阅读说明：本技术 一系列新型硒醚酰胺类有机硒化合物及其抗癌用途 (A series of novel selenoether amide organic selenium compounds and anticancer application thereof ) 是由 冯书晓 杜冠华 齐凯言 马军营 高嘉宇 杨春梅 赵鹏宇 于 2021-08-10 设计创作，主要内容包括：本发明涉及一系列新型硒醚酰胺类有机硒化合物及其抗癌应用,属于药物化学领域,本发明共合成制备了43种硒醚酰胺类有机硒化合物,合成步骤简单,适合大批量生产,合成的化合物显示出显著的抗肿瘤活性,体外抗肿瘤效果好,并且可抑制人硫氧还蛋白还原酶(TrxR 1)作用,是一种具有高效的抗肿瘤药物,具有极大的药物价值,在制备抗肿瘤药物方面具有巨大的市场前景,尤其是在治疗人胶质母细胞瘤、结直肠癌、乳腺癌、食道癌、白血病、胃癌、肝癌、卵巢癌、宫颈癌、前列腺癌、口腔癌、舌癌的药物中的应用,以及在制备治疗癌症患者辅助降低毒副作用、提高化疗药物敏感性、降低耐药性中的应用。(The invention relates to a series of novel selenoamide organic selenium compounds and anticancer application thereof, belonging to the field of pharmaceutical chemistry, 43 selenoamide organic selenium compounds are prepared by co-synthesis, the synthetic steps are simple, the compounds are suitable for mass production, the synthesized compounds show significant antitumor activity and good in vitro antitumor effect, can inhibit the action of human thioredoxin reductase (TrxR 1), are high-efficiency antitumor drugs, have great pharmaceutical value, and have great market prospect in the preparation of antitumor drugs, in particular the application in the preparation of drugs for treating human glioblastoma, colorectal cancer, breast cancer, esophageal cancer, leukemia, gastric cancer, liver cancer, ovarian cancer, cervical cancer, prostate cancer, oral cancer and tongue cancer, and the application in the preparation of drugs for assisting in reducing the toxic and side effects of cancer patients and improving the sensitivity of chemotherapeutic drugs, Reducing drug resistance.)

1. A series of selenoether amide organic selenium compounds are characterized in that: the structural formula is as follows:

wherein R is₂The substituents are respectively substituted by the following chemical functional groups to form 18 compounds in total from 1a to 1 r:

2. a series of selenoether amide organic selenium compounds are characterized in that: the structural formula is as follows:

wherein R is₂The substituent groups are respectively substituted by the following chemical functional groups to form 4 compounds in total from 2a to 2 d:

3. a series of selenoether amide organic selenium compounds are characterized in that: the structural formula is as follows:

wherein R is₂The substituent groups are respectively substituted by the following chemical functional groups to form 2 compounds in total from 3a to 3 b:

4. a series of selenoether amide organic selenium compounds are characterized in that: the structural formula is as follows:

wherein R is₂The substituents are respectively substituted by the following chemical functional groups to form 9 compounds in total from 4a to 4 i:

5. a series of selenoether amide organic selenium compounds are characterized in that: the structural formula is as follows:

wherein R is₂The substituent groups are respectively substituted by the following chemical functional groups to form 8 compounds in total from 5a to 5 h:

6. a series of selenoether amide organic selenium compounds are characterized in that: the structural formula is as follows:

7. the use of selenoamide organoselenium compounds of claim 4 for the preparation of anti-esophageal cancer drugs.

8. The use of the selenoamide organoselenium compounds of any one of claims 1 to 6 for the preparation of an anti-tumor medicament for the treatment of human glioblastoma, colorectal cancer, leukemia, esophageal cancer, gastric cancer, liver cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, oral cancer, or tongue cancer.

9. A human thioredoxin reductase inhibitor comprising at least one of the selenoether amide organoselenium compounds as claimed in any of claims 1 to 6.

10. The use of the selenoamide organoselenium compounds of any of claims 1-6 for the preparation of inhibitors of human thioredoxin reductase.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a novel selenoether amide organic selenium compound with thioredoxin reductase inhibiting effect and cancer inhibiting activity and potential application thereof.

Background

Cancer is one of the important diseases that seriously threaten human health and life. The world cancer statistics report 2018 states that there will be 1810 ten thousand new cases and 960 ten thousand dead cases of cancer worldwide in 2018. Data published by the National Cancer Center (NCC) in 2018 show that about 380.4 ten thousand new malignant tumor cases and 229.6 ten thousand death cases are published nationwide in 2014; among them, lung cancer, liver cancer, stomach cancer, esophageal cancer, colorectal cancer, pancreatic cancer, breast cancer, brain tumor, leukemia and lymph cancer are the most important causes of death, accounting for about 83% of all cases of tumor death. There is still a rapidly rising trend in cancer morbidity and mortality worldwide. Cancer therapy has progressed significantly over the last two decades. However, current chemotherapeutic drugs have serious side effects and poor quality of life. Therefore, there is an urgent need to develop novel tumor therapeutic drugs that can effectively combat diseases and improve quality of life.

Thioredoxin reductase (TrxR) is a dimeric selenase that is overexpressed in a variety of cancer cells and is closely related to malignancy, growth, invasion, drug resistance, and the like of tumors. Research shows that the thioredoxin reductase can enhance the sensitivity of tumor cells to chemotherapeutic drugs, inhibit the migration/invasion capacity of the tumor cells and greatly reduce the risk of metastasis and recurrence of residual cancer cells after treatment of patients by reducing the activity of the thioredoxin reductase in the tumor cells, so that the thioredoxin reductase becomes a star target spot for new generation tumor treatment. The C-terminal selenocysteine residue (Sec) of the reductase has high activity and plays an important role in the physiological activity of thioredoxin reductase. Sec is exposed on the outer surface of thioredoxin reductase, is in a SeH/SH state under reductive physiological conditions, is easily modified by electronegative compounds, and is a main action target of thioredoxin reductase inhibitor drugs.

Numerous organoselenium compounds have affinity activity for thioredoxin reductase. Metabolism of these selenium-containing compounds oxidizes NADPH and thioredoxin in a reduced state (Trx) by thioredoxin reductase and generates ROS, thereby inducing apoptosis in vivo. For example, ebselen, a substrate of thioredoxin reductase 1, acts on residues Cys497 and Sec498 of thioredoxin reductase 1 at the same time, and high levels of ebselen inhibit the reduction of disulfide bonds of proteins such as Trx by thioredoxin reductase to thiol groups by competing with NADPH and Trx for electrons, thereby destroying the antioxidant system and killing cancer cells. Cystine selenide is a synergistic inhibitor of thioredoxin reductase 1, induces apoptosis by inducing ROS-dependent apoptosis, causing mitochondrial function damage, inducing DNA-damage mediated phosphorylation of p53, and down-regulating phosphorylated Akt and ERK in human breast cancer MCF-7 cells. Butaselen is another thioredoxin reductase selenium-containing inhibitor, and on one hand, the Butaselen can reduce the expression of PD-L1 to inhibit the STAT3 signal pathway to enhance immune response, thereby playing a role in inhibiting tumorigenesis. On the other hand, Butaselen can also induce the generation of ROS by inhibiting TrxR/Ref-1 and NF-kB pathways, and cause the block of G2/M phase of cell cycle, and inhibit the proliferation of tumor cells. The selenadiazole derivative is also a potent thioredoxin reductase inhibitor, and enhances the radiosensitivity of human melanoma and cervical cancer cells by triggering excessive ROS-mediated DNA damage, including inhibition of Akt and MAPKs. The selenium-containing compound can be used in combination with other antitumor drugs to enhance antitumor activity and reduce adverse side effects of radiotherapy and chemotherapy. The organic selenium compounds have the potential of being used as a potent thioredoxin reductase inhibitor and have a remarkable development prospect in the field of cancer treatment. Moreover, researches show that the thioredoxin reductase inhibitor has potential effects on the treatment of AIDS and autoimmune diseases such as rheumatoid arthritis besides the application in the treatment of cancer, so that the development of a novel organic selenium thioredoxin reductase inhibitor has great research value.

Ebselen is a low-toxicity small-molecule organic selenium thioredoxin reductase inhibitor, and from the perspective of drug discovery, modification of the structure of ebselen is helpful for discovery of a new thioredoxin reductase inhibitor. It has been reported in the literature (Engman, l., cotgreat, i., Angulo, m., ethyl anticancer Research,1997,17(6D), 4599-. Therefore, a series of selenoamide organic selenium compounds with novel structures are obtained by simple and efficient synthesis by using self-developed amphiphilic fragment modification strategies and synthesis technologies (Shuxiao Feng, Kaiyan Qi, Yafei Guo, equivalent. tetrahedron Letters,2020,61(48):152561.) and using different ketone reagents as one of nucleophilic reagents and different amines as the other of nucleophilic reagents to doubly modify the selenoamide part and the amide part of ebselen. All the compounds in the application are novel compounds which are found for the first time and are not reported. And the synthesized compound has obvious thioredoxin reductase inhibiting activity and anticancer activity.

Disclosure of Invention

In view of the above, the first purpose of the present invention is to provide a series of selenoamide organic selenium compounds with cancer-suppressing activity, the second purpose is to provide applications of the selenoamide organic selenium compounds in the preparation of anti-tumor drugs, the third purpose is to provide a thioredoxin reductase inhibitor, and the fourth purpose is to provide applications of the selenoamide organic selenium compounds in the preparation of thioredoxin reductase inhibitors. The selenoether amide organic selenium compound provided by the invention is novel in structure, low in toxicity and remarkable in anticancer activity.

In order to achieve the purpose, the invention adopts the following specific scheme:

a series of novel selenoether amide compounds have a structural formula shown as the following:

in the formula, R₁Substituent and R₂The substituent groups are respectively substituted by corresponding chemical functional groups to form new compounds shown as formulas I to V;

the formula I is:wherein R is₂The substituents are respectively substituted by the following chemical functional groups to form 18 compounds in total from 1a to 1 r:

the formula II is as follows:wherein R is₂The substituent groups are respectively substituted by the following chemical functional groups to form 4 compounds in total from 2a to 2 d:

the formula III is as follows:wherein R is₂The substituent groups are respectively substituted by the following chemical functional groups to form 2 compounds in total from 3a to 3 b:

the formula IV is as follows:wherein R is₂The substituents are respectively substituted by the following chemical functional groups to form 9 compounds in total from 4a to 4 i:

the formula V is:wherein R is₂The substituents are respectively substituted by the following chemical functional groups to form 8 compounds in total, wherein the 8 compounds are 5a to 5 g:

the formula VI is 2 compounds in total from 6a to 6b, and the structural formulas are respectively as follows:

the invention also provides application of the 9 compounds in the formula IV in preparing anti-esophageal cancer medicaments.

The invention also provides the application of the 43 novel seleno-ether-amide organic selenium compounds with obvious thioredoxin reductase inhibition effects in preparing antitumor drugs. Furthermore, the anti-tumor drug is a drug for treating human glioblastoma, leukemia, esophageal cancer, gastric cancer, liver cancer, colorectal cancer, non-small cell lung cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, oral cancer or tongue cancer.

The invention also provides a thioredoxin reductase inhibitor which comprises at least one selenoether amide organic selenium compound.

In addition, the invention provides application of 43 selenoamide organic selenium compounds in preparation of human thioredoxin reductase inhibitors.

Has the advantages that: the invention synthesizes and prepares six series of selenoamide organic selenium compounds with 43 novel structural characteristics in formulas I-VI, the synthesis method is mild and simple, is suitable for mass production, the synthesized compounds have low toxicity, show good antitumor activity and have obvious inhibition effect on human thioredoxin reductase, has potential therapeutic application to diseases related to a thioredoxin system, has great medicinal value, has great market prospect in the preparation of antitumor medicaments, and particularly has application in medicaments for treating human glioblastoma, leukemia, esophageal cancer, gastric cancer, liver cancer, colorectal cancer, non-small cell lung cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, oral cancer or tongue cancer, and the application in preparing medicines for adjuvant treatment of cancer patients to reduce toxic and side effects, improve chemotherapy drug sensitivity, and reduce drug resistance. In vitro thioredoxin reductase inhibition experiments and anti-tumor experiments show that the compound has a remarkable inhibition effect on human thioredoxin reductase, on human gastric cancer, colorectal cancer and non-small cell lung cancer cells, and particularly has a remarkable inhibition effect on the compound 6 b.

Detailed Description

The invention aims to find a novel organic selenium compound of selenoamides, which has good activity, low toxicity and obvious inhibition effect on tumor cells, and a series of compounds are not reported and are synthesized for the first time.

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 18 compounds belonging to formula I:

0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) was dissolved in 5mL of butanone and after stirring for 15 minutes at room temperature, 1mmol of a different R was added₂And (3) continuing stirring the amine substituted by the functional group at room temperature for 15 minutes, concentrating under reduced pressure to dryness, adding 20mL of distilled water to wash residues, filtering, and recrystallizing the crude product with acetone/water (1: 5, V/V), separating and purifying to obtain a pure compound 1 a-1 r.

Compound 1 a: white needle-like solid, melting point 106-107 ℃, yield 70%, Rf 0.36 (petroleum ether: ethyl acetate (V/V) ═ 3:1), structure by nuclear magnetic resonance hydrogen spectrum and carbon spectrum (NMR) analysis, results were as follows:¹H NMR(400MHz,CDCl₃)δ8.09(s,1H,NH),7.76–7.59(m,4H,ArH),7.46–7.35(m,4H,ArH),7.21–7.13(m,1H,ArH),3.99(q,J＝7.1Hz,1H,CH),2.23(s,3H,CH₃),1.54(d,J＝7.1Hz,3H,CH₃).¹³C NMR(101MHz,Chloroform-d)δ206.52,166.76,139.55,137.80,135.15,131.00,129.14,128.17,128.12,127.87,124.71,120.00,46.34,26.48,16.30.

compound 1 b: a beige needle-shaped solid, the melting point is 113-114 ℃, the yield is 60 percent, R_f0.35 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ8.27(s,1H,NH),7.74–7.56(m,4H,ArH),7.46–7.30(m,4H,ArH),3.98(q,J＝7.0Hz,1H,CH),2.21(s,3H,CH₃),1.53(d,J＝7.1Hz,3H,CH₃).¹³C NMR(101MHz,Chloroform-d)δ206.64,166.80,139.30,136.44,135.29,131.10,129.61,129.11,128.24,128.20,127.68,121.25,46.41,26.54,16.31.

compound 1 c: a beige needle-shaped solid, the melting point is 130-131 ℃, the yield is 75 percent, R_f0.36 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ8.18(s,1H,NH),7.71–7.66(m,1H,ArH),7.65–7.62(m,1H,ArH),7.61–7.57(m,2H,ArH),7.50(d,J＝2.2Hz,1H,ArH),7.48(d,J＝2.1Hz,1H,ArH),7.44–7.39(m,2H,ArH),3.99(q,J＝7.1Hz,1H,CH),2.22(s,3H,CH₃),1.54(d,J＝7.1Hz,3H,CH₃).¹³C NMR(101MHz,CDCl₃)δ206.59,166.76,139.47,136.92,135.52,132.09,131.12,128.36,128.21,127.46,121.52,117.27,46.47,26.56,16.31.

compound 1 d: white needle-shaped solid, the melting point is 139-140 ℃, the yield is 80 percent, R_f0.35 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ8.19(s,1H,NH),7.69–7.66(m,3H,ArH),7.64–7.61(m,1H,ArH),7.50–7.46(m,2H,ArH),7.42–7.39(m,2H,ArH),3.98(q,J＝7.1Hz,1H,CH),2.22(s,3H,CH₃),1.53(d,J＝7.1Hz,3H,CH₃).¹³C NMR(101MHz,CDCl₃)δ206.58,166.78,139.49,138.03,137.63,135.51,131.11,128.34,128.21,127.46,121.80,87.93,46.47,26.55,16.31.

compound 1 e: yellow oily liquid, 74% yield, R_f0.41 (petroleum ether: ethyl acetate (V/V) ═ 0.413:1), the structure is analyzed by nuclear magnetic resonance hydrogen spectrum and carbon spectrum (NMR), and the results are as follows:¹H NMR(400MHz,CDCl₃)δ8.21–7.99(m,1H,NH),7.68–7.58(m,2H,ArH),7.55(d,J＝7.9Hz,2H,ArH),7.41–7.31(m,2H,ArH),7.21–7.11(m,3H,ArH),4.04–3.91(m,1H,CH),2.35(s,3H,CH₃),2.24–2.16(m,3H,CH₃),1.56–1.49(m,3H,CH₃).¹³C NMR(101MHz,CDCl₃)δ206.69,166.77,139.26,135.35,134.57,134.28,130.87,129.54,128.11,127.87,125.51,120.18,46.18,26.48,20.98,16.28.

compound 1 f: yellow oily liquid, 67% yield, R_f0.25 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,Chloroform-d)δ8.10(s,1H,NH),7.67–7.54(m,4H,ArH),7.40–7.31(m,2H,ArH),6.91–6.87(m,2H,ArH),3.98(q,J＝7.1Hz,1H,CH),3.82(s,3H,CH₃),2.22(s,3H,CH₃),1.53(d,J＝7.1Hz,3H,CH₃).¹³CNMR(101MHz,Chloroform-d)δ206.74,166.73,156.56,139.06,134.35,131.06,130.84,128.09,127.76,121.93,114.13,55.51,46.12,26.47,16.28.

compound 1 g: yellow needle-shaped solid, the melting point is 149-150 ℃, the yield is 68 percent, R_f0.18 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ8.79(s,1H,NH),8.28(d,J＝2.1Hz,1H,ArH),8.26(s,1H,ArH),7.93–7.87(m,2H,ArH),7.73–7.69(m,1H,ArH),7.69–7.64(m,1H,ArH),7.47–7.42(m,2H,ArH),4.05(d,J＝7.1Hz,1H,CH),2.22(s,3H,CH₃),1.56(d,J＝7.1Hz,3H,CH₃).¹³C NMR(101MHz,Chloroform-d)δ206.91,167.10,143.75,139.24,136.01,134.06,131.46,128.64,128.57,127.05,125.17,119.39,46.93,26.76,16.41.

compound 1 h: yellow solid, melting point 160-161 ℃, yield 78%, R_f0.33 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ12.77(s,1H,COOH),10.72(s,1H,NH),7.96(d,J＝2.2Hz,1H,Ar-H),7.94(d,J＝2.0Hz,1H,Ar-H),7.89–7.82(m,2H,Ar-H),7.70(t,J＝1.5Hz,1H,Ar-H),7.68(d,J＝1.5Hz,1H,Ar-H),7.52–7.41(m,2H,Ar-H),4.20(q,J＝7.0Hz,1H,CH),2.20(s,3H,CH₃),1.43(d,J＝7.0Hz,3H,CH₃).¹³C NMR(101MHz,DMSO-d₆)δ205.95,167.53,167.39,143.50,139.33,133.34,131.36,130.81,129.51,128.82,127.58,126.12,119.55,45.55,27.30,16.75.

compound 1 i: yellow oily liquid, 75% yield, R_f0.48 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,Chloroform-d)δ8.32(s,1H),7.70(q,J＝1.4Hz,1H),7.68(q,J＝1.0Hz,1H),7.48–7.30(m,5H),7.11(ddd,J＝8.1,7.4,1.6Hz,1H),4.01(q,J＝7.1Hz,1H),2.27(s,3H),1.56(d,J＝7.1Hz,3H).¹³C NMR(101MHz,Chloroform-d)δ206.16,166.40,137.50,134.50,133.66,131.56,130.35,129.16,127.86,127.79,127.54,125.16,123.28,121.79,45.94,26.24,16.25.

compound 1 j: yellow oily liquid, 78% yield, R_f0.36 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ7.98(s,1H,NH),7.78–7.62(m,4H,ArH),7.46–7.36(m,2H,ArH),7.25(d,J＝7.3Hz,1H,ArH),7.14(t,J＝7.5Hz,1H,ArH),4.02(q,J＝7.0Hz,1H,CH),2.35(s,3H,CH₃),2.25(s,3H,CH₃),1.55(d,J＝7.1Hz,3H,CH₃).¹³C NMR(101MHz,CDCl₃)δ206.46,166.96,138.82,135.53,134.27,132.39,131.05,130.65,129.02,127.96,127.76,126.77,125.69,123.44,46.15,26.44,18.04,16.29.

compound 1 k: yellow oily liquid, 71% yield, R_f0.26 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ8.71(s,1H,OH),8.60(s,1H,NH),7.67–7.61(m,2H,ArH),7.46(d,J＝7.9Hz,1H,ArH),7.42–7.33(m,2H,ArH),7.14–7.09(m,1H,ArH),7.00(d,J＝8.1Hz,1H,ArH),6.90(t,J＝7.6Hz,1H,ArH),3.98(q,J＝7.0Hz,1H,CH),2.22(s,3H,CH₃),1.51(d,J＝7.1Hz,3H,CH₃).¹³C NMR(101MHz,Chloroform-d)δ206.90,168.06,148.14,138.57,135.56,131.35,128.44,128.38,127.66,126.94,125.66,122.31,120.66,118.79,46.67,26.56,16.27.

compound 1 l: yellow solid, melting point 157-158 deg.C, yield 90%, R_f0.31 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ13.78(s,1H,COOH),11.85(s,1H,NH),8.63–8.56(m,1H,ArH),8.05(d,J＝7.9Hz,1H,ArH),7.80(d,J＝7.6Hz,1H,ArH),7.53(t,J＝7.6Hz,1H,ArH),7.46(t,J＝7.5Hz,1H,ArH),7.27–7.21(m,1H,ArH),4.25(q,J＝6.8Hz,1H,CH),2.22(s,3H,CH₃),1.46(d,J＝7.0Hz,3H,CH₃).¹³C NMR(101MHz,DMSO-d₆)δ206.31,170.20,166.55,141.05,137.32,134.75,132.25,132.02,131.74,131.68,128.14,127.40,123.83,120.46,117.45,45.03,27.17,16.64.

compound 1 m: yellow oily liquid, 75% yield, R_f0.41 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ8.35–8.20(m,1H,NH),7.65–7.52(m,3H,ArH),7.43(d,J＝8.2Hz,1H,ArH),7.33(m,2H,ArH),7.26–7.20(m,1H,ArH),6.97(d,J＝7.5Hz,1H,ArH),4.05–3.88(m,1H,CH),2.36–2.33(m,3H,CH₃),2.21–2.19(m,3H,CH₃),1.56–1.46(m,3H,CH₃).¹³C NMR(101MHz,Chloroform-d)δ206.67,166.85,139.17,138.97,137.82,134.50,130.93,128.87,128.41,128.09,127.86,125.48,120.74,117.22,46.16,26.45,21.57,16.28.

compound 1 n: yellow oily liquid, 69% yield, R_f0.29 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ8.41(s,H,NH),8.02–7.98(m,1H,ArH),7.92–7.88(m,1H,ArH),7.76(d,J＝8.2Hz,2H,ArH),7.73–7.68(m,1H,ArH),7.55–7.49(m,4H,ArH),7.44–7.40(m,2H,ArH),4.03(q,J＝7.0Hz,1H,CH),2.22(s,3H,CH₃),1.54(d,J＝7.0Hz,3H,CH₃).¹³C NMR(101MHz,CDCl₃)δ206.63,167.70,138.66,134.22,134.14,132.35,131.47,131.04,129.08,128.84,128.61,128.21,127.71,126.44,126.32,126.10,125.63,121.54,46.21,26.48,16.28.

compound 1 o: beige solid, melting point 157-158 ℃, yield 58%, R_f0.35 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ7.61(d,J＝7.7Hz,1H,ArH),7.48(d,J＝7.4,1.9Hz,1H,ArH),7.35(t,J＝7.5,1H,ArH),7.31(d,J＝7.4Hz,1H,ArH),6.01(d,J＝8.0Hz,1H,NH),4.00(d,J＝7.2Hz,1H,CH),2.27(s,3H,CH₃),2.06(d,J＝11.6Hz,2H,CH₂),1.77(d,J＝13.4Hz,2H,CH₂),1.66(d,J＝12.7Hz,1H,CH),1.56(d,J＝7.1Hz,3H,CH₃),1.49–1.38(m,2H,CH₂),1.24(m,4H,CH₂).¹³C NMR(101MHz,Chloroform-d)δ206.52,167.76,138.75,133.66,130.68,129.11,127.63,127.38,48.97,46.05,33.07,26.43,25.53,24.89,16.33.

compound 1 p: yellow oily liquid, 49% yield, R_f0.56 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ7.58(d,J＝7.7Hz,1H,ArH),7.44(d,J＝6.7Hz,1H,ArH),7.35–7.27(m,2H,ArH),5.92(s,1H,NH),4.04–3.98(m,1H,CH),2.25(d,J＝1.4Hz,3H,CH₃),1.57–1.53(m,3H,CH₃),1.48(d,J＝1.3Hz,9H,CH₃).¹³C NMR(101MHz,CDCl₃)δ206.47,168.19,140.11,133.92,130.40,128.37,127.55,127.52,52.06,46.16,28.81,26.61,16.34.

compound 1 q: yellow oily liquid, 64% yield, R_f0.29 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ7.55(d,J＝7.9Hz,1H,ArH),7.46(dd,J＝7.6Hz,1H,ArH),7.31(d,J＝7.5Hz,1H,ArH),7.22(t,J＝7.5Hz,1H,ArH),7.04(t,J＝5.5Hz,1H,NH),3.94(q,J＝7.1Hz,1H,CH),3.73(t,J＝5.1Hz,2H,CH₂),3.51(q,J＝5.7Hz,2H,CH₂),2.22(s,3H,CH₃),1.49(d,J＝7.1Hz,3H,CH₃).¹³C NMR(101MHz,Chloroform-d)δ206.96,169.58,138.29,133.88,130.86,128.80,127.85,127.52,61.58,45.99,42.76,26.48,16.27.

compound 1 r: beige solid, melting point 157-158 ℃, yield 63%, R_f0.32 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ7.61(d,J＝7.7Hz,1H,ArH),7.48(d,J＝7.5Hz,1H,ArH),7.35(t,J＝7.7Hz,1H),7.32–7.27(m,1H,ArH),6.20(s,1H,NH),3.99(q,J＝7.1Hz,1H,CH),3.48–3.42(m,2H,CH₂),2.27(s,3H,CH₃),1.64–1.59(m,2H,CH₂),1.55(d,J＝7.1Hz,3H,CH₃),1.47–1.39(m,2H,CH₂),0.97(t,J＝7.3Hz,3H,CH₃).¹³C NMR(101MHz,CDCl₃)δ206.53,168.65,138.73,133.83,130.71,128.95,127.67,127.46,46.01,39.88,31.60,26.43,20.18,16.29,13.80.

example two: synthesis of 4 compounds belonging to formula II:

0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) was dissolved in 3mL of acetonitrile solvent containing 10mmol of 3-pentanone, stirred at room temperature for 60 minutes, and then 1mmol of the different R was added₂And (3) continuing stirring the amine substituted by the functional group at room temperature for 1h, concentrating under reduced pressure to dryness, adding 20mL of distilled water to wash residues, filtering, and recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain pure compounds 2 a-2 d.

Compound 2 a: yellow oily liquid, 77% yield, R_f0.47 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ8.49(s,1H,NH),7.67–7.57(m,4H,ArH),7.41–7.34(m,2H,ArH),7.34–7.29(m,2H,ArH),4.04(q,J＝7.2Hz,1H,CH),2.56(q,J＝7.2Hz,2H,CH₂),1.58–1.48(m,3H,CH₃),0.95(t,J＝7.2Hz,3H,CH₃).¹³C NMR(101MHz,CDCl₃)δ209.66,166.98,138.98,136.59,134.79,131.01,129.49,128.95,128.37,127.95,121.51,116.28,45.59,32.69,16.61,8.19.

compound 2 b: white oily liquid, 73% yield, R_f0.43 (petroleum ether: ethyl acetate)(V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ8.65(s,1H,NH),7.64–7.50(m,4H,Ar-H),7.45–7.40(m,2H,Ar-H),7.37–7.27(m,2H,Ar-H),4.01(q,J＝7.1Hz,1H,CH),2.54(q,J＝7.3Hz,2H,CH₂),1.50(d,J＝7.1Hz,3H,CH₃),0.93(t,J＝7.3Hz,3H,CH₃).¹³C NMR(101MHz,CDCl₃)δ209.66,166.98,138.98,136.59,134.79,131.01,129.49,128.95,128.37,127.95,121.51,116.28,45.59,32.69,16.61,8.19.

compound 2 c: white oily liquid, 74% yield, R_f0.42 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,CDCl₃)δ8.28(s,1H,NH),7.65–7.52(m,4H,Ar-H),7.35(d,J＝6.5Hz,2H,Ar-H),7.16(d,J＝8.2Hz,2H,Ar-H),4.02(q,J＝7.1Hz,1H,CH),2.57(q,J＝7.3Hz,2H,CH₂),2.35(s,3H,Ar-CH₃),1.53(d,J＝7.1Hz,3H,CH₃),0.97(t,J＝7.3Hz,3H,CH₃).¹³C NMR(101MHz,Chloroform-d)δ209.58,166.75,139.28,135.38,134.66,134.25,130.85,129.52,128.33,128.29,127.90,120.20,45.48,32.52,20.98,16.55,8.23.

compound 2 d: yellow solid, melting point 161-162 ℃, yield 88%, R_f0.31 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ12.81(s,1H,-COOH),10.74(s,1H,NH),7.94(d,J＝8.8Hz,2H,Ar-H),7.85(d,J＝8.8Hz,2H,Ar-H),7.69(d,J＝7.5Hz,2H,Ar-H),7.47(m,2H,Ar-H),4.22(q,J＝6.9Hz,1H,CH),2.72–2.53(m,2H,CH₂),1.43(d,J＝6.9Hz,3H,CH₃),0.90(t,J＝7.2Hz,3H,CH₃).¹³C NMR(101MHz,DMSO-d₆)δ208.75,167.54,167.40,143.51,139.39,133.38,131.38,130.81,129.55,128.82,127.61,126.08,119.53,44.75,32.63,16.96,8.68.

example three: synthesis of 2 compounds belonging to formula III:

0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) was dissolved in 5mL of dichloromethane solvent containing 10mmol of cyclohexanone at room temperatureAfter stirring for 30 minutes, 1mmol of a different R are added₂And (3) continuing stirring the amine substituted by the functional group at room temperature for 1h, concentrating under reduced pressure to dryness, adding 20mL of distilled water to wash residues, filtering, and recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain pure compounds 3 a-3 b.

Compound 3 a: white-like solid with melting point of 123-124 ℃, yield of 59 percent, R_f0.39 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,Chloroform-d)δ8.98(s,1H),7.70–7.51(m,4H),7.34–7.19(m,4H),4.02(t,J＝5.5Hz,1H),2.88(ddd,J＝15.1,9.8,5.7Hz,1H),2.23(dtt,J＝30.2,14.5,7.4Hz,3H),1.96–1.65(m,4H).¹³C NMR(101MHz,Chloroform-d)δ209.05,166.81,138.32,136.39,134.28,130.93,129.10,128.71,128.33,128.02,127.48,121.11,50.85,38.53,33.32,26.54,22.80.

compound 3 b: white solid, melting point 130-131 ℃, yield 62%, R_f0.12 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.55(s,1H,NH),7.73–7.63(m,4H,Ar-H),7.56–7.53(m,2H,Ar-H),7.46(t,J＝7.6Hz,1H,Ar-H),7.38(t,J＝7.5Hz,1H,Ar-H),4.31(t,J＝5.6Hz,1H,CH),2.69(d,J＝13.9Hz,1H,CH),2.38–2.18(m,2H,CH₂),1.95(d,J＝14.0Hz,1H,CH),1.80(p,J＝6.4Hz,2H,CH₂),1.70(t,J＝6.7Hz,2H,CH₂).¹³C NMR(101MHz,DMSO-d₆)δ208.36,167.32,138.88,138.50,132.45,132.00,131.32,130.39,128.62,126.83,122.25,115.89,50.07,39.66,34.33,26.93,23.77.

example four: synthesis of 9 compounds belonging to formula IV:

dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of acetonitrile solvent containing 10mmol of acetophenone, stirring at room temperature for 10 hours, and adding 1mmol of different R₂And (3) continuing stirring the amine substituted by the functional group at room temperature for 1h, concentrating under reduced pressure to dryness, adding 20mL of distilled water to wash residues, filtering, and recrystallizing, separating and purifying the crude product by acetone/water (5: 1, V/V) to obtain pure compounds 4 a-4 i.

Compound 4 a: rice and its production processYellow solid, melting point 124-125 ℃, yield 40%, R_f0.30 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.51(s,1H,NH),8.07–7.97(m,2H,Ar-H),7.84–7.68(m,4H,Ar-H),7.66–7.61(m,1H,Ar-H),7.56–7.45(m,3H,Ar-H),7.43–7.34(m,3H,Ar-H),4.48(s,2H,CH₂).¹³C NMR(101MHz,DMSO-d₆)δ196.15,167.06,138.34,135.89,135.77,133.86,132.82,131.71,130.63,129.17,129.12,129.05,128.91,127.90,126.18,122.08,31.69.

compound 4 b: beige solid, melting point 118-119 ℃, yield 46 percent R_f0.32 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.51(s,1H,NH),8.04–7.99(m,2H,Ar-H),7.82–7.71(m,2H,Ar-H),7.70–7.66(m,2H,Ar-H),7.66–7.61(m,1H,Ar-H),7.56–7.46(m,5H,Ar-H),7.41–7.33(m,1H,Ar-H),4.48(s,2H,CH₂).¹³C NMR(101MHz,DMSO-d₆)δ196.15,167.07,138.75,135.87,135.76,133.87,132.82,131.97,131.72,130.63,129.17,129.12,128.91,126.18,122.45,115.98,31.69.

compound 4 c: beige solid, melting point 300-301 ℃, yield 97 percent R_f0.12 (petroleum ether: ethyl acetate (V/V) ═ 1:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ12.80(s,1H,COOH),10.70(s,1H,NH),8.05–7.99(m,2H,Ar-H),7.95–7.91(m,2H,Ar-H),7.87–7.73(m,4H,Ar-H),7.67–7.60(m,1H,Ar-H),7.51(t,J＝7.7Hz,3H,Ar-H),7.38(t,J＝7.5Hz,1H,Ar-H),4.49(s,2H,CH₂).¹³C NMR(101MHz,DMSO-d₆)δ196.12,167.40,167.34,143.46,135.75,135.71,133.89,132.91,131.85,130.76,130.65,129.18,129.14,129.08,126.19,126.11,119.76,31.67.

compound 4 d: yellow solid, melting point 114-115 ℃, yield 54%, R_f0.31 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.30(s,1H,NH),8.04–7.99(m,2H,Ar-H),7.78(d,J＝8.0Hz,1H,Ar-H),7.73(d,J＝6.2Hz,1H,Ar-H),7.68–7.43(m,6H,Ar-H),7.40–7.31(m,1H,Ar-H),7.14(d,J＝8.2Hz,2H,Ar-H),4.46(s,2H,CH₂),2.27(s,3H,Ar-CH₃).¹³C NMR(101MHz,DMSO-d₆)δ196.22,166.79,136.85,136.09,135.79,133.85,133.27,132.86,131.51,130.40,129.49,129.17,129.12,128.81,126.08,120.58,31.58,20.97.

compound 4 e: yellow solid, melting point 114-115 ℃, yield 65%, R_f0.37 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ9.98(s,1H,NH),8.06–8.00(m,2H,Ar-H),7.85–7.77(m,2H,Ar-H),7.67–7.61(m,1H,Ar-H),7.55–7.47(m,3H,Ar-H),7.40–7.14(m,5H,Ar-H),4.47(s,2H,CH₂),2.19(s,3H,CH₃).

compound 4 f: beige solid, melting point 143-144 ℃, yield 38%, R_f0.36 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.33(s,1H),8.05–7.98(m,2H),7.79(d,J＝6.9Hz,1H),7.74(d,J＝6.2Hz,1H),7.68–7.59(m,1H),7.60–7.42(m,5H),7.36(t,J＝7.0Hz,1H),7.22(t,J＝7.8Hz,1H),6.92(d,J＝7.5Hz,0H),4.47(s,2H),2.30(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ196.19,166.94,139.29,138.32,136.02,135.73,133.87,132.88,131.57,130.39,129.18,129.15,128.97,128.87,126.08,124.98,121.02,117.74,31.52,21.69.

compound 4 g: beige solid, melting point 105-106 ℃, yield 38%, R_f0.36 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.16(s,1H,NH),8.05–8.01(m,2H,Ar-H),7.86(d,J＝7.7Hz,0H),7.80(d,J＝8.1Hz,1H),7.67–7.62(m,1H),7.57–7.49(m,5H),7.38(tt,J＝7.7,1.5Hz,2H),7.30(td,J＝7.7,1.7Hz,1H),4.47(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ196.31,167.10,135.83,135.18,134.42,133.88,133.85,131.94,130.27,130.06,129.81,129.16,129.02,128.76,128.07,127.95,126.03,31.56.

compound 4 h: yellow solid, melting point 170-171 ℃, yield 54%, R_f0.30 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.95(s,1H),8.28–8.22(m,2H),8.03–7.99(m,2H),7.85–7.76(m,2H),7.66–7.59(m,1H),7.52(tdd,J＝7.3,5.8,1.5Hz,5H),7.40(t,J＝7.0Hz,0H),4.50(s,2H).

compound 4 i: beige solid, melting point of 127-128 ℃, yield of 29 percent, R_f0.36 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ8.06–7.99(m,2H),7.89(s,1H),7.70(d,J＝6.9Hz,1H),7.67–7.62(m,1H),7.57–7.49(m,3H),7.39(td,J＝7.7,1.5Hz,1H),7.25(td,J＝7.5,1.1Hz,1H),4.39(s,2H),1.33(s,9H).¹³C NMR(101MHz,DMSO-d₆)δ196.44,168.17,137.16,135.87,133.81,132.30,130.81,130.02,129.14,128.55,125.81,51.38,31.50,28.94.

example five: synthesis of 8 compounds belonging to formula v:

dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of dichloromethane solvent containing 10mmol of p-hydroxyacetophenone, stirring at room temperature for 12 hours, and adding 1mmol of different R₂And (3) continuing stirring the amine substituted by the functional group at room temperature for 1h, concentrating under reduced pressure to dryness, adding 20mL of distilled water to wash residues, filtering, and recrystallizing the crude product with acetone/water (5: 1, V/V), separating and purifying to obtain a pure compound for 5 a-5 h.

Compound 5 a: yellow solid, melting point 140-141 ℃, yield 58%, R_f0.32 (petroleum ether: ethyl acetate (V/V) ═ 3:1), and the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.46(s,1H,Ar-OH),10.42(s,1H,NH),7.91(d,J＝8.8Hz,2H,Ar-H),7.80(d,J＝8.1Hz,1H,Ar-H),7.78–7.68(m,3H,Ar-H),7.48(t,J＝7.7Hz,1H,Ar-H),7.39–7.32(m,3H,Ar-H),7.11(t,J＝7.4Hz,1H,Ar-H),6.85(d,J＝8.8Hz,2H,Ar-H),4.37(s,2H,CH₂).¹³C NMR(101MHz,DMSO-d₆)δ194.56,167.04,162.77,139.40,136.03,133.18,131.79,131.56,130.48,129.15,128.84,127.29,125.99,124.29,120.55,115.71,31.46.

compound 5 b: beige solid, melting point 142-143 ℃, yield 29%, R_f0.28 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.51(s,1H,NH),10.42(s,1H,Ar-OH),7.92–7.88(m,2H,Ar-H),7.79(d,J＝8.0Hz,1H,Ar-H),7.77–7.66(m,4H,Ar-H),7.56–7.44(m,2H,Ar-H),7.43–7.32(m,3H,Ar-H),6.84(d,J＝8.8Hz,2H,Ar-H),4.37(s,2H,CH₂).¹³C NMR(101MHz,DMSO-d₆)δ194.50,167.10,162.77,138.37,135.90,133.13,131.76,130.66,129.57,129.06,128.84,127.89,127.32,126.06,122.07,115.71,31.58.

compound 5 c: beige solid, melting point 154-156 ℃, yield 31 percent, R_f0.30 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.54(s,1H,Ar-OH),10.46(s,1H,NH),7.90(d,J＝8.7Hz,2H,Ar-H),7.79(d,J＝8.3Hz,1H,Ar-H),7.76–7.66(m,3H,Ar-H),7.57–7.45(m,3H,Ar-H),7.36(t,J＝7.5Hz,1H,Ar-H),6.84(d,J＝8.8Hz,2H,Ar-H),4.37(s,2H,CH₂).¹³C NMR(101MHz,DMSO-d₆)δ194.51,167.10,162.77,138.78,135.76,133.21,131.98,131.78,131.71,130.57,128.87,127.27,126.03,122.41,115.97,115.70,31.51.

compound 5 d: beige solid, melting point 156-158 ℃, yield 37%, R_f0.33 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.42(s,1H),10.29(s,1H),7.92–7.87(m,2H),7.78(d,J＝7.0Hz,1H),7.72(d,J＝6.1Hz,1H),7.59(d,J＝8.3Hz,2H),7.47(td,J＝7.6,1.5Hz,1H),7.35(td,J＝7.5,1.1Hz,1H),7.15(d,J＝8.2Hz,2H),6.86–6.81(m,2H),4.35(s,2H),2.28(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ194.58,166.84,162.76,136.88,136.12,133.25,133.15,131.75,131.46,130.46,129.50,128.74,127.34,125.97,120.58,115.70,31.48,20.97.

compound 5 e: white solid, melting point 150-152 ℃, yield 67%, R_f0.25 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.45(s,1H,Ar-OH),9.97(s,1H,NH),7.93–7.89(m,2H,Ar-H),7.83–7.76(m,2H,Ar-H),7.48(t,J＝6.9Hz,1H,Ar-H),7.38–7.29(m,3H,Ar-H),7.26(d,J＝7.3Hz,1H,Ar-H),7.25–7.12(m,2H,Ar-H),6.85(d,J＝8.7Hz,2H,Ar-H),4.35(s,2H,CH₂),2.21(s,3H,CH₃).¹³C NMR(101MHz,DMSO-d₆)δ194.68,167.11,162.73,136.51,135.41,134.01,133.63,131.79,131.55,130.81,130.31,128.76,127.33,126.87,126.56,126.48,125.93,115.68,31.40,18.43.

compound 5 f: beige solid, melting point 263-265 ℃, yield 61%, R_f0.25 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ12.83(s,1H,-COOH),10.71(s,1H,NH),10.45(s,1H,Ar-OH),7.98–7.74(m,8H,Ar-H),7.50(t,J＝7.6Hz,1H,Ar-H),7.37(t,J＝7.5Hz,1H,Ar-H),6.84(d,J＝8.8Hz,2H,Ar-H),4.38(s,2H,CH₂).¹³C NMR(101MHz,DMSO-d₆)δ194.47,167.40,167.22,162.79,143.48,135.89,133.15,131.77,130.97,130.76,128.98,127.31,126.14,126.10,123.87,119.78,115.72,31.64.

compound 5 g: beige solid, melting point 206-207 ℃, yield 24%, R_f0.12 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ13.75(s,1H,-COOH),11.97(s,1H,NH),10.44(s,1H,Ar-OH),8.59(d,J＝8.4Hz,1H,Ar-H),8.05(d,J＝7.8Hz,1H,Ar-H),7.96–7.81(m,4H,Ar-H),7.66(t,J＝7.9Hz,1H,Ar-H),7.53(t,J＝7.6Hz,1H,Ar-H),7.41(t,J＝7.5Hz,1H,Ar-H),7.23(t,J＝7.6Hz,1H,Ar-H),6.85(d,J＝8.3Hz,2H,Ar-H),4.39(s,2H,CH₂).¹³C NMR(101MHz,DMSO-d₆)δ194.62,170.27,166.39,162.80,141.13,134.89,134.73,134.53,132.28,131.77,131.73,130.51,127.97,127.38,126.28,123.75,120.44,117.38,115.72,31.53.

compound 5 h: beige solid, melting point 162-163 ℃, yield 39%, R_f0.33 (petroleum ether: ethyl acetate (V/V) ═ 3:1), the structure was analyzed by nuclear magnetic resonance hydrogen spectroscopy and carbon spectroscopy (NMR), and the results were as follows:¹H NMR(400MHz,DMSO-d₆)δ10.96(s,1H),10.42(s,1H),8.29–8.24(m,2H),8.01–7.96(m,2H),7.92–7.87(m,2H),7.85–7.75(m,2H),7.51(td,J＝7.6,1.5Hz,1H),7.39(td,J＝7.5,1.1Hz,1H),6.86–6.79(m,2H),4.40(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ194.40,167.65,162.79,145.63,143.06,135.54,133.23,132.03,131.77,130.98,129.12,127.28,126.19,125.33,120.17,115.71,31.76.

example six: synthesis of 2 compounds belonging to formula VI:

dissolving 0.25g (1mmol) of 2-chloroseleno-benzoyl chloride (a) in 5mL of butanone, stirring for 15 minutes at room temperature, adding 1mmol of ethylenediamine or o-phenylenediamine, stirring for 15 minutes at room temperature, concentrating under reduced pressure to dryness, adding 20mL of distilled water, washing residues, filtering, recrystallizing the crude product with acetone/water (1: 5, V/V), separating and purifying to obtain pure compounds 6 a-6 b respectively.

Compound 6 a: beige solid, melting point: 83.6-85.2 ℃, and the yield is 76%;¹H NMR(400MHz,CDCl₃)δ8.19–8.16(m,2H,Ar-H),7.65–7.62(m,2H,Ar-H),7.55–7.49(m,2H,Ar-H),7.32–7.29(m,2H,Ar-H),4.07(q,J＝7.2Hz,2H),2.35(s,6H,CH₃),1.66(d,J＝7.1Hz,6H,CH₃),1.08(t,J＝7.3Hz,4H,CH₂).¹³C NMR(101MHz,CDCl₃)δ207.42,171.78,137.49,133.82,132.75,128.96,128.17,125.54,44.57,33.98,25.60,16.11.

compound 6 b: beige solid, melting point: 112.9-114.3 ℃, and the yield is 77%;¹H NMR(400MHz,CDCl₃)δ9.03(s,2H,NH),7.73(d,J＝7.7Hz,2H,Ar-H),7.71–7.58(m,4H,Ar-H),7.44–7.34(m,4H,Ar-H),7.23(t,J＝5.5Hz,2H,Ar-H),3.94–3.85(m,2H,CH),2.20(d,J＝5.6Hz,6H,CH₃),1.50–1.44(m,6H,CH₃).¹³C NMR(101MHz,CDCl₃δ206.78,167.63,137.24,133.66,131.41,130.28,128.46,128.43,127.55,126.61,125.48,45.84,26.26,16.18

screening the anticancer activity:

MTT cytotoxicity assay: the esophageal cancer EC109 cell line is selected as a test cell line model with in vitro anti-cancer activity. The above cells were grown in RPMI-1640 complete medium containing 10% fetal bovine serum, 100U/mL penicillin and 100mg/mL streptomycin. The cells were cultured in a 37 ℃ incubator containing 5% carbon dioxide. Digesting SGC7901 (or EC109, A549) cells in logarithmic growth phase by pancreatin containing EDTA, placing in a 15mL centrifuge tube, and centrifuging for 4min at room temperature of 800 rpm; discarding supernatant, adding RPMI-1640 complete culture medium, and beating uniformly; adding 20 mu L of cell suspension into a counting plate hole, and counting; inoculating 100 mu L of EC109 cell suspension into a 96-well plate (the number of cells is about 5000 per well), and culturing overnight in a cell culture box at 37 ℃ to allow the cells to adhere to the wall; the supernatant was aspirated off, 100. mu.L of fresh medium was added, and 20. mu.L of each of the 9 compounds of formula IV (compound concentration 100. mu.g/mL, drug dissolved in DMSO) was added to each well; after the drug acts for 24 hours, observing the survival condition of the cells, adding 25 mu L of MTT (the concentration is 5mg/mL, and the dissolved preparation is performed by PBS) into each hole, continuously culturing for more than 4 hours, completely sucking supernatant, adding 150 mu L of DMSO, dissolving crystals, and oscillating for 10min in a dark place at room temperature; reading the OD value at 490nm of an enzyme-labeling instrument, and calculating the inhibition rate according to the formula of the inhibition rate percent 1-addition medicine OD value/negative group OD value multiplied by 100%. The results are shown in table 1 below.

TABLE 1 coarse screening of esophageal cancer cell inhibition (100. mu.g/mL)

CCK-8 cell inhibition assay: the cell lines are selected from human glioblastoma cell lines U251-MG and U87-MG; human triple negative breast cancer cell line MDA-MB-231; human colon cancer cell lines HCT116 and SW 620. The test method comprises the following steps: selecting cells in logarithmic growth phase, digesting with pancreatin, inoculating into 96-well culture plate with cell density of 3000 cells/100 μ l, 37 deg.C, and 5% CO₂And culturing for 24 h. After 24 hours, the medium is discarded and serum-free medium is added: (Or 1% serum-containing medium) for 24 hours (or overnight). Changing the culture medium to 190 μ l fresh complete culture medium before experiment, adding 10 μ l sample (final concentration monomer compound 5 μ g/ml) of the initial concentration into the experimental group, changing the culture medium containing equal volume of solvent into the control group, 37 deg.C, and 5% CO₂The culture was carried out for 3 days. Discard media 100. mu.L of serum-free media containing 10% CCK-8 was added to each well. Incubating the culture plate in an incubator for 1-4 hours, measuring absorbance at 450nm with a microplate reader, and determining the tumor cell growth inhibition rate (%) (OD)_Control-OD_{Experiment of})/(OD_Control-OD_{Blank space}) Inhibition was calculated 100%. The results are shown in table 2 below.

TABLE 2 preliminary screening results (5. mu.g/mL) for the inhibition rate of 43 compounds of formulas I to VI in vitro

Compound 6b was rescreened at a rescreening concentration of (0.1-10. mu.g/ml) and IC calculated₅₀Values for human glioblastoma cell lines U251-MG and U87-MG; human triple negative breast cancer cell line MDA-MB-231; IC of five cells of human colon cancer cell lines HCT116 and SW620₅₀The values were 2.579. mu.M, 2.628. mu.M, 0.3335. mu.M, 1.008. mu.M, 1.253. mu.M, respectively. The results are shown in Table 3.

TABLE 3 Compound 6b rescreening results (5. mu.g/mL)

The anticancer activity data show that the cell inhibition rate coarse screening result of the table 1 shows that 9 compounds (100 mu g/mL) described in the formula IV have certain inhibition effect on the esophageal cancer EC109 cells.

Further, the results of the preliminary screening of the cell inhibition rate in table 2 show that the 43 selenoether amide compounds shown in formulas I to VI respectively show differential inhibition on five cancer cell lines, namely, human glioblastoma cell line U251-MG and U87-MG, human triple-negative breast cancer cell line MDA-MB-231, human colon cancer cell line HCT116 and SW620, at the screening concentration of 5 μ g/mL, wherein the compound 6b >5b >5g >1h >2d has inhibition on the human glioblastoma cell line U251-MG cell line; the obvious compound 6b has more than 90% inhibition rate (91.01% and 96.18% respectively) on two cell strains of human glioblastoma cell lines U251-MG and U87-MG, and is superior to the results of a 5-fluorouracil positive drug control group (84.59% and 86.31% respectively). The compound 6b >1g >1n >1q >4a has an inhibition effect on a human triple negative breast cancer cell line MDA-MB-231 cell line, and the inhibition effect of the compound 6b is most obvious (the inhibition rate is 98.11 percent) and is better than the result of a 5-fluorouracil positive drug control group (84.59 percent). Remarkably, the 43 seleno-etheramide compounds shown in the formulas I to VI generally show inhibition effect on human colon cancer cell line SW620 cell lines under the screening concentration of 5 mu g/mL, and the inhibition effect is more remarkable in that the compounds 6b >1q >1I >1k >1f >2d >4c >6a, and the compounds 6b have inhibition rates of more than 98% (respectively 98.99% and 99.03%) on human colon cancer cell line HCT116 and SW620 cell lines, and are superior to the control results of 5-fluorouracil positive drugs (respectively 85.87% and 81.83%).

Table 3 further rescreens the cytotoxic activity of Compound 6b at concentrations (0.1-10. mu.g/ml) and calculates IC₅₀Values, results show that IC of Compound 6b on five cells of human glioblastoma cell lines U251-MG and U87-MG, human triple negative breast cancer cell line MDA-MB-231, human colon cancer cell line HCT116 and SW620₅₀The values were 2.579. mu.M, 2.628. mu.M, 0.3335. mu.M, 1.008. mu.M, 1.253. mu.M, respectively.

The research results support the anticancer function application of the structural characteristics of the selenoamides shown in the formulas I to VI, and the anticancer activity examples of the compounds can show that the compounds have obvious cancer inhibition activity on human glioblastoma, esophageal cancer, lung cancer, gastric cancer, colon cancer, liver cancer, breast cancer, leukemia, ovarian cancer, cervical cancer, prostate cancer, oral cancer or tongue cancer and the like.

Human thioredoxin reductase (TrxR 1) virtual molecule docking:

the 43 compounds described in formulas I-VI are used as potential molecules of human thioredoxin reductase (TrxR 1) inhibitors, and virtual activity screening is completed through computer molecule docking simulation, and the method comprises the following steps: the structure of the ligand small molecules was mapped by ChemDraw Ultra 8.0 software and stored in MDL molfield (x, mol) format. The plotted molecular structure of the ligand was hydrotreated by Open Babel GUI software at pH 7.2. SYBYL-X2.0 software is used for completing the site optimization of ligand small molecules and the establishment of a molecule database, receptor protein is directly downloaded from an RCSB PDB protein database (http:// www.rcsb.org /), the downloading format is a PDB format, and a protein card (PDB:2ZZ0) of human thioredoxin reductase is obtained by downloading. The 3D structure of the ligand molecule was performed by the SYBYL program (St. Louis Tripos, USA), and the energy-minimizing mechanism was hydroprocessing with the help of the Tripos force field using Gasteiger-Huckel. Docking of TrxR 1 with ligands docking studies were performed on the Surflex-Dock program for hydrotreating target proteins and removing water molecules and other residues using Gasteiger-Huckel. TrxR 1 is subjected to docking preparation and molecular docking work by a Surflex-Dock program in SYBYL-X2.0 software, and other various parameters are endowed with default values for the software. The molecular docking analysis is completed by means of a Surflex-Dock module in SYBYL-X2.0, after TrxR 1 target protein is optimized, an A/FAD-900 micromolecule ligand in the target protein is extracted to perform molecular docking with a ligand micromolecule in an established ligand micromolecule database, and the inhibitory activity of TrxR 1 is evaluated by using 43 compounds in formulas I-VI according to the high and low analysis values of Total-Score. The results are shown in Table 4.

TABLE 4 molecular docking results of 43 compounds described in formulas I-VI with human thioredoxin reductase target protein (2ZZ0)

The virtual molecular docking results in table 4 show that the 43 compounds shown in formulas I to VI all have stronger affinity with human thioredoxin reductase (TrxR 1) than positive drug ebselen, which indicates that the series of selenoether amide compounds of the present invention have the potential as human thioredoxin reductase inhibitors superior to ebselen. The compound 6b with the most outstanding cancer inhibition activity has a molecular docking result score of more than 8, and further shows that the action mechanism of the compound for inhibiting cancer is related to the inhibition of the human thioredoxin reductase.

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.