.6Hz,1H),8.41(s,1H),7.78(d,J＝2.4Hz,1H),7.71(dd,J＝8.8,2.2Hz,1H),7.65(d,J＝6.5Hz,1H),7.23(d,J＝4.0Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ191.88,156.74,152.60,143.41,142.66,136.99,131.63,129.83,123.03,119.88,118.43,117.91.
(4) Synthesis of Compound 6:
Figure BDA0004088510340000131
POCl was added to the ice-water bath 3 (0.1 mL,1.1 mmol) was dissolved in DMF (5 mL), a solution of compound 4 (1.0 mmol) in DMF (2 mL) was added under stirring, and the reaction was stirred at 60-70℃for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, a saturated aqueous sodium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL. Times.3). After the water layer is kept stand overnight, yellow solid is precipitated, filtered, washed by deionized water and dried to obtain a crude product. The crude product was separated by column chromatography on silica gel (dichloromethane: petroleum ether=5:1) to give yellow powders 6a-g. The technical route is shown in figure 2.
6a： 1 H-NMR(400MHz,DMSO-d 6 )δ10.17(d,J＝6.8Hz,1H),8.83(s,1H),7.92(d,J＝8.7Hz,1H),7.43(d,J＝6.8Hz,1H),7.11(m,1H),7.06(dd,J＝8.7,1.8Hz,1H),3.91(s,3H). 13 CNMR(100MHz,CDCl 3 )δ192.31,165.22,157.72,156.13,145.05,144.01,130.81,128.25,117.96,114.20,112.29,100.30,56.23.
6b： 1 H-NMR(400MHz,DMSO-d 6 )δ10.17(d,J＝6.8Hz,1H),8.82(s,1H),7.90(d,J＝8.7Hz,1H),7.43(d,J＝6.8Hz,1H),7.08(m,1H),7.04(dd,J＝8.6,1.8Hz,1H),4.19(q,J＝6.8Hz,2H),1.37(t,J＝6.9 Hz,3H). 13 C NMR(100 MHz,DMSO-d 6 )δ190.34,163.36,156.10,149.78,146.50,132.51,130.94,126.98,118.29,113.59,111.60,100.97,64.38,14.34.
6c： 1 H-NMR(400 MHz,CDCl 3 )δ10.29(d,J＝6.8 Hz,1H),8.47(s,1H),7.68(d,J＝6.7 Hz,1H),7.54(d,J＝8.7 Hz,1H),6.92(dd,J＝8.7,2.3 Hz,1H),6.82(d,J＝2.3 Hz,1H),4.02(t,J＝6.5 Hz,2H),1.87(m,2H),1.07(t,J＝7.4 Hz,4H). 13 C NMR(100 MHz,CDCl 3 )δ192.32,164.84,157.78,156.13,145.11,144.10,130.77,128.13,117.67,114.53,112.11,100.70,70.62,22.38,10.53.
6d： 1 H-NMR(400 MHz,CDCl 3 )δ10.29(d,J＝6.8 Hz,1H),8.47(s,1H),7.68(d,J＝6.5 Hz,1H),7.53(d,J＝8.7 Hz,1H),6.88(dd,J＝8.7,2.3 Hz,1H),6.81(d,J＝2.3 Hz,1H),4.65(m,1H),1.40(d,J＝6.0 Hz,6H). 13 C NMR(100 MHz,CDCl 3 )δ192.33,163.77,157.82,156.18,145.10,144.14,130.85,128.09,117.56,115.21,111.93,101.45,71.45,21.87(2C).
6e： 1 H-NMR(400 MHz,CDCl 3 )δ10.29(d,J＝6.7 Hz,1H),8.47(s,1H),7.66(d,J＝6.8 Hz,1H),7.55(d,J＝8.7 Hz,1H),7.42(m,4H),7.38(m,1H),7.00(dd,J＝8.7,2.5 Hz,1H),6.90(d,J＝2.4 Hz,1H),5.17(s,2H). 13 C NMR(100 MHz,CDCl 3 )δ192.24,164.19,157.68,155.99,144.96,143.93,135.34,130.83,128.99(2C),128.74,128.29,127.69(2C),118.09,114.76,112.45,101.34,70.99.
6f： 1 H-NMR(400 MHz,DMSO-d 6 )δ10.17(dd,J＝6.8,1.7 Hz,1H),8.84(s,1H),8.28(d,J＝8.6 Hz,2H),7.95(d,J＝8.7 Hz,1H),7.76(d,J＝8.5 Hz,2H),7.42(d,J＝6.8 Hz,1H),7.21(s,1H),7.17(dd,J＝8.7,1.9 Hz,1H),5.46(s,2H). 13 C NMR(100 MHz,CDCl 3 )δ188.22,162.97,156.49,148.09,145.32,142.65,133.01,131.05,130.51,129.89,127.93(2C),124.24(2C),114.37,112.18,108.58,101.95,69.46.
6g： 1 H-NMR(400MHz,CDCl 3 )δ10.30(d,J＝6.7Hz,1H),8.49(s,1H),7.68(d,J＝6.7Hz,1H),7.58(d,J＝13.4Hz,2H),7.50(d,J＝7.9Hz,1H),7.36(d,J＝7.8Hz,1H),7.30(d,J＝7.9Hz,1H),7.00(d,J＝8.1Hz,1H),6.89(d,J＝8.5Hz,1H),5.14(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ192.17,163.49,161.35,155.50,154.50,146.01,140.25,138.80,131.81,130.86,130.63,127.12,127.01,121.82,117.35,114.26,112.54,101.08,69.22.
Antitumor Activity:
(1) Inhibitory Activity against tumor cell proliferation:
the MTT method is adopted to detect the activity of the compound for inhibiting the proliferation of tumor cells, and A549, KB, hela and MCF-7 cells are mixed according to the ratio of 4 multiplied by 10 3 The density of individual cells/wells was seeded into 96-well plates (190 uL) and incubated at 37 ℃ for 24h. Sequentially adding 10 mu L of compound culture solutions with different concentrations (final concentrations of 50, 25, 12.5, 6.25, 3.125 and 1.5625 mu M) into each well of a 96-well plate, setting 3 compound wells in each group, taking the group without adding the drug as a negative control, adding 5-FU (final concentrations of 50, 25, 12.5, 6.25, 3.125 and 1.5625 mu M) into the positive control group, adding 10 mu L of MTT solution (5 mg/mL) into each well after each tested sample is cultured for 72 hours under the same conditions as cells, and measuring the optical density value (OD) of each well at 540/655nm by using an enzyme-labeling instrument after culturing for 4 hours; the inhibition ratios of the compounds to the cell proliferation were calculated using the absorbance values, respectively, and the formula was as follows:
I/％＝(1－OD 1 /OD)×100
wherein: i is the inhibition rate of cell proliferation; OD (optical density) 1 Absorbance values for dosing group cells; OD is the absorbance value of the control cells. The obtained data were processed by GraphpadPrism 7 software to obtain IC of each compound 50 . Each set of experiments was repeated three times.
The experimental results are shown in table 1, most of the compounds tested have better inhibition activity on proliferation of four tumor cells, and the activity of a plurality of compounds is better than that of positive control 5-fluorouracil. Compounds 5d and 6e showed the best antiproliferative activity on A549 and KB cells, IC 50 The values reached 0.70.+ -. 0.05. Mu.M and 0.39.+ -. 0.07. Mu.M. Therefore, the compounds can be used for developing antitumor drugs.
Inhibitory Activity of Compounds 5a-g and 6a-g of Table 1 on tumor cell proliferation
Figure BDA0004088510340000161
Figure BDA0004088510340000171
(2) Inhibiting tumor cell migration activity
KB cells (5X 10) 5 Cells/well) were inoculated into 6-well plates at 37℃with 5% CO 2 Is incubated for 12 hours in a humidified atmosphere. The cell layer was scratched with a 200 μl pipette tip. After washing with phosphate buffered saline, the compounds were used at various concentrations (final concentration 0.5IC 50 ,IC 50 ,2IC 50 ) Cells were treated for 24h. Photographs were taken with an inverted fluorescence microscope at magnification x 400 and analyzed with Image J analysis software. Images of the wound area were taken with a microscope at 0 and 24 hours. The areas of the scratched wound not covered by cells were quantified using Image J, and each set of values is expressed as a percentage of the untreated control group's cell wound closure rate. Each set of experiments was repeated three times.
The experimental results are shown in fig. 3, and the compound 6e with the best activity on KB cells shows remarkable anti-tumor cell migration effect in low, medium and high concentration groups.
(3) Inhibiting tumor cell invasiveness Activity
Using a transwell challenge experiment, the filter insert of the transwell device was coated with Matrigel (Corning, 356234 Matrigel). 1X 10 5 KB cells were inoculated into 200. Mu.L of serum-free RMPI-1640 medium with a pore size of 8. Mu.m, and 600. Mu.L of 10% fetal bovine serum was added to the medium. With different concentrations (final concentration of 0.5IC 50 ,IC 50 ,2IC 50 ) Is a compound of formula (i). After 48 hours, the invaded cells were fixed with paraformaldehyde for 1 hour, stained with 0.1% crystal violet solution for 2 hours, and the uninfluenced cells in the top chamber of the transwell plate were scraped off with a cotton swab. Each insertion point was imaged at 10 x magnification and analyzed using Image J software. Each set of experiments was repeated three times.
As a result, as shown in fig. 4, compound 6e showed significant anti-invasion activity against KB cells in the low, medium and high concentration groups, and was concentration-dependent.
(4) Induction of apoptosis activity in tumor cells
Inoculation of 5X 10 in 6 well plates 5 KB cells/well with different concentrations of drug(final concentration 0.5 IC) 50 、IC 50 、2IC 50 ) And (5) treating for 48 hours. Cells were collected, washed twice with cold PBS, resuspended in 400. Mu.L of 1 Xannexin buffer (Sanchi Kogyo, AB 2000) and then 5. Mu.L of FITC (50. Mu.g/ml) and 5. Mu.L of PI dye (50. Mu.g/ml) were mixed, respectively, and incubated in the dark at room temperature for 5 minutes each. At the end of incubation, the samples were immediately analyzed by a beckmann flow cytometer. Each set of experiments was repeated three times.
The experimental results are shown in fig. 5, and after the treatment of the compound 6e with low, medium and high concentrations, the proportion of early apoptosis and late apoptosis in KB cells is increased, and the total apoptosis rate is obviously increased, so that the compound 6e has obvious effect of inducing KB cell apoptosis.

Claims (10)

1. Coumarin acrolein derivative or pharmaceutically acceptable salt thereof, and has a structural formula shown in formula (I):
Figure FDA0004088510330000011
wherein R is 1 Selected from hydrogen, hydroxy, alkoxy, halogen or amino; r is R 2 Selected from hydrogen, hydroxy, alkyl or halogen atoms.
2. The coumarin acrolein derivative according to claim 1, wherein the alkyl group is methyl; the amino group is diethyl amine.
3. The coumarin acrolein derivative according to claim 1, wherein the halogen atom is a bromine atom.
4. A process for preparing coumarin acrolein derivatives according to claim 1, characterized in that 3-acetylcoumarin and POCl containing different substituents are used 3 And DMF through Vilsmeier-Haack-Arnold reaction.
5. The method according to claim 4, wherein the 3-acetylcoumarin having different substituents is represented by any one of the compounds represented by the formula (II) or the formula (III):
Figure FDA0004088510330000012
6. the method according to claim 4, characterized by the specific steps of: POCl was added to the ice-water bath 3 Is dissolved in
Adding a DMF solution of a compound 2 shown in a formula (II) into DMF under stirring, and reacting at 60 ℃ for 5 hours; after the reaction is completed, the compounds 5a-g are obtained after extraction and purification, and the structural formula is shown as the formula (IV):
Figure FDA0004088510330000021
7. the method according to claim 4, characterized by the specific steps of: POCl was added to the ice-water bath 3 Is dissolved in
Adding DMF solution of the compound 4 shown in the formula (III) into DMF under stirring, and stirring and reacting for 5 hours at 60-70 ℃; after the reaction is completed, the compounds 6a-g are obtained through extraction and purification, and the structural formula is shown as a formula (V):
Figure FDA0004088510330000022
8. the use of coumarin acrolein derivatives or pharmaceutically acceptable salts thereof according to claim 1 in the manufacture of an antitumor agent.
9. The use according to claim 8, wherein the antineoplastic agent is an agent against non-small cell lung cancer, oral epithelial cancer, cervical cancer or breast cancer.
10. An antitumor agent comprising an effective amount of the coumarin acrolein derivative or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.
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