CN110563624B - 2-acetonyl selenium-based benzamide compound with cancer inhibition activity and application thereof - Google Patents

2-acetonyl selenium-based benzamide compound with cancer inhibition activity and application thereof Download PDF

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CN110563624B
CN110563624B CN201910935132.6A CN201910935132A CN110563624B CN 110563624 B CN110563624 B CN 110563624B CN 201910935132 A CN201910935132 A CN 201910935132A CN 110563624 B CN110563624 B CN 110563624B
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冯书晓
杨春梅
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Henan Pratt & Whitney Tiancheng Biotechnology Co ltd
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Abstract

The invention relates to a 2-acetonyl selenium-based benzamide compound with cancer inhibition activity and application thereof, belonging to the field of pharmaceutical chemistry, wherein the invention synthesizes and prepares 18 2-acetonyl selenium-based benzamide compounds, the synthesis steps are simple, the compound is suitable for mass production, the synthesized compound has small toxicity, good anti-tumor activity and good anti-tumor effect, can simulate the function of glutathione peroxidase in vivo, is an anti-tumor drug with double functions, has great drug value, has great market prospect in the preparation of anti-tumor drugs, and especially has application in the preparation of drugs for treating lung cancer, colorectal cancer, leukemia, esophageal cancer, gastric cancer, liver cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, oral cancer and tongue cancer, and the application in the preparation of drugs for treating cancer patients to assist in reducing toxic and side effects, Improving the sensitivity of chemotherapeutic drugs and reducing drug resistance.

Description

2-acetonyl selenium-based benzamide compound with cancer inhibition activity and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a 2-acetonyl selenium-based benzamide compound with cancer inhibition activity and application thereof.
Background
Selenium is one of the essential trace elements of human body, and is closely related to the occurrence of cancer. The research shows that: the blood selenium level of cancer patients is 3-6 times lower than that of normal people; the incidence rate of cancer of people with selenium deficiency is up to 50 percent. The selenium supplement can inhibit the expression of oncogene, eliminate free radicals in vivo by enhancing the activity of glutathione peroxidase, protect the structure of cell membrane and prevent gene mutation; the selenium supplement can enhance the immunologic function of the human body and prevent the occurrence of cancer; selenium supplement can enhance the level of cyclic adenosine monophosphate (cAMP) in cancer cells, inhibit the synthesis of DNA and RNA proteins, and inhibit the division and proliferation of cancer cells; the selenium supplement can block the energy supply of cancer cells by inhibiting the aerobic glycolysis of glucose, and promote the apoptosis of the cancer cells; selenium supplement can promote the integrity of immature blood vessel basement membrane in the tumor, and reduce the chance of tumor cells entering blood circulation to generate distant metastasis. The cancer patient can be supplemented with selenium to enhance immunity and reduce the toxicity and drug resistance of chemotherapeutic drugs; the chemotherapy medicine and selenium are combined for use, so that the sensitivity of the chemotherapy medicine can be enhanced, the treatment effect can be improved, and harmful free radicals can be removed. The organic selenium compound has significant therapeutic effect on breast cancer, liver cancer, skin cancer, gastrointestinal cancer and the like. Therefore, the search for the structure of the activated selenium compound and the development of the organic selenium medicine with high efficiency and low toxicity are one of the important subjects of the current tumor chemotherapy.
In the application, the evaluation and research on the anti-ischemic cerebral apoplexy activity of the amino acid derivatives of the parent nucleus with the novel structure of the 2-acetonylseleno benzamide, which is firstly discovered, are carried out. As a continuation of the research, the compound types with the structures are continuously synthesized and expanded, and the application value of the compound in other fields of anti-tumor medicines and the like is researched.
Disclosure of Invention
In view of the above objects, the first object of the present invention is to provide a series of 2-acetonylseleno benzamide compounds with cancer-suppressing activity, and the application of the 2-acetonylseleno benzamide compounds in the preparation of anti-tumor drugs. The 2-acetonyl selenium-based benzamide compound has good activity and low toxicity, and has a remarkable inhibiting effect on tumor cells.
In order to achieve the purpose, the invention adopts the specific scheme that:
the structural formula of the 2-acetonyl selenium-based benzamide compound with the cancer inhibition activity is shown as a formula I, a formula II, a formula III or a formula IV;
the formula I is as follows:
Figure BDA0002221413210000021
in the formula I, R-NH-is R-NH2An amino side chain in which one hydrogen atom is substituted; the R-NH2Is aniline, p-carboxyaniline, p-chloroaniline, o-methylaniline, p-nitroaniline, o-chloroaniline, p-methylaniline or p-formanilineOxyaniline, p-bromoaniline, p-fluoroaniline, anthranilic acid, α -naphthylamine, p-iodoaniline, p-ethylaniline or 2,4, 6-trimethylaniline;
the formula II is as follows:
Figure BDA0002221413210000022
the formula III is as follows:
Figure BDA0002221413210000023
the formula IV is as follows:
Figure BDA0002221413210000024
the invention also provides the application of the 2-acetonyl selenium-based benzamide compound with cancer inhibition activity in preparing anti-tumor drugs. Further, the anti-tumor drug is a drug for treating lung cancer, colorectal cancer, leukemia, esophageal cancer, gastric cancer, liver cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, oral cancer or tongue cancer.
Has the advantages that:
the invention synthesizes and prepares 18 2-acetonyl selenium-based benzamide compounds, has simple synthesis steps, is suitable for mass production, and one-to-one verification shows that the synthesized compounds have small toxicity, good anti-tumor activity and good anti-tumor effect, can simulate the function of glutathione peroxidase in vivo, are anti-tumor medicaments with double functions, have great medicinal value, have great market prospect in preparing anti-tumor medicaments, and particularly have application in medicaments for treating lung cancer, colorectal cancer, leukemia, esophageal cancer, gastric cancer, liver cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, oral cancer and tongue cancer, and have application in preparing medicaments for treating cancer patients to assist in reducing toxic and side effects, improving the sensitivity of chemotherapeutic medicaments and reducing the medicament resistance. In vitro anti-tumor experiments show that the compound has a remarkable inhibitory effect on human esophageal cancer cells (EC109 cell line), and particularly the inhibitory rate of part of compounds (compound 2, compound 12, compound 17 and compound 18) reaches more than 85% when the concentration is 100 mu g/mL. Further preferably, the test compounds 2 and 12 have better inhibitory effects on five cancer cell lines, namely HepG2 (human liver cancer cell line), SGC7901 (human stomach cancer cell line), HCT116 (human colon cancer cell line), A549 (human lung adenocarcinoma cell line) and MCF-7 (human breast cancer cell line), than the commercial anticancer drug cisplatin (DDP) group, wherein the IC50 value (24h) of HCT116 (human colon cancer cell line) and A549 (human lung adenocarcinoma cell line) is significantly lower than that of the cisplatin group, and is respectively 5.77 mu g/mL and 4.55 mu g/mL. The research result further indicates that the tested object 2-acetonyl selenium-based benzamide compound has obvious cancer inhibition activity on lung cancer, gastric cancer, colon cancer, liver cancer and breast cancer.
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FIG. 1 shows a general synthesis of a part of the compounds of the present invention.
Detailed Description
The invention aims to find a novel candidate compound of 2-acetonyl selenium-based benzamide, which has good activity, low toxicity and obvious inhibition effect on tumor cells, and a series of compounds are discovered and synthesized by the applicant for the first time.
The synthesis general formula is as follows:
Figure BDA0002221413210000031
the synthesis method comprises the following steps:
dissolving 2-chloroseleno-benzoyl chloride (a) in acetone, stirring for 30 minutes at room temperature, adding 1mmol of amine (b) or water, continuing stirring for 0.5-6 hours at room temperature, concentrating under reduced pressure to dryness, adding distilled water to wash residues, filtering, and recrystallizing, separating and purifying crude products by acetone/water to obtain pure compounds 1-18. Wherein the molar ratio of the 2-chloroseleno-benzoyl chloride to R-NH2 or water is 1: 1; the volume ratio of acetone to water in the acetone/water is 5: 1.
The structures of this series of novel compounds are shown below:
Figure BDA0002221413210000032
Figure BDA0002221413210000041
the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention.
The first embodiment is as follows: synthesis of Compound 1:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of aniline, continuing to stir at room temperature for 0.5 hour, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing the residue, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 1.
2-acetonylseleno benzanilide (1): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, yield 86%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),7.73(dd,J＝7.7,1.5Hz,3H),7.60(dd,J＝8.0,1.2Hz,1H),7.46(td,J＝7.6,1.6Hz,1H),7.43–7.29(m,3H),7.12(t,J＝7.4Hz,1H),3.84(s,2H),2.22(s,3H).13C NMR(101MHz,DMSO)δ204.82,167.04,139.43,136.42,132.30,131.51,130.37,129.17,128.87,126.14,124.30,120.52,35.85,28.73.HRMS(ESI):m/z 334.0338[M+H]+(calcd.for C16H16NO2Se+,334.0341). Nuclear magnetic analysis was consistent with the structure. The compound 1 has 85.82% inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 μ g/mL by MTT method.
Example two: synthesis of Compound 2:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of acetone, stirring for 45 minutes at room temperature, adding 1mmol of p-carboxyaniline, continuing stirring for 1 hour at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing the residue, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 2.
2-acetonylselenobenzoyl-4-carboxyaniline (1):Rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, 88% yield. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),10.73(s,1H),7.95(d,J＝8.8Hz,2H),7.86(d,J＝8.8Hz,2H),7.76(dd,J＝7.7,1.6Hz,1H),7.62(dd,J＝8.1,1.1Hz,1H),7.48(td,J＝7.6,1.5Hz,1H),7.38(td,J＝7.5,1.2Hz,1H),3.85(s,2H),2.22(s,3H).13C NMR(101MHz,DMSO)δ204.75,167.39,143.51,136.13,132.37,131.76,130.79,130.56,129.05,126.23,126.12,119.74,35.94,28.74.HRMS(ESI):m/z 376.0089[M-H]-(calcd.for C17H14NO4Se-,376.0094). Nuclear magnetic analysis was consistent with the structure. The compound 2 has 14.33 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by MTT method.
Example three: synthesis of Compound 3:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 3mL of acetone, stirring for 45 minutes at room temperature, adding 1mmol of parachloroaniline, continuing stirring for 2 hours at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 3.
2-acetonylselenobenzoyl-4-chloroaniline (3): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, yield 86%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),7.77(d,J＝8.9Hz,2H),7.74(dd,J＝7.7,1.6Hz,1H),7.61(dd,J＝8.0,1.1Hz,1H),7.47(td,J＝7.6,1.5Hz,1H),7.43(d,J＝8.9Hz,2H),7.36(td,J＝7.5,1.2Hz,1H),3.84(s,2H),2.22(s,3H).13C NMR(101MHz,DMSO)δ204.77,167.10,138.40,136.14,132.36,131.66,130.46,129.10,128.92,127.89,126.18,122.04,35.91,28.74.HRMS(ESI):m/z 367.9948[M+H]+(calcd.for C16H15ClNO2Se+,367.9951). Nuclear magnetic analysis was consistent with the structure. The compound 3 has 12.02 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by MTT method.
Example four: synthesis of Compound 4:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 3mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of o-toluidine, continuing stirring for 3 hours at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 4.
2-acetonylselenobenzoyl-2-methylaniline (4): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, yield 82%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),7.81(d,J＝7.6Hz,1H),7.60(dd,J＝8.0,1.2Hz,1H),7.46(td,J＝7.7,1.5Hz,1H),7.39–7.33(m,2H),7.28(dd,J＝7.2,1.7Hz,1H),7.26–7.21(m,1H),7.19(dd,J＝7.3,1.6Hz,1H),3.82(s,2H),2.26(s,3H),2.24(s,3H).13C NMR(101MHz,DMSO)δ204.95,167.12,136.53,135.78,134.02,132.77,131.51,130.85,130.15,128.82,126.86,126.59,126.52,126.07,35.82,28.73,18.46.HRMS(ESI):m/z 348.0494[M+H]+(calcd.for C17H18NO2Se+,348.0497). Nuclear magnetic analysis was consistent with the structure. The compound 4 has 6.97 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by MTT method.
Example five: synthesis of Compound 5:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 3mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of p-nitroaniline, continuing stirring for 1 hour at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 5.
2-acetonylselenobenzoyl-4-nitroaniline (5): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, yield 82%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.29(d,J＝9.2Hz,2H),8.08–7.96(m,2H),7.79(dd,J＝7.7,1.5Hz,1H),7.64(d,J＝7.9Hz,1H),7.50(td,J＝7.7,1.5Hz,1H),7.40(dd,J＝8.1,7.0Hz,1H),3.87(s,2H),2.23(s,3H).13C NMR(101MHz,DMSO)δ204.64,167.65,145.65,143.09,135.79,132.48,132.02,130.77,129.19,126.31,125.36,120.17,36.06,28.75.HRMS(ESI):m/z 379.0189[M+H]+(calcd.for C16H15N2O4Se+,379.0192). Nuclear magnetic analysis was consistent with the structure. The compound 5 has 14.94 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by MTT method.
Example six: synthesis of Compound 6:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 3mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of o-chloroaniline, continuing stirring for 1 hour at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 6.
2-acetonylselenobenzoyl-2-chloroanilide (6): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, yield 80%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),7.88–7.83(m,1H),7.63–7.57(m,2H),7.57–7.52(m,1H),7.52–7.45(m,1H),7.44–7.36(m,1H),7.36–7.27(m,2H),3.83(s,2H),2.25(s,3H).13C NMR(101MHz,DMSO)δ204.93,167.12,135.22,134.74,133.40,133.31,131.91,131.86,130.13,130.10,129.79,129.03,128.84,128.76,128.55,128.08,127.99,126.03,125.53,35.82,35.32,28.90,28.78.HRMS(ESI):m/z 367.9946[M+H]+(calcd.for C16H15ClNO2Se+,367.9951). Nuclear magnetic analysis was consistent with the structure. The compound 6 has 20.59 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by MTT method.
Example seven: synthesis of compound 7:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 3mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of water, continuing stirring for 1 hour at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 7.
2-acetonylselenobenzoic acid (7): rf0.15 (petroleum ether: ethyl acetate: 3:1), white solid, yield 80%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ13.32(s,1H),7.98(dd,J＝7.8,1.5Hz,1H),7.62–7.40(m,2H),7.30(td,J＝7.3,6.8,1.4Hz,1H),3.84(s,2H),3.32(s,2H),2.27(s,3H).13C NMR(101MHz,DMSO)δ205.17,168.53,137.05,133.31,131.91,128.84,128.55,125.53,35.31,28.90.HRMS(ESI):m/z 256.9720[M-H]-(calcd.for C10H9O3Se-,256.9722). Nuclear magnetic analysis was consistent with the structure. The compound 7 has the inhibition rate of 29.36 percent on human esophageal cancer cell lines EC109 under the concentration of 100 mu g/mL by an MTT method.
Example eight: synthesis of compound 8:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 3mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of p-methylaniline, continuing stirring for 1 hour at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 8.
2-acetonylselenobenzoyl-4-methylaniline (8): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, yield 86%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),7.72(dd,J＝7.6,1.5Hz,1H),7.64–7.57(m,3H),7.45(td,J＝7.6,1.5Hz,1H),7.35(td,J＝7.4,1.2Hz,1H),7.16(d,J＝8.2Hz,2H),3.82(s,2H),2.29(s,3H),2.22(s,3H).13C NMR(101MHz,DMSO)δ204.80,166.83,136.92,136.48,133.26,132.31,131.42,130.33,129.52,128.79,126.11,120.55,35.87,28.73,20.98.HRMS(ESI):m/z 348.0494[M+H]+(calcd.for C17H18NO2Se+,348.0497). Nuclear magnetic analysis was consistent with the structure. The compound 8 has 15.55 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by MTT method.
Example nine: synthesis of compound 9:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 4mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of p-anisidine, continuously stirring for 0.5 hour at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing the residue, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain the pure compound 9.
2-acetonylselenobenzoyl-4-methoxyaniline (9): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, 88% yield. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),7.72(dd,J＝7.6,1.6Hz,1H),7.64(d,J＝9.1Hz,3H),7.59(dd,J＝8.0,1.1Hz,1H),7.44(td,J＝7.6,1.6Hz,1H),7.34(td,J＝7.5,1.2Hz,1H),6.94(d,J＝9.1Hz,1H),3.82(s,2H),3.75(s,3H),2.22(s,3H).13C NMR(101MHz,DMSO)δ204.83,166.59,156.12,136.42,132.51,132.36,131.38,130.26,128.73,126.08,122.10,114.28,55.68,35.84,28.73.HRMS(ESI):m/z364.0445[M+H]+(calcd.for C17H18NO3Se+,364.0446). Nuclear magnetic analysis was consistent with the structure. The compound 9 has 25.82 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by MTT method.
Example ten: synthesis of compound 10:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 4mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of para-bromoaniline, continuously stirring for 5 hours at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 10.
2-acetonylselenobenzoyl-4-bromoaniline (10): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, yield 75%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),7.76–7.69(m,3H),7.61(dd,J＝8.0,1.2Hz,1H),7.55(d,J＝8.8Hz,2H),7.47(td,J＝7.7,1.6Hz,1H),7.36(td,J＝7.5,1.2Hz,1H),3.84(s,2H),2.22(s,3H).13C NMR(101MHz,DMSO)δ204.71,167.11,138.82,136.22,132.32,131.99,131.64,130.52,128.89,126.19,122.42,115.98,35.94,28.73.HRMS(ESI):m/z 411.9443[M+H]+(calcd.for C16H15BrNO2Se+,411.9446). Nuclear magnetic analysis was consistent with the structure. The compound 10 has 23.52 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by MTT method.
Example eleven: synthesis of compound 11:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 4mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of para-fluoroaniline, continuing stirring for 2 hours at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 11.
2-acetonylselenobenzoyl-4-fluoroaniline (11): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, yield 75%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),7.82–7.71(m,3H),7.61(dd,J＝8.0,1.1Hz,1H),7.46(td,J＝7.6,1.6Hz,1H),7.36(td,J＝7.5,1.2Hz,1H),7.21(t,J＝8.9Hz,2H),3.83(s,2H),2.22(s,3H).13C NMR(101MHz,DMSO)δ204.75,166.93,136.30,135.81,135.79,132.30,131.55,130.45,128.82,126.17,122.39,122.31,115.87,115.65,35.91,28.73.HRMS(ESI):m/z 352.0238[M+H]+(calcd.for C16H15FNO2Se+,352.0247). Nuclear magnetic analysis was consistent with the structure. The compound 11 has 0.75 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mug/mL by MTT method.
Example twelve: synthesis of compound 12:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of anthranilic acid, continuing to stir at room temperature for 0.5 hour, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing the residue, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain the pure compound 12.
2-acetonylselenobenzoyl-2-carboxyaniline (12): rf0.20 (petroleum ether: ethyl acetate: 1), yellow solidYield 89%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ13.77(s,1H),11.97(s,1H),8.61(dd,J＝8.4,1.1Hz,1H),8.06(dd,J＝7.9,1.7Hz,1H),7.84(dd,J＝7.8,1.5Hz,1H),7.73–7.61(m,2H),7.51(td,J＝7.7,1.5Hz,1H),7.41(td,J＝7.5,1.1Hz,1H),7.29–7.21(m,1H),3.87(s,2H),2.24(s,3H).13C NMR(101MHz,DMSO)δ204.91,170.28,166.39,141.14,134.76,134.75,134.14,132.25,131.75,130.27,128.06,126.39,123.78,120.48,117.43,35.85,28.84.HRMS(ESI):m/z 376.0088[M-H]-(calcd.for C17H14NO4Se-,376.0094). Nuclear magnetic analysis was consistent with the structure. The compound 12 has 90.95 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by MTT method.
Example thirteen: synthesis of compound 13:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of alpha-naphthylamine, continuing stirring for 1 hour at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 13.
2-acetonylselenobenzoyl-1-naphthylamine (13): rf0.20 (petroleum ether: ethyl acetate: 3:1), white solid, yield 82%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.11–8.04(m,1H),7.99(qd,J＝6.2,3.5Hz,2H),7.88(d,J＝8.1Hz,1H),7.66–7.62(m,2H),7.61–7.54(m,3H),7.50(td,J＝7.7,1.6Hz,1H),7.41(td,J＝7.5,1.2Hz,1H),3.85(s,2H),2.26(s,3H).13C NMR(101MHz,DMSO)δ204.91,167.95,135.87,134.25,133.94,132.78,131.60,130.32,129.36,129.00,128.55,126.81,126.58,126.46,126.18,126.02,123.98,123.77,35.95,28.76.HRMS(ESI):m/z 384.0495[M+H]+(calcd.for C20H18NO2Se+,384.0497). Nuclear magnetic analysis was consistent with the structure. The compound 13 has the inhibition rate of 19.98 percent on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by an MTT method.
Example fourteen: synthesis of compound 14:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of p-iodoaniline, continuously stirring for 2 hours at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 14.
2-acetonylselenobenzoyl-4-iodoaniline (14): rf0.20 (petroleum ether: ethyl acetate: 3:1), white solid, yield 74%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),7.75–7.68(m,3H),7.62–7.56(m,3H),7.46(td,J＝7.7,1.5Hz,1H),7.36(td,J＝7.5,1.2Hz,1H),3.84(s,2H),2.22(s,3H).13C NMR(101MHz,DMSO)δ204.73,167.10,139.29,137.83,136.23,132.31,131.64,130.50,128.89,126.19,122.66,88.00,35.94,28.74.HRMS(ESI):m/z 459.9303[M+H]+(calcd.for C16H15INO2Se+,459.9307). Nuclear magnetic analysis was consistent with the structure. The compound 14 has 29.55 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by MTT method.
Example fifteen: synthesis of compound 15:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of p-ethylaniline, continuing stirring for 2 hours at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 15.
2-acetonylselenobenzoyl-4-ethylaniline (15): rf0.35 (petroleum ether: ethyl acetate: 3:1), white solid, yield 78%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),7.72(d,J＝7.2Hz,1H),7.61(dd,J＝13.0,8.2Hz,3H),7.45(td,J＝7.6,1.6Hz,1H),7.38–7.31(m,1H),7.19(d,J＝8.4Hz,2H),3.82(s,2H),2.51(s,2H),2.22(s,3H),1.18(t,J＝7.6Hz,3H).13C NMR(101MHz,DMSO)δ204.81,166.85,139.77,137.11,136.50,132.29,131.43,130.34,128.79,128.35,126.12,120.63,35.86,28.72,28.13,16.24.HRMS(ESI):m/z362.0652[M+H]+(calcd.for C18H20NO2Se+,362.0654). Nuclear magnetic analysis was consistent with the structure. The compound 15 has 28.51 percent of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mu g/mL by MTT method.
Example sixteen: synthesis of compound 16:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of acetone, stirring for 30 minutes at room temperature, adding 1mmol of 2,4, 6-trimethylaniline, continuously stirring for 2 hours at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 16.
2-acetonylselenobenzoyl-2, 4, 6-trimethylaniline (16): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, yield 86%. The structure was analyzed by hydrogen and carbon Nuclear Magnetic Resonance (NMR) and the results were as follows:1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.98(d，1H),7.80(d,1H),7.59(d,1H),7.55–7.50(m,1H),7.45(m,1H),7.35(m,1H),3.82(d,J＝11.1Hz,2H),2.26(s,3H),2.24(s,3H),2.19(s,6H).13C NMR(101MHz,DMSO)δ204.94,167.13,137.06,136.02,135.71,133.32,132.64,131.91,130.10,128.83,128.47,126.05,125.53,35.71,28.90,28.62,21.02,18.53.HRMS(ESI):m/z 424.0656[M+H]+(calcd.for C19H22NO5Se+,424.0658). Nuclear magnetic analysis was consistent with the structure. The compound 16 has the inhibition rate of 4.43 percent on human esophageal cancer cell line EC109 under the concentration of 100 mug/mL by an MTT method.
Example seventeen: synthesis of compound 17:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of acetone, stirring for 30 minutes at room temperature, adding 0.5mmol of ethylenediamine, stirring for 2 hours at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing the residue, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 17.
Bis (2-acetonylselenobenzoyl) -ethylDiamine (17): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, yield 86%. HRMS (ESI) M/z 512.9818[ M + H [ ]]+(calcd.for C20H21N2O4Se2 +,512.9826). The compound 17 has 90.50% of inhibition rate on human esophageal cancer cell line EC109 under the concentration of 100 mug/mL by MTT method.
Example eighteen: synthesis of compound 18:
dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of acetone, stirring for 30 minutes at room temperature, adding 1.0mmol of dichloroethylamine hydrochloride and 1.0mmol of potassium carbonate, stirring for 2 hours at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing the residue, filtering, recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound 18.
2-acetonylselenobenzoyl-dichloroethylamine (18): rf0.30 (petroleum ether: ethyl acetate: 3:1), yellow solid, yield 86%. HRMS (ESI) M/z 367.9714[ M + H [ ]]+(calcd.for C13H16Cl2NO2Se+,367.9718). The compound 18 has 85.20% inhibition rate to human esophageal cancer cell line EC109 at 100 μ g/mL concentration tested by MTT method.
Related experiments:
MTT cytotoxicity assay: the centrifuged EC109 cell suspension was poured into a sterile tank, and the cell suspension was pipetted into a 96-well plate at 0.2ml per well using a pipette gun. The test compounds were removed from the freezer and 3 wells of 0.02ml per well were added for each test compound. Put into an incubator and cultured for 24 hours. The dosing time was marked and the dosing sequence was recorded. Preparing an MTT solution: MTT solution was prepared at 5ml/mg in PBS buffer. Care was taken to avoid light. The MTT solvent was poured into another sterile incubator, 0.02ml of MTT solution was added to each well using a pipette, sterilized and placed in a sterile incubator. After 4 hours, the liquid in the petri dish was aspirated by a needle tube, 0.15ml of isopropanol was added, the wavelength was set at 570, the plate was shaken for 30s, and the enzyme labeling solution was placed. Absorbance data was recorded. This was repeated three times. EC109 cell inhibition% was calculated. The results are shown in table 1 below.
TABLE 1 inhibition of EC109 cell proliferation by Compounds 1-18 at a concentration of 100. mu.g/mL
Figure BDA0002221413210000121
The CCK8 method tested IC50 values for compound 2 and compound 12 against five cancer cell lines: on the first day, the cell plates were subjected to digestion with 0.25% pancreatin (containing EDTA) for about 2 minutes (37 ℃ C.), and the cells were collected and centrifuged at 1000rpm for 4 minutes. Centrifuging, removing the upper culture medium, adding 4ml of fresh culture medium, blowing, beating and mixing. And (3) taking 20 mu l of cell suspension, adding 20 mu l of trypan blue solution, counting cells, and ensuring that the cell survival rate is more than 90%. Adjusting the cell density to 5000 cells/100 μ l; a96-well plate was taken and the cell suspension was added in an amount of 100. mu.l per well. Placing into cell culture box, 37 deg.C, 5% CO2Incubate overnight (16-24 hours). The next day: the cells were administered by placing in a cell incubator at 37 deg.C with 5% CO2Incubation was performed for 24h and measured. Placing in a cell culture box at 37 deg.C and 5% CO on the third day2And culturing, incubating for 48h, and measuring. And (3) detection: on day 2 the 96-well plate was removed, the cell supernatant medium was discarded, 100. mu.l of fresh medium containing 0.5% FBS was added to each well, 10. mu.l of CCK8 was added to each well and incubated at 37 ℃ for 2 hours (care was taken not to generate bubbles in the wells which would affect the OD readings). The 96-well plate was placed in a microplate reader and read at 450 nm. Analysis data processing was performed using prism 5.
TABLE 2 IC50 values for Compounds 2 and 12 against five cancer cell lines
Figure BDA0002221413210000122
Figure BDA0002221413210000131
The data show that the inhibition effect of the compounds 2 and 12 on five cancer cell lines is equal to or superior to that of the commercial anticancer drug cisplatin (DDP), wherein the IC50 value (24h) of HCT116 (human colon cancer cell line) and A549 (human lung adenocarcinoma cell line) is significantly lower than that of cisplatin group, and is 5.77 mu g/mL and 4.55 mu g/mL respectively. The research result further supports that the 2-acetonyl selenium-based benzamide compound has obvious cancer inhibition activity on lung cancer, gastric cancer, colon cancer, liver cancer and breast cancer.
It should be noted that the above-mentioned embodiments illustrate rather than limit the scope of the invention, which is defined by the appended claims. It will be apparent to those skilled in the art that certain insubstantial modifications and adaptations of the present invention can be made without departing from the spirit and scope of the invention.

Claims (4)

1. The 2-acetonyl selenium-based benzamide compound with cancer inhibition activity is characterized in that: the structural formula is as follows:
Figure FDA0003120361400000011
2. the 2-acetonyl selenium-based benzamide compound with cancer inhibition activity is characterized in that: the structural formula is as follows:
Figure FDA0003120361400000012
3. the use of 2-acetonylseleno benzamides compound with cancer suppressing activity according to claim 1 in the preparation of anti-tumor drugs; the anti-tumor drug is a drug for treating colon cancer, lung cancer, esophageal cancer, gastric cancer, liver cancer and breast cancer.
4. The use of 2-acetonylseleno benzamides compound with cancer suppressing activity according to claim 2 in the preparation of anti-tumor drugs; the anti-tumor drug is a drug for treating esophageal cancer.
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