Seleno-lactone compound and application thereof

Abstract

The invention relates to a selenolactone compound. The preparation method comprises the following steps: firstly, chemically synthesizing a chiral selenium-containing alpha-exo-methylene lactone compound 1 to improve the selectivity of the compound 1 to tumor cells; then, a hydrophilic group is adopted to attack alpha-exo-methylene lactone to obtain a selenolactone-containing compound 2, the water solubility of the selenolactone-containing compound 2 is enhanced, tumor cells are expected to preferentially uptake a selenolactone-containing prodrug 2, then methylation is carried out under the action of in-vivo SAM enzyme to generate ammonia positive ions I, and finally alpha-exo-methylene lactone warheads 1 are released; therefore, the selectivity of the anti-tumor effect is improved. The selenolactone compound provided by the invention can effectively inhibit proliferation of various cancer cells, and has good selectivity to tumor cells; meanwhile, the growth speed and volume of tumors in vivo can be remarkably inhibited, and the compound has excellent anti-tumor activity and good safety. The invention provides sufficient scientific basis and theoretical basis for exploring the development of selenium antitumor drugs, and has important social value and scientific significance.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical medicine, in particular to selenolactone compounds and applications thereof. Background Art

[0002] Research on designing and synthesizing selenium-containing molecules for cancer treatment has attracted widespread attention because tumor cells are more sensitive to selenium-containing compounds than normal cells, and after being treated with selenium-containing compounds, tumor cells are more likely to undergo natural apoptosis and block angiogenesis, thereby preventing tumor progression and invasion.

[0003] Selenium-containing compounds are generally considered antioxidants, known for their ability to maintain the redox balance of normal cells. For example, replacing the sulfur in cysteine ​​with selenium can protect normal cells from the toxic effects of reactive oxygen species (ROS). Studies have shown that selenium-containing molecules (including organic and inorganic selenium compounds) can promote cell growth at low concentrations, while exhibiting cytotoxic activity at high concentrations. Consequently, selenium-containing compounds have been reported to exhibit cytotoxic activity, inhibiting cell proliferation and inducing apoptosis, representing a new strategy for cancer treatment. Furthermore, as an essential trace element for the human body, incorporating selenium into active molecules has the potential to be a relatively safe approach to cancer treatment. Many selenium-containing compounds enhance drug efficacy without exhibiting the toxic side effects often associated with selenium. Therefore, selenium-containing compounds hold great potential in drug development. Summary of the Invention

[0004] The present invention aims to address the problems existing in the prior art and thus provides a selenolactone compound and its application. The selenolactone compound provided by the present invention can effectively inhibit the proliferation of various cancer cells and has good selectivity for tumor cells. It can also significantly inhibit the growth rate and volume of tumors in vivo, has excellent anti-tumor activity, and is safe.

[0005] To achieve the above object, the present invention is achieved by the following means: The first aspect of the present invention provides a selenolactone compound, the structural formula of which is shown in Formula I: ; Where n = 1 or 2; Ar is selected from aromatic rings; R 1 A phenyl group selected from hydrogen, a C1-C8 alkyl group, a C1-C8 heterocyclic group, a phenyl group, a halophenyl group or a phenyl group substituted with a hydroxyl group; R 2 is selected from hydrogen, C1~C8 alkyl, C1~C8 heterocyclic group or phenyl; R 3 is selected from hydrogen, C1~C8 alkyl, C1~C8 heterocyclic group or phenyl.

[0006] Preferably, the C1~C8 alkyl group is selected from one or more of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, n-heptyl, isoheptyl, neoheptyl, sec-heptyl, tert-heptyl, n-octyl, isooctyl, neooctyl, sec-octyl, and tert-octyl.

[0007] Preferably, the C1-C8 heterocyclic group is selected from one or more of pyrrole, piperidine, cycloheximide, morpholine, thiomorpholine, piperazine, and 4-methylpiperazine.

[0008] Preferably, the selenolactone compound is selected from one or more of the following compounds: 3-((Dimethylamino)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2a), 3-((Dimethylamino)methyl)-5-phenyl-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2b), 3-((Dimethylamino)methyl)-5-(4-fluorophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2c), 3-((Dimethylamino)methyl)-5-(4-chlorophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2d), 3-((Dimethylamino)methyl)-5-(4-bromophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2e), 3-((Dimethylamino)methyl)-5-(4-trifluoromethylphenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2f), 3-((Dimethylamino)methyl)-5-(4-methoxyphenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2 g), 5-(3,4-difluorophenyl)-3-((dimethylamino)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2h), 5-(3,4-Dichlorophenyl)-3-((dimethylamino)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2i), 3-((Dimethylamino)methyl)-5-benzyl-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2j), 3-((Dimethylamino)methyl)-5-methyl-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2k), 3-((Dimethylamino)methyl)-5-(iodomethyl)-5-phenyl-dihydrofuran-2(3H)-one (2l), 3-((Dimethylamino)methyl)-5-phenyl-5-((phenyl(phenylselenyl)methyl)dihydrofuran-2(3H)-one (2m), 4'-((Dimethylamino)methyl)-5-(phenylselenyl)-3',4',5,7,8,9-6-hydro-5'H-spiro[phenyl[7]annulene-6,2'-furan]-5'-one (2n), 6-(4-Bromophenyl)-3-((dimethylamino)methyl)-6-((phenylselenyl)methyl)tetrahydro-2H-pyran-2-one (2o), 5-(4-Chlorophenyl)-5-((phenylselenyl)methyl)-3-(pyrrolylmethyl)dihydrofuran-2(3H)-one (2p), 5-(4-Chlorophenyl)-5-((phenylselenyl)methyl)-3-(piperidinylmethyl)dihydrofuran-2(3H)-one (2q), 3-(Cyclohexyliminomethyl)-5-(4-chlorophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2r), 5-(4-Chlorophenyl)-3-((morpholinyl)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2s), 5-(4-Chlorophenyl)-3-((thiomorpholinyl)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2t), 5-(4-Chlorophenyl)-3-((piperazinyl)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2u), 5-(4-chlorophenyl)-3-((4-methylpiperazinyl)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2v), 5-(4-chlorophenyl)-3-((methylamino)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one (2w), 5-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((4-fluorophenylselenyl)methyl)dihydrofuran-2(3H)-one (2x), 5-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((4-chlorophenylselenyl)methyl)dihydrofuran-2(3H)-one (2y), 5-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((4-methoxyphenylselenyl)methyl)dihydrofuran-2(3H)-one (2z), 5-(4-Chlorophenyl)-3-((dimethylamino)methyl)-5-((phenylthio)methyl)dihydrofuran-2(3H)-one (2zz).

[0009] The second aspect of the present invention provides the use of one or more of the above-mentioned selenolactone compounds, pharmaceutically acceptable salts thereof or solvates thereof in the preparation of drugs for treating tumors.

[0010] Preferably, the tumor is selected from one or more of brain tumor, lung cancer and breast cancer.

[0011] The third aspect of the present invention provides a pharmaceutical composition for treating tumors, comprising the above-mentioned selenolactone compound, one or more of its pharmaceutically acceptable salts or solvates, and a pharmaceutically acceptable carrier.

[0012] Preferably, the tumor is selected from one or more of brain tumor, lung cancer and breast cancer.

[0013] Preferably, the pharmaceutically acceptable carrier includes one or more of a filler, a binder, a disintegrant, a solvent, a preservative, a lubricant, and a flavoring agent.

[0014] The present invention first chemically synthesizes chiral selenium-containing α- exo- Methylene lactone compound 1 improves its selectivity for tumor cells; then a hydrophilic group, such as dimethylamine, is used to attack α- exo- Methylene lactone obtains selenolactone compound 2, which enhances its water solubility. It is expected that tumor cells will preferentially take up selenolactone prodrug 2, which will then be methylated to generate ammonia cation I under the action of SAM (S-adenosylmethionine, S-adenosylmethionine) enzyme in the body, and finally release α- exo- Methylene lactone warhead 1, thereby achieving enhanced selectivity in anti-tumor effects. The selenolactone compounds prepared by the present invention can effectively inhibit the proliferation of various cancer cells and have good selectivity for tumor cells. They can also significantly inhibit the growth rate and volume of tumors in vivo, exhibiting excellent anti-tumor activity and good safety. This invention provides a sufficient scientific basis and theoretical foundation for the development of selenium-based anti-tumor drugs and has important social value and scientific significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 Schematic diagram of the mechanism of action of selenolactone.

[0016] Figure 2Schematic diagram of the cytotoxic effects of compounds 2a-2o.

[0017] Figure 3 Schematic diagram of the cytotoxic effect of compound 2p-2zz.

[0018] Figure 4 Schematic diagram of the tumor inhibition activity of compound 2d on mice; (A) is a schematic diagram of the tumor inhibition rate; (B) is a schematic diagram of the average tumor volume; and (C) is a schematic diagram of the average body weight. DETAILED DESCRIPTION

[0019] In order to make the purpose, technical solution and effect of the present invention clearer and more specific, the present invention is further described in detail with reference to the following examples. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0020] Unless otherwise specified, the cell lines used in the present invention, including U87 (human glioblastoma), C6 (rat glioma), 4T1 (mouse breast cancer), A549 (lung cancer, EGFR-overexpressing), and HEK293T, were cultured according to ATCC guidelines. All cell lines were authenticated by short tandem repeat analysis at the China Center for Type Culture Collection (Wuhan) and verified for mycoplasma contamination using a PCR detection kit (Shanghai Biothrive Sci). They were then frozen in liquid nitrogen and used for subsequent experiments. The reagents and consumables used in the present invention were commercially available or prepared according to conventional methods. The various chemical reaction starting materials, intermediates, and catalysts used in the present invention were commercially available or synthesized. The experimental methods used in the present invention, such as cell culture, cell proliferation assays, and animal experiments, are conventional methods and techniques in the art. The English abbreviations used in the present invention are interpreted according to common understanding in the art, e.g., Me represents methyl, Ph represents phenyl, Bn represents benzyl, NMR represents nuclear magnetic resonance, and HRMS represents high-resolution mass spectrometry.

[0021] Representative results from replicates are presented in the accompanying figures. Data are presented as mean ± SD as indicated in the figures. All experiments were repeated at least three times. Data were analyzed using GraphPad Prism 8.0. Student's t-test or analysis of variance was used to compare the mean values ​​of two or more groups. p A difference of <0.05 was considered significant.

[0022] Example 1 Preparation of 3-((dimethylamino)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0023] The specific steps involved were as follows: 1a (268.1 mg, 1.0 mmol) was dissolved in acetone (4 mL), and dimethylamine (90.0 mg, 2.0 mmol) was added at room temperature. After the reaction was completed at room temperature, the solvent was removed by rotary evaporation. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2a (250.4 mg, 80% yield) as a light yellow oil. The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.57-7.30 (m, 5H), 4.75-4.52 (m, 1H), 3.35-1.76 (m, 7H), 2.26 (s, 6H); 13 CNMR (CDCl3, 100MHz): d177.8, 133.3, 129.4, 127.7, 59.9, 45.5, 40.1, 38.5, 34.7, 32.1; HRMS (TOF) m / z: [M+H] + Calcd for C 14 H 19 NO2Se314.2748; found 314.2749.

[0024] Example 2 Preparation of 3-((dimethylamino)methyl)-5-phenyl-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0025] The reaction process involved the following steps: 1b (344.1 mg, 1.0 mmol) was dissolved in acetone (4 mL), and dimethylamine (90.0 mg, 2.0 mmol) was added at room temperature. After the reaction was complete, the solvent was removed by rotary evaporation. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2b (338.4 mg, 87% yield) as a pale yellow oil.

[0026] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.47-7.23 (m, 10H), 3.56 (dd, J 1 =12.0Hz, J 2 =52.0Hz, 2H), 2.91-2.54 (m, 4H), 2.24 (s, 6H); 13CNMR (CDCl3, 100MHz): d176.8, 141.9, 133.3, 130.3, 129.3, 128.7, 128.2, 127.4, 124.9, 86.4, 59.5, 45.6, 41.4, 39.8, 39.1; HRMS (TOF) m / z: [M+H] + Calcd for C 20 H 23 NO2Se 390.1784; found 390.1785.

[0027] Example 3 Preparation of 3-((dimethylamino)methyl)-5-(4-fluorophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0028] The reaction process involved dissolving 1c (362.2 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction was complete, the solvent was removed by rotary evaporation. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2c (346.0 mg, 87% yield) as a yellow oil.

[0029] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.45-7.00 (m, 9H), 3.51-3.35 (m, 2H), 2.91-2.31 (m, 5H), 2.23 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.5, 163.7 (d, J =246.0Hz), 137.6, 133.3, 127.4, 126.9 (d, J =8.0Hz), 115.7(d, J =22.0Hz), 86.1, 59.4, 45.6, 41.4, 39.8, 39.2, 38.5; HRMS (TOF) m / z: [M+H] + Calcd for C 20 H 22 FNO2Se 408.3329; found408.3328.

[0030] Example 4 Preparation of 3-((dimethylamino)methyl)-5-(4-chlorophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0031] The reaction process involved the following steps: 1d (378.0 mg, 1.0 mmol) was dissolved in acetone (4 mL), and dimethylamine (90.0 mg, 2.0 mmol) was added at room temperature. After the reaction was complete, the solvent was removed by rotary evaporation. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2d (363.8 mg, 86% yield) as a yellow oil.

[0032] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.45-7.22 (m, 9H), 3.50-3.19 (m, 2H), 3.11-2.31 (m, 5H), 2.16 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.5, 140.3, 134.2, 133.4, 129.2, 128.8, 127.5, 126.5, 86.0, 59.4, 45.5, 41.2, 39.8, 39.1; HRMS (TOF) m / z: [M+H] + Calcd for C 20 H 22 ClNO2Se 424.2046; found 424.2047.

[0033] Example 5 Preparation of 3-((dimethylamino)methyl)-5-(4-bromophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0034] The reaction process involved dissolving 1e (422.0 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction was complete, the solvent was removed by rotary evaporation. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2e (411.0 mg, 88% yield) as a yellow oil.

[0035] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.47-7.22 (m, 9H), 3.50-3.34 (m, 2H), 3.18-2.30 (m, 5H), 2.23 (s, 6H); 13CNMR (CDCl3, 100MHz): d176.5, 140.3, 134.2, 133.4, 129.2, 128.8, 127.5, 126.5, 86.0, 59.4, 45.5, 41.2, 39.8, 39.1; HRMS (TOF) m / z: [M+H] + Calcd for C 20 H 22 BrNO2Se 468.1962; found 468.1963.

[0036] Example 6 Preparation of 3-((dimethylamino)methyl)-5-(4-trifluoromethylphenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0037] The reaction process involved the following steps: 1f (412.2 mg, 1.0 mmol) was dissolved in acetone (4 mL), followed by the addition of dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction was complete, the solvent was removed by rotary evaporation. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2f (388.5 mg, 85% yield) as a yellow oil.

[0038] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.61-7.17 (m, 9H), 3.52-3.37 (m, 2H), 3.19-2.46 (m, 5H), 2.23 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.3, 145.8, 133.4, 129.8, 129.2, 127.6, 125.6 (q, J =40.0Hz), 86.0, 59.4, 45.6, 41.0, 39.9, 39.0; HRMS (TOF) m / z: [M+H] + Calcd for C 21 H 22 F3NO2Se 458.4229; found 458.4230.

[0039] Example 7 Preparation of 3-((dimethylamino)methyl)-5-(4-methoxyphenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0040] The method involves dissolving 1 g (374.1 mg, 1.0 mmol) of the compound in 4 mL of acetone, then adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to yield 2 g (398.1 mg) of the compound, with a yield of 95%, as a yellow oil.

[0041] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.46-6.87 (m, 9H), 3.82 (s, 3H), 3.54-3.37 (m, 2H), 2.97-2.49 (m, 5H), 2.24 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.4, 159.5, 133.2, 129.1, 127.3, 126.3, 114.0, 86.6, 59.3, 55.3, 45.2, 41.5, 39.7, 39.0; HRMS (TOF) m / z: [M+H] + Calcd for C 21 H 25 NO3Se 420.4718; found 420.4719.

[0042] Example 8 Preparation of 5-(3,4-difluorophenyl)-3-((dimethylamino)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0043] The method involves dissolving 1h (380.1 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2h (365.5 mg, 86% yield) as a yellow oil.

[0044] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.43-7.09 (m, 8H), 3.48-3.32 (m, 2H), 3.17-2.31 (m, 5H), 2.22 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.3, 151.2 (d, J=261.0Hz), 138.9, 133.3 (d, J =30.0Hz), 129.3, 127.7 (d, J =11.0Hz), 121.3, 121.2, 117.5, 114.9 (d, J =19.0Hz), 85.5, 59.4, 45.6, 41.1, 39.9, 39.8, 39.1, 38.4; HRMS (TOF) m / z: [M+H] + Calcd for C 20 H 21 F2NO2Se 426.3951; found 426.3952.

[0045] Example 9 Preparation of 5-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0046] The reaction process involved dissolving 1i (412.0 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction was complete, the solvent was removed by rotary evaporation. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2i (397.6 mg, 87% yield) as a yellow oil.

[0047] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.49-7.19 (m, 8H), 3.48-3.17 (m, 2H), 3.09-2.36 (m, 5H), 2.24 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.2, 142.0, 133.4, 133.1, 130.6, 129.2, 127.6, 127.4, 124.5, 85.5, 59.4, 45.6, 41.0, 39.8, 39.1; HRMS (TOF) m / z: [M+H] + Calcd for C 20 H 21 Cl2NO2Se 458.5291; found 458.5292.

[0048] Example 10 Preparation of 3-((dimethylamino)methyl)-5-benzyl-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0049] The method involves dissolving 1j (358.1 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2j (338.5 mg, 84% yield) as a yellow oil.

[0050] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.59-7.25 (m, 10H), 3.39-1.63 (m, 9H), 2.05 (s, 6H); 13 CNMR (CDCl3, 100MHz): d177.4, 135.2, 133.3, 131.0, 130.4, 129.4, 128.7, 127. 6, 127.3, 86.5, 60.0, 45.7, 45.1, 39.9, 38.6, 36.5, 34.6; HRMS (TOF) m / z: [M+H] + Calcd for C 21 H 25 NO2Se 404.6131; found 404.6132.

[0051] Example 11 Preparation of 3-((dimethylamino)methyl)-5-methyl-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0052] The specific steps involved were as follows: 1k (282.0 mg, 1.0 mmol) was dissolved in acetone (4 mL), and dimethylamine (90.0 mg, 2.0 mmol) was added at room temperature. After the reaction was completed at room temperature, the solvent was removed by rotary evaporation. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2k (271.4 mg, 83% yield) as a yellow oil.

[0053] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.58-7.28 (m, 5H), 3.24-2.45 (m, 6H), 2.20 (s, 6H), 1.95-1.89 (m, 1H), 1.57 (s, 3H); 13CNMR (CDCl3, 100MHz): d177.3, 133.0, 130.2, 129.4, 127.6, 84.7, 60.5, 45.3, 40.2, 38.7, 38.3, 28.0; HRMS (TOF) m / z: [M+H] + Calcdfor C 15 H 21 NO2Se 328.4046; found 328.4047.

[0054] Example 12 Preparation of 3-((dimethylamino)methyl)-5-(iodomethyl)-5-phenyl-dihydrofuran-2(3H)-one The preparation process is as follows:

[0055] The method involves dissolving 1l (314.0 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2l (312.1 mg, 87% yield) as a yellow oil.

[0056] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.43-7.36 (m, 5H), 3.69 (q, J =8.0Hz, 2H), 2.98-2.53 (m, 4H), 2.26 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.3, 139.9, 128.9, 128.7, 125.0, 84.3, 59.4, 45.6, 40.0, 39.4, 16.3; HRMS (TOF) m / z: [M+H] + Calcd for C 14 H 18 INO2 360.5167;found 360.5168.

[0057] Example 13 Preparation of 3-((dimethylamino)methyl)-5-phenyl-5-((phenyl(phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0058] The method involves dissolving 1m (420.1 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2m (395.3 mg, 85% yield) as a yellow oil.

[0059] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.40-7.02 (m, 15H), 4.48 (s, 1H), 3.23-2.67 (m, 5H), 2.27 (s, 6H); 13 CNMR (CDCl3, 100MHz): d177.1, 141.7, 137.8, 135.3, 130.3, 129.3, 128.5, 1 27.7, 126.0, 86.7, 60.5, 45.4, 41.6, 39.6, 35.7, 23.0; HRMS (TOF) m / z: [M+H] + Calcd for C 26 H 27 NO2Se 466.8012; found 466.8013.

[0060] Example 14 Preparation of 4'-((dimethylamino)methyl)-5-(phenylselenyl)-3',4',5,7,8,9-6-hydro-5'H-spiro[phenyl[7]annulene-6,2'-furan]-5'-one The preparation process is as follows:

[0061] The method involves dissolving 1n (429.2 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2n (360.4 mg, 84% yield) as a yellow oil.

[0062] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.44-6.60 (m, 9H), 4.48 (s, 1H), 3.23-2.67 (m, 5H), 2.27 (s, 6H); 13CNMR (CDCl3, 100MHz): d177.1, 140.9, 139.5, 134.9, 129.9, 129.5, 129.1, 128.1, 128.0 , 127.7, 127.6, 126.8, 125.4, 89.3, 61.2, 59.7, 45.5, 41.1, 38.3; HRMS (TOF) m / z: [M+H] + Calcd for C 23 H 27 NO2Se 430.5077; found 430.5078.

[0063] Example 15 Preparation of 6-(4-bromophenyl)-3-((dimethylamino)methyl)-6-((phenylselenyl)methyl)tetrahydro-2H-pyran-2-one The preparation process is as follows:

[0064] The method involves dissolving 1o (481.1 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2o (399.2 mg, 83% yield) as a yellow oil.

[0065] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.48-7.23 (m, 9H), 3.51-3.37 (m, 2H), 3.16-2.25 (m, 6H), 2.23 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.4, 140.8, 133.4, 131.8, 129.2, 127.5, 126.8, 122.4, 86.1, 59.4, 45.5, 45.3, 41.1, 39.8, 39.1; HRMS (TOF) m / z: [M+H] + Calcd for C 21 H 24 BrNO2Se 482.3729; found 482.3730.

[0066] Example 16 Preparation of 5-(4-chlorophenyl)-5-((phenylselenyl)methyl)-3-(pyrrolylmethyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0067] The method involves dissolving 1p (378.0 mg, 1.0 mmol) in acetone (4 mL) and adding tetrahydropyrrole (142.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2p (390.6 mg, 87% yield) as a yellow oil.

[0068] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.43-7.22 (m, 9H), 3.51-3.37 (m, 2H), 3.14-2.40 (m, 9H), 1.78-1.73 (s, 4H); 13 CNMR (CDCl3, 100MHz): d176.5, 140.3, 133.4, 129.2, 128.8, 127.5, 126.5, 86.0, 55.8, 54.4, 41.2, 40.3, 39.8, 23.5; HRMS (TOF) m / z: [M+H] + Calcd for C 22 H 24 ClNO2Se 450.4268; found 450.4267.

[0069] Example 17 Preparation of 5-(4-chlorophenyl)-5-((phenylselenyl)methyl)-3-(piperidinylmethyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0070] The method involves dissolving 1p (378.0 mg, 1.0 mmol) in acetone (4 mL) and adding hexahydropyridine (170.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2q (412.7 mg, 89% yield) as a yellow oil.

[0071] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.44-7.22 (m, 9H), 3.51-3.37 (m, 2H), 3.18-2.17 (m, 9H), 1.54-1.40 (s, 6H); 13CNMR (CDCl3, 100MHz): d176.9, 140.5, 133.4, 129.2, 128.8, 127.5, 126.5, 85.9, 58.8, 54.7, 41.2, 39.9, 8.9, 25.9, 24.1; HRMS (TOF) m / z: [M+H] + Calcd for C 23 H 26 ClNO2Se 464.7012; found 464.7013.

[0072] Example 18 Preparation of 3-(cyclohexyliminomethyl)-5-(4-chlorophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0073] The method involves dissolving 1p (378.0 mg, 1.0 mmol) in acetone (4 mL) and adding cycloheximide (198.1 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2r (412.7 mg, 87% yield) as a yellow oil.

[0074] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.44-7.21 (m, 9H), 3.51-3.38 (m, 2H), 3.07-2.44 (m, 8H), 1.62-1.52 (s, 7H); 13 CNMR (CDCl3, 100MHz): d177.0, 140.6, 133.4, 129.2, 128.8, 127.4, 126.6, 86.0, 57.5, 55.5, 41.3, 39.8, 39.7, 28.1, 27.0; HRMS (TOF) m / z: [M+H] + Calcd for C 24 H 28 ClNO2Se 478.5293; found 478.5294.

[0075] Example 19 Preparation of 5-(4-chlorophenyl)-3-((morpholinyl)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0076] The method involves dissolving 1p (378.0 mg, 1.0 mmol) in acetone (4 mL) and adding morpholine (174.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2s (409.2 mg, 88% yield) as a yellow oil.

[0077] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.44-7.23 (m, 9H), 3.67-3.38 (m, 6H), 2.38-2.26 (s, 9H); 13 CNMR (CDCl3, 100MHz): d176.5, 140.3, 134.2, 133.3, 133.0, 129.3, 128.8, 127.5, 126.5, 86.0, 66.8, 58.1, 53.8; HRMS (TOF) m / z: [M+H] + Calcd for C 22 H 24 ClNO3Se 466.3984; found 466.3985.

[0078] Example 20 Preparation of 5-(4-chlorophenyl)-3-((thiomorpholinyl)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0079] The method involves dissolving 1p (378.0 mg, 1.0 mmol) in acetone (4 mL) and adding thiomorpholine (406.0 mg, 2.0 mmol) at room temperature. After completion of the reaction at room temperature, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2t (413.7 mg, 86% yield) as a yellow oil.

[0080] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.45-7.21 (m, 9H), 3.51-3.37 (m, 2H), 3.17-2.34 (s, 12H); 13CNMR (CDCl3, 100MHz): d176.6, 140.4, 133.3, 133.0, 130.0, 129.4, 129.2, 128.8, 1 28.7, 127.5, 126.5, 85.9, 58.4, 55.2, 41.1, 39.4, 38.9, 27.9; HRMS (TOF) m / z: [M+H] + Calcd for C 22 H 24 ClNO2SSe 482.5192; found 482.5193.

[0081] Example 21 Preparation of 5-(4-chlorophenyl)-3-((piperazinyl)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0082] The method involves dissolving 1p (378.0 mg, 1.0 mmol) in acetone (4 mL) and adding piperazine (172.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2u (394.0 mg, 85% yield) as a yellow oil.

[0083] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.43-7.24 (m, 9H), 4.84 (s, 2H), 4.39 (s, broad, containsH2O, 1H), 3.50-3.37 (m, 2H), 2.97-2.38 (s, 11H); 13 CNMR (CDCl3, 100MHz): d176.5, 140.2, 134.3, 133.3, 130.0, 129.3, 128.9, 1 27.5, 126.5, 85.0, 57.8, 52.6, 44.8, 41.0, 39.3, 38.9; HRMS (TOF) m / z: [M+H] + Calcd for C 22 H 25 ClN2O2Se 465.6133; found 465.6134.

[0084] Example 22 Preparation of 5-(4-chlorophenyl)-3-((4-methylpiperazinyl)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0085] The method involves dissolving 1p (378.0 mg, 1.0 mmol) in acetone (4 mL) and adding 4-methylpiperazine (200.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2v (411.1 mg, 86% yield) as a yellow oil.

[0086] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.43-7.21 (m, 9H), 3.87-3.36 (m, 3H), 2.86-2.33 (s, 12H), 2.28 (s, 3H); 13 CNMR (CDCl3, 100MHz): d176.6, 140.3, 134.2, 133.4, 129.3, 129.2, 128.8, 128.6, 1 27.5, 126.5, 126.5, 85.9, 57.7, 54.9, 45.8, 41.1, 39.7, 38.8; HRMS (TOF) m / z: [M+H] + Calcd for C 23 H 27 ClN2O2Se 479.5268; found 479.5269.

[0087] Example 23 Preparation of 5-(4-chlorophenyl)-3-((methylamino)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0088] The method involves dissolving 1p (378.0 mg, 1.0 mmol) in acetone (4 mL) and adding methylamine (62.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2w (356.6 mg, 87% yield) as a yellow oil.

[0089] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CD3OD, 400MHz): d7.42-7.17 (m, 9H), 3.66-3.42 (m, 3H), 3.36-2.95 (m, 4H), 2.74 (s, 3H), 2.60-2.34 (m, 1H); 13CNMR (CD3OD, 100MHz): d175.0, 134.9, 134.0, 132.8, 132.7, 129.8, 128.8, 128.2 , 127.0, 126.8, 126.3, 87.2, 39.7, 38.4, 37.9, 37.5, 33.1; HRMS (TOF) m / z: [M+H] + Calcd for C 19 H 20 ClNO2Se 410.3977; found410.3976.

[0090] Example 24 Preparation of 5-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((4-fluorophenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0091] The method involves dissolving 1x (396.0 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2x (388.1 mg, 88% yield) as a yellow oil.

[0092] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.40-6.87 (m, 8H), 3.43-3.32 (m, 2H), 3.16-2.29 (m, 5H), 2.23 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.4, 163.8 (d, J =247.0Hz), 140.2, 136.1 (d, J =8.0Hz), 134.2, 128.8, 126.5, 116.4 (d, J =22.0Hz), 85.9, 59.4, 45.6, 42.0, 39.9, 39.1; HRMS (TOF) m / z: [M+H] + Calcd for C 20 H 21 ClFNO2Se 442.6057; found442.6058.

[0093] Example 25 Preparation of 5-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((4-chlorophenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0094] The method involves dissolving 1y (412.1 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2y (406.7 mg, 89% yield) as a yellow solid; MP: 116-117°C.

[0095] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.31-7.12 (m, 8H), 3.43-3.32 (m, 2H), 3.12-2.27 (m, 5H), 2.19 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.3, 140.2, 134.8, 134.5, 134.2, 129.4, 129.2, 12 8.8, 128.6, 126.5, 85.8, 59.3, 45.6, 41.5, 39.9, 39.1; HRMS (TOF) m / z: [M+H] + Calcd for C 20 H 21 Cl2NO2Se 458.3966; found 458.3967.

[0096] Example 26 Preparation of 5-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((4-methoxyphenylselenyl)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0097] The method involves dissolving 1z (408.0 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2z (443.9 mg, 89% yield) as a yellow oil.

[0098] The nuclear magnetic resonance identification data are as follows: 1HNMR (CDCl3, 400MHz): d7.36-6.72 (m, 8H), 3.76 (s, 3H), 3.40-3.27 (m, 2H), 2.88-2.29 (m, 5H), 2.22 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.5, 159.5, 140.4, 136.0, 135.6, 134.1, 128.7, 126. 5, 120.0, 114.8, 86.1, 59.4, 55.3, 45.6, 42.2, 39.8, 39.1; HRMS (TOF) m / z: [M+H] + Calcd for C 21 H 24 ClNO3Se 454.5792; found 454.5793.

[0099] Example 27 Preparation of 5-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((phenylthio)methyl)dihydrofuran-2(3H)-one The preparation process is as follows:

[0100] The method involves dissolving 1zz (330.1 mg, 1.0 mmol) in acetone (4 mL) and adding dimethylamine (90.0 mg, 2.0 mmol) at room temperature. After the reaction is complete, the solvent is removed by rotary evaporation. The concentrated residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3, v / v) to afford 2zz (360.4 mg, 84% yield) as a yellow oil; and 2zz (318.8 mg, 85% yield) as a yellow oil.

[0101] The nuclear magnetic resonance identification data are as follows: 1 HNMR (CDCl3, 400MHz): d7.35-7.22 (m, 9H), 3.52-3.49 (m, 2H), 3.42-2.35 (m, 5H), 2.27 (s, 6H); 13 CNMR (CDCl3, 100MHz): d176.3, 140.1, 135.7, 130.5, 130.1, 129.2, 129.1, 128.9, 12 8.7, 126.9, 126.5, 126.3, 86.2, 59.4, 47.2, 45.5, 45.2, 38.8; HRMS (TOF) m / z: [M+H] + Calcd for C 20 H 22 ClNO2S 376.8144; found 376.8145.

[0102] Example 28 Cytotoxic activity experiment α- exo -methylene-lactone structure exists in many natural products and has a variety of biological activities. The present invention first chemically synthesizes chiral selenium-containing α- exo- Methylene lactone compound 1 improves its selectivity for tumor cells; then a hydrophilic group, such as dimethylamine, is used to attack α- exo- Methylene lactone obtains selenolactone compound 2, which enhances its water solubility. It is expected that tumor cells will preferentially take up selenolactone prodrug 2, which will then be methylated to generate ammonia cation I under the action of SAM (S-adenosylmethionine, S-adenosylmethionine) enzyme in the body, and finally release α- exo- Methylene lactone warhead 1, thereby achieving improved selectivity of anti-tumor effects, its mechanism of action is as follows Figure 1 shown.

[0103] In order to verify the anti-tumor activity of the selenolactone compounds prepared by the present invention, the selenolactone compounds 2a-2zz prepared in Examples 1-27 were respectively used to conduct cytotoxic activity experiments. The specific steps are as follows: (1) U87, C6, 4T1, A549, and HEK293T cells in the logarithmic growth phase were seeded in 96-well plates at a density of 3,000 cells / well. The cells were cultured in DMEM medium containing 10% FBS (fetal bovine serum) and 1% antibiotics. Three replicate wells were set up for each group.

[0104] (2) After culturing for 24 hours, different concentrations of selenolactone compounds 2a-2zz were added and the culture was continued for 48 hours; pathenolide, temozolomide and sorafenib were used as controls.

[0105] (3) After 48 h, the culture medium containing the compound was removed and the IC of each group was detected by MTT method. 50 The results (mean ± SEM) are the average of three measurements.

[0106] Test results such as Figure 2-3 The results show that the selenolactone compounds prepared by the present invention can inhibit the proliferation of various cancer cells and have good selectivity for tumor cells.

[0107] Example 29 In vivo tumor inhibition experiment (1) One day before the experiment, place the already packaged Matrigel from -20℃ into a 4℃ refrigerator overnight to melt it from solid to liquid.

[0108] (2) U87 cells in the logarithmic growth phase were digested and evenly mixed with Matrigel matrix gel, and then injected subcutaneously into the back of 4-week-old male BALB / C-nu mice.

[0109] (3) After the tumors were formed, the mice were randomly divided into three groups, designated as Group 1 to Group 3, with 6 mice in each group; the mice in Group 1 were injected subcutaneously (SQ) with the compound (30 mg / kg) every day for 2 days, for 15 consecutive days; the mice in Group 2 were injected intraperitoneally (IP) with the compound (30 mg / kg) every day for 2 days, for 15 consecutive days; the mice in Group 3 served as blank controls and were injected intraperitoneally (IP) with an equal volume of solvent every day for 15 consecutive days.

[0110] (4) Observe the growth and mental state of mice daily, measure the weight and tumor size of each group of mice regularly, and calculate the tumor volume. The tumor volume is calculated using the following formula: Volume (mm 3 )=Length(mm)×Width 2 (mm 2 ) / 2.

[0111] (5) After the treatment, the mice were killed by over-anesthesia. The tumors of the mice in each group were removed and weighed and the tumor volume was measured.

[0112] Test results such as Figure 4 The results showed that within a 15-day treatment period, selenolactone compounds significantly inhibited the growth of U87 tumors. At a dose of 30 mg / kg injected intraperitoneally, the tumor growth inhibition (TGI) was 35.2%, and the tumor weight inhibition (TWI) was 39%, while there was no effect on the body weight of nude mice, indicating that it has excellent anti-tumor activity and good safety. The difference was statistically significant (* p <0.05,** p <0.01,*** p <0.001, **** p <0.0001, vs group 3).

[0113] The above detailed description of the analytical methods involved in the present invention provides a detailed introduction. It should be noted that the above description is intended solely to help those skilled in the art better understand the methods and concepts of the present invention, and is not intended to limit the relevant content. Without departing from the principles of the present invention, those skilled in the art may make appropriate adjustments or modifications to the present invention, and such adjustments and modifications shall also fall within the scope of protection of the present invention.

Claims

1. A selenolactone compound, characterized in that: Its structural formula is shown in Formula I: ； Where n = 1 or 2; Ar is selected from aromatic rings; R 1 A phenyl group selected from hydrogen, a C1-C8 alkyl group, a C1-C8 heterocyclic group, a phenyl group, a halophenyl group or a phenyl group substituted with a hydroxyl group; R 2 is selected from hydrogen, C1~C8 alkyl, C1~C8 heterocyclic group or phenyl; R 3 is selected from hydrogen, C1~C8 alkyl, C1~C8 heterocyclic group or phenyl.

2. The selenolactone compound according to claim 1, characterized in that The C1~C8 alkyl group is selected from one or more of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, sec-hexyl, tert-hexyl, n-heptyl, isoheptyl, neoheptyl, sec-heptyl, tert-heptyl, n-octyl, isooctyl, neooctyl, sec-octyl, and tert-octyl.

3. The selenolactone compound according to claim 1, characterized in that The C1-C8 heterocyclic group is selected from one or more of pyrrole, piperidine, cycloheximide, morpholine, thiomorpholine, piperazine, and 4-methylpiperazine.

4. The selenolactone compound according to any one of claims 1 to 3, characterized in that The selenolactone compound is selected from one or more of the following compounds: 3-((Dimethylamino)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 3-((Dimethylamino)methyl)-5-phenyl-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 3-((Dimethylamino)methyl)-5-(4-fluorophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 3-((Dimethylamino)methyl)-5-(4-chlorophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 3-((Dimethylamino)methyl)-5-(4-bromophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 3-((Dimethylamino)methyl)-5-(4-trifluoromethylphenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 3-((Dimethylamino)methyl)-5-(4-methoxyphenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 5-(3,4-difluorophenyl)-3-((dimethylamino)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 5-(3,4-dichlorophenyl)-3-((dimethylamino)methyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 3-((Dimethylamino)methyl)-5-benzyl-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 3-((Dimethylamino)methyl)-5-methyl-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 3-((Dimethylamino)methyl)-5-(iodomethyl)-5-phenyl-dihydrofuran-2(3H)-one, 3-((Dimethylamino)methyl)-5-phenyl-5-((phenyl(phenylselenyl)methyl)dihydrofuran-2(3H)-one, 4'-((dimethylamino)methyl)-5-(phenylselenyl)-3',4',5,7,8,9-6-hydro-5'H-spiro[phenyl[7]annulene-6,2'-furan]-5'-one, 6-(4-bromophenyl)-3-((dimethylamino)methyl)-6-((phenylselenyl)methyl)tetrahydro-2H-pyran-2-one, 5-(4-chlorophenyl)-5-((phenylselenyl)methyl)-3-(pyrrolylmethyl)dihydrofuran-2(3H)-one, 5-(4-chlorophenyl)-5-((phenylselenyl)methyl)-3-(piperidinylmethyl)dihydrofuran-2(3H)-one, 3-(cyclohexyliminomethyl)-5-(4-chlorophenyl)-5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 5-(4-chlorophenyl)-3-((morpholinyl)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 5-(4-chlorophenyl)-3-((thiomorpholinyl)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 5-(4-chlorophenyl)-3-((piperazinyl)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 5-(4-chlorophenyl)-3-((4-methylpiperazinyl)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 5-(4-chlorophenyl)-3-((methylamino)methyl)5-((phenylselenyl)methyl)dihydrofuran-2(3H)-one, 5-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((4-fluorophenylselenyl)methyl)dihydrofuran-2(3H)-one, 5-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((4-chlorophenylselenyl)methyl)dihydrofuran-2(3H)-one, 5-(4-chlorophenyl)-3-((dimethylamino)methyl)-5-((4-methoxyphenylselenyl)methyl)dihydrofuran-2(3H)-one, 5-(4-Chlorophenyl)-3-((dimethylamino)methyl)-5-((phenylthio)methyl)dihydrofuran-2(3H)-one.

5. Use of one or more of the selenolactone compounds according to any one of claims 1 to 4, or pharmaceutically acceptable salts or solvates thereof in the preparation of drugs for treating tumors.

6. The use according to claim 5, characterized in that The tumor is selected from one or more of brain tumor, lung cancer and breast cancer.

7. A pharmaceutical composition for treating tumors, characterized in that: It comprises the selenolactone compound according to any one of claims 1 to 4, one or more of its pharmaceutically acceptable salts or solvates, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, characterized in that The tumor is selected from one or more of brain tumor, lung cancer and breast cancer.

9. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutically acceptable carrier includes one or more of a filler, a binder, a disintegrant, a solvent, a preservative, a lubricant, and a flavoring agent.

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