Piperlongumine derivative with anti-tumor and anti-aging activity as well as preparation method and application of piperlongumine derivative

Abstract

The invention discloses a piperlongumine derivative shown in a structural general formula (I), a dialkyl amino coumarin fluorescent skeleton is introduced into a piperlongumine pharmacophore, and the piperlongumine derivative which has a lipid droplet targeting fluorescence labeling function and has anti-tumor and anti-aging activity is developed. The piperlongumine derivative disclosed by the invention can be used for lipid droplet imaging in tumor and senescence cells, is used for selectively acting on the tumor cells in vivo, inside and outside, and can selectively remove replicative senescence cells, recover senescence-related markers and gene expression, improve somatic function decline caused by senescence and improve the anti-aging effect of the piperlongumine derivative. And a new way is provided for treatment of clinical related diseases, drug development and preparation of in-vitro preparations or daily necessities.

Description

Technical Field

[0001] This invention relates to a class of piperazine derivatives that can target lipid droplets, their preparation methods, and their anti-tumor and anti-aging applications, belonging to the field of medicinal chemistry technology. Background Technology

[0002] Aging is a universal natural phenomenon in the biological world. It is a dynamic, gradual, multi-step process that is ultimately irreversible. With aging, the incidence of various age-related diseases, such as tumors, diabetes, and Alzheimer's disease, increases accordingly. Research on anti-aging and anti-aging drugs has become a hot topic in the global life sciences field. Natural products with extremely diverse chemical scaffolds are often used as the starting point for developing anti-aging drugs. Considering the potential carcinogenic risks associated with the large-scale use of certain anti-aging molecules, developing drugs with both anti-tumor and anti-aging activities can effectively avoid the carcinogenic risks posed by anti-aging molecules. Piperazine, also known as long pepper alkaloid, is a natural alkaloid derived from the Piper longum plant (Piper longum). It possesses various pharmacological and biological activities, such as antiplatelet aggregation, anti-diabetic, anti-aging, and cardiovascular protection. Its anti-tumor activity, in particular, has received increasing attention in recent years. Its anti-tumor activity has been confirmed in various tumor cell lines and various transplanted tumor animal models. Recently, studies have found that long pepper alkaloid also has certain anti-aging activities. Although the natural product long pepperamide possesses both antitumor and anti-aging activities, its activity and selectivity against tumor cells and senescent cells are low. Therefore, there is an urgent need to develop drugs based on its pharmacophore to improve the activity and selectivity of drug molecules against tumor cells and senescent cells. Summary of the Invention

[0003] In view of this, the purpose of the present invention is to provide a piperazine derivative with both anti-tumor and anti-aging activities that can target lipid droplets, as well as its preparation method and application.

[0004] The implementation process of this invention is as follows: The piperazine derivative represented by general structural formula (Ⅰ)

[0005] Wherein R is selected from C1-C10 alkyl or C3-C10 alkynylalkyl; R' is selected from H, halogen, nitro, amino, C1-C10 alkylamino, C1-C10 alkoxy.

[0006] The method for synthesizing the above-mentioned piperazine derivatives includes the following synthetic steps: (1) Compound (A) is subjected to acyl chloride reaction to obtain compound (B).

[0007] (2) Compound (B) was condensed with 3-R'-5,6-dihydro-2(1H)-pyridone under organic base catalysis to obtain the compound shown in formula (I). .

[0008] In step (1) of the above synthesis method, the acyl chloride reagent is selected from thionyl chloride, oxalyl chloride, acetyl chloride, and propionyl chloride.

[0009] In step (1) of the above synthesis method, the organic solvent used in the reaction is selected from acetonitrile, dichloromethane, 1,4-dioxane, tetrahydrofuran, benzene, and toluene.

[0010] In step (2) of the above synthesis method, the organic base is selected from triethylamine, pyridine, and piperidine.

[0011] In step (2) of the above synthesis method, the organic solvent used in the reaction is selected from acetonitrile, dichloromethane, 1,4-dioxane, tetrahydrofuran, benzene, and toluene.

[0012] The above-mentioned piperazine derivatives are used in the preparation of drugs, health foods or cosmetics for lipid droplet imaging in tumor and senescent cells, or for selectively clearing tumor and senescent cells, for in vivo anti-tumor treatment, or for selectively clearing replicating senescent cells and aging-related diseases.

[0013] The above-mentioned piperazine derivative pharmaceutical compositions, cosmetic compositions, food compositions, or health product compositions contain a compound of general structural formula (1) and a pharmaceutically acceptable carrier or excipient. The compositions are tablets, capsules, granules, suspensions, pills, solutions, syrups, or injections.

[0014] Cellular senescence is an important manifestation of aging in the body. Clearing senescent cells can alleviate, delay, and treat aging and age-related diseases. This invention has the following significant advantages: (1) This series of long pepperamide derivatives can selectively target lipid droplets in tumor cells and senescent cells. (2) This series of long pepperamide derivatives can promote the increase of reactive oxygen species levels in tumor cells and senescent cells. (3) This series of long pepperamide derivatives has excellent anti-tumor activity at both the cellular and in vivo levels. (4) This series of long pepperamide derivatives can selectively clear replicating senescent cells at the cellular level, exerting an anti-aging effect. (5) This prodrug can clear senescent cells in naturally aging mice, reverse the expression of aging-related markers and genes, and improve the decline in bodily functions caused by aging. Attached Figure Description

[0015] Figure 1Lipid droplet imaging experiment for compound 1. Figure A shows colocalization imaging of compound 1 in A549 cells; Figure B shows colocalization imaging of compound 1 in HCT-116, senescent HCT-116, and senescent MRC-5 cells; Figure 2 This study investigated the activation of reactive oxygen species (ROS) in tumor cells and senescent cells by compound 1. Figure A shows ROS imaging of HCT-116 cells stimulated with different concentrations of compound 1 or long peppermint amide; Figure B shows the corresponding fluorescence intensity map in Figure A; Figure C shows ROS imaging of senescent HCT-116 and senescent MRC-5 cells stimulated with different concentrations of compound 1; Figure D shows the corresponding fluorescence intensity map in Figure C. Figure 3 This study investigated the in vivo antitumor activity of compounds 1, 2, and long pepperamide. Figure A shows the changes in tumor volume and body weight in different groups of mice at different treatment durations; Figure B shows the tumor volume and body weight in different groups of mice after treatment. Figure 4 This image shows the expression of compound 1 and long peppermint in the liver and brain of mice undergoing treatment to reverse natural aging. Figure A shows the expression of the aging-related biomarker p53 in each group; Figure B shows the expression of the aging-related biomarker p21 in each group. Figure 5 Compound 1 was used to treat and improve age-related physiological dysfunction and reverse the expression of age-related genes in the liver, kidneys, and brain of naturally aging mice. Figure A shows the behavioral results of each group of mice; Figure B shows the transcriptome sequencing results of each group of tissues. Detailed Implementation

[0016] The inventors of this application, through extensive and in-depth research, designed and synthesized a series of piperazine derivatives with both anti-tumor and anti-aging activities that can selectively target lipid droplets. This series of compounds exhibits excellent anti-tumor activity at both the cellular and in vivo levels, and can eliminate senescent cells in naturally aging mice, reverse the expression of aging-related markers and genes, and improve age-related physiological dysfunction. Based on this, the present invention was completed.

[0017] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0019] Example 1: Preparation of Compound 1

[0020] Under argon protection, 7-(diethylamino)-2-oxo-2H-chromene-3-acrylic acid (287.4 mg, 1.0 mmol) and oxalyl chloride (426.8 μL, 2.2 mmol) were dissolved in anhydrous dichloromethane. The reaction mixture was refluxed for 4 h, and then excess oxalyl chloride and dichloromethane were evaporated to dryness before proceeding to the next step. The residue was dissolved in ultra-dry THF, and then sodium hydride (69.0 mg, 3.0 mmol) and 5,6-dihydro-2(1H)-pyridone (145.5 mg, 1.5 mmol) were added. The reaction mixture was refluxed for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and saturated NH4Cl (70.0 mL) was added to quench the reaction. The system was extracted multiple times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, concentrated and then subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, V / V) to give compound 1 (43.5 mg, 11.8%). 1 H NMR (400 MHz, CDCl3) δ:7.80-7.76 (m, 2H), 7.65 (d, J = 15.5 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 6.94-6.89 (m, 1H), 6.62 (d, J = 8.8 Hz 1H), 6.50 (s, 1H), 6.04 (d, J = 9.8 Hz, 1H), 4.01 (t, J = 6.4 Hz, 2H), 3.46-3.40 (m, 4H), 2.50-2.42 (m, 2H), 1.22 (t, J = 7.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ: 169.4, 165.6, 160.6, 156.8,151.4, 145.3, 143.2, 137.8, 129.8, 125.9, 122.5, 115.5, 109.2, 108.9, 97.0,45.0, 41.7, 24.8, 12.5; IR (KBr, cm -1 ): 2973, 1716, 1683,1627, 1576, 1514,1419, 1327, 1184, 1131, 1033, 976, 810, 602, 462; HRMS (ESI) calculated for[M+Na] + : 389.1472, found 389.1499.

[0021] Example 2 Preparation of Compound 2

[0022] Under argon protection, 7-(diethylamino)-2-oxo-2H-chromene-3-acrylic acid (287.4 mg, 1.0 mmol) and oxalyl chloride (426.8 μL, 2.2 mmol) were dissolved in anhydrous dichloromethane. The reaction mixture was refluxed for 4 h, and then excess oxalyl chloride and dichloromethane were evaporated to dryness before proceeding to the next step. The residue was dissolved in ultra-dry THF, and sodium hydride (69.0 mg, 3.0 mmol) was added. The system was then cooled to 0 °C. 3-chloro-5,6-dihydro-2(1h)-pyridone (196.5 mg, 1.5 mmol) was dissolved in tetrahydrofuran and slowly added to the prepared reaction mixture. The reaction system was heated to reflux for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and saturated NH4Cl was added to quench the reaction. The system was extracted multiple times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, concentrated and then subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, V / V) to obtain a yellow solid, which was compound 2 (26.3 mg, 6.5%). 1 H NMR (400 MHz, CDCl3) δ: 7.82 (s, 1H), 7.71 (s, 2H), 7.30 (d, J = 9.1 Hz, 1H), 7.06 (s, 1H), 6.59-6.61 (d, J = 8.2 Hz, 1H), 6.48 (s, 1H), 4.06 (t, J= 5.7 Hz, 2H), 3.43(q, J = 6.8 Hz, 4H), 2.55 (d, J = 4.6 Hz, 2H) 1.22 (t, J = 6.4 Hz, 6H); 13 CNMR (100 MHz, CDCl3) δ: 169.0, 161.4, 160.6, 156.9, 151.8, 143.1, 141.0,139.1, 130.0, 128.4, 121.7, 115.3, 109.6, 108.9, 97.2, 45.1, 42.0, 25.5, 12.6; IR (KBr, cm -1 ): 2973, 2920, 1713, 1624, 1574, 1520, 1413, 1327, 1282, 1193,1134, 1012, 819, 664, 602, 471; HRMS (ESI) calculated for [M+Na] + : 423.1082,found 423.1110.

[0023] Example 3 Preparation of Compound 3

[0024] Compound 7-(di-di-propynyl)-2-oxo-2H-chromene-3-acrylic acid (0.7 g, 2.5 mmol) was dissolved in oxalyl chloride (2.1 mL, 10.8 mmol). The reaction system was subjected to argon protection and reacted at room temperature for 4 h. Excess oxalyl chloride was evaporated to dryness, and the residue was dissolved in toluene. The system was then cooled to 0 °C. 5,6-Dihydro-2(1H)-pyridone (0.3 g, 3.0 mmol) was dissolved in toluene and slowly added to the prepared reaction solution. The reaction system was heated under reflux for 24 h. After the reaction was completed, the system was cooled to room temperature, and saturated NH4Cl was added to quench the reaction. The system was extracted multiple times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, V / V) to give compound 3 (123.0 mg, 12.7%). 1H NMR (400 MHz, CDCl3) δ: 7.81-7.84 (m, 2H), 7.61-7.64 (m,1H) 7.39 (m, 1H), 6.95-6.90 (m, 1H), 6.84-6.71 (m, 2H), 6.04 (d, J = 9.7 Hz,1H), 4.20 (s, 4H), 4.01 (t, J = 6.4 Hz, 2H), 2.46 (q, J = 5.8 Hz, 2H), 2.31(s, 2H); 13 C NMR (101 MHz, CDCl3) δ: 169.4, 165.8, 160.1, 151.1, 145.6, 143.0,137.3, 129.7, 125.8, 124.3, 118.2, 111.4, 111.1, 100.4, 77.9, 73.5, 41.8,40.5, 24.9; IR (KBr, cm -1 ): 1701, 1675, 1624, 1591, 1511, 1478, 1392, 1363,1315, 1247, 1229, 1196, 1134, 1018, 834, 807, 762, 730, 614, 531, 483; HRMS(ESI) calculated for [M+Na] + : 409.1159 found 409.1154.

[0025] Example 4 Preparation of Compound 4

[0026] Compound 7-(di-di-propynyl)-2-oxo-2H-chromene-3-acrylic acid (0.6 g, 2.0 mmol) was dissolved in oxalyl chloride (0.9 mL, 4.6 mmol). The reaction system was subjected to argon protection and reacted at room temperature for 4 h. Excess oxalyl chloride was evaporated to dryness, and the residue was dissolved in toluene. The system was then cooled to 0 °C. Compound 3-chloro-5,6-dihydro-2(1h)-pyridone (0.3 g, 2.5 mmol) was dissolved in toluene and slowly added to the prepared reaction solution. The reaction system was heated to reflux for 24 h. After the reaction was completed, the system was cooled to room temperature, and saturated NH4Cl was added to quench the reaction. The system was extracted multiple times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, V / V) to give a yellow solid, which was compound 4 (86.1 mg, 10.2%). 1 H NMR (400 MHz, CDCl3) δ: 7.87 (s,1H), 7.78-7.67 (m, 2H), 7.41 (d, J = 8.7 Hz, 1H), 7.08 (t, J =4.2 Hz, 1H),6.85-6.72 (m, 2H), 4.21 (s, 4H), 4.06 (t, J = 6.4 Hz, 2H), 2.56 (q, J = 5.6Hz, 2H), 2.31 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ: 191.8, 182.4, 180.7, 175.5,169.8, 159.1, 157.2, 153.4, 142.9, 141.0, 134.9, 128.2, 120.2, 119.6, 106.2,78.2, 72.6, 33.2, 31.4, 12.5; IR (KBr, cm -1 ): 3301, 3253, 1725, 1678, 1663,1597, 1544, 1499, 1464, 1398, 1324, 1300, 1273, 1178, 1128, 982, 816, 777,661; HRMS (ESI) calculated for [M+Na] + : 443.0769, found 443.0757.

[0027] Example 5 Preparation of Compound 5

[0028] Compound 7-(diethylamino)-2-oxo-2H-chromene-3-acrylic acid (287.4 mg, 1.0 mmol) and oxalyl chloride (426.8 μL, 2.2 mmol) were dissolved in anhydrous dichloromethane. The reaction mixture was refluxed for 4 h, and excess oxalyl chloride and dichloromethane were evaporated to dryness. The residue was directly used for the next reaction. The residue was dissolved in ultra-dry THF, and sodium hydride (69.0 mg, 3.0 mmol) and 2-azhexanecycloone (148.5 mg, 1.5 mmol) were added. The reaction mixture was refluxed for 24 h. After the reaction was completed, the mixture was cooled to room temperature, and saturated NH4Cl (70.0 mL) was added to quench the reaction. The system was extracted multiple times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, V / V) to give compound 5 (43.5 mg, 11.8%). 1 H NMR (400 MHz, CDCl3) δ: 7.75-7.70 (m, 2H), 7.61-7.57 (m, 1H), 7.28 (d, J = 9.4 Hz, 1H), 6.60 (d, J = 8.16 Hz, 1H), 6.48 (s,1H), 3.77 (s, 2H), 3.47 (q, J = 6.9 Hz, 4H), 2.59 (s, 2H), 1.87 (s, 4H), 1.21(t, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ: 173.6, 170.2, 160.4, 156.5,151.5, 143.2, 137.6, 129.8, 122.9, 115.4, 109.4, 108.7, 97.0, 45.0, 44.7,34.8, 22.6, 20.7, 12.5; IR (KBr, cm -1 ): 2966, 2859, 1710, 1663, 1630, 1582,1517, 1410, 1324, 1279, 1193, 1137, 1015, 863, 792, 712, 676, 608, 471, 444;HRMS (ESI) calculated for [M+Na] +: 391.1628, found 391.166.

[0029] Example 6 Preparation of Compound 6

[0030] Compound 7-(diethylamino)-2-oxo-2-benzopyran-3-carboxylic acid (500.0 mg, 1.7 mmol) was dissolved in oxalyl chloride (0.8 mL, 4.1 mmol). The reaction system was subjected to argon protection at room temperature for 4 h. Excess oxalyl chloride was evaporated to dryness, and the residue was dissolved in toluene. The system was then cooled to 0 °C. 2-Zahexane (247.0 mg, 2.5 mmol) was dissolved in toluene (100.0 mL) and slowly added to the prepared reaction solution. The reaction system was heated to reflux for 24 h. After the reaction was completed, the system was cooled to room temperature, and saturated NH4Cl was added to quench the reaction. The system was extracted multiple times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, V / V) to give compound 6 (75.6 mg, 13.0%). 1 H NMR (400 MHz, CDCl3) δ: 7.98 (s, 1H), 7.31 (d, J =8.9 Hz, 1H), 6.58 (dd, J 1 = 2.2 Hz, J 2 = 8.9 Hz, 1H), 6.43 (d, J =2.0 Hz, 1H), 3.80 (t, J = 5.4 Hz, 2H), 3.41 (q, J = 7.2 Hz, 4H), 2.60 (t, J = 6.5 Hz, 2H),1.96-1.88 (m, 4H), 1.20 (t, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ:174.7, 168.9, 159.3, 157.5, 151.8, 144.9, 130.5, 117.8, 109.4, 108.2, 97.2,45.7, 45.1, 34.5, 22.7, 21.4, 12.5; IR (KBr, cm -1): 2952, 1716, 1695, 1651,1615, 1576, 1517, 1416, 1351, 1294, 1229, 1187, 1140, 1077, 819, 736, 638;HRMS (ESI) calculated for [M+Na] + : 365.1472 found 365.1467.

[0031] Example 7 Imaging study of compound 1, prepared in Example 1, which has both anti-tumor and anti-aging activities, targeting lipid droplets in tumor cells and senescent cells.

[0032] Tumor cells or senescent cells were incubated with 5 μM compound 1 for 20 min, followed by incubation with commercial dyes for different organelles for 30 min, and then co-localization imaging was performed. Figure 1 As shown in Figure A, the Ernst-Marshon correlation coefficient (PCC) between compound 1 and lipid droplet dyes was as high as 0.92, while the PCCs with mitochondria and lysosomes were both less than 0.85, indicating that compound 1 can selectively localize to lipid droplets in tumor cells. Meanwhile, Figure 1 B-mode imaging results also demonstrated that compound 1 can locate lipid droplets in senescent cells.

[0033] Example 8: Study on the activation of reactive oxygen species in tumor cells and senescent cells by compound 1 prepared in Example 1.

[0034] Laser confocal imaging was used to investigate the levels of reactive oxygen species (ROS) in tumor cells and senescent cells after stimulation with different concentrations of compound 1 for 3 h. Cellular ROS levels were detected using a commercially available reactive oxygen species detection fluorescent probe (DHE). Tumor cells and senescent cells were stimulated for 3 h with different concentrations of compound 1 or long peppermint amide, followed by the addition of 10 μM DHE, and then confocal imaging was performed. Figure 2 As shown in A and 2B, with increasing concentrations of compound 1 or the natural product long pepperamide, the concentration of reactive oxygen species (ROS) in colon cancer cells gradually increased. Furthermore, under the same concentration conditions, the ROS concentration in colon cancer cells stimulated by compound 1 was higher than that of the natural product long pepperamide. This demonstrates that compound 1 can more effectively promote ROS expression in tumor cells. Meanwhile, as... Figure 2 Compound 1, shown in C and 2D, can also increase the level of reactive oxygen species in senescent cells.

[0035] Example 9: Activity study of piperazine and its derivatives in tumor cells and senescent cells.

[0036] The activity of long pepperamide derivatives in tumor cells and senescent cells was detected using the CCK-8 assay. As shown in Table 1, compounds 1, 2, 3, and 4, which retain the long pepperamide pharmacophore, exhibited high activity against tumor cells (HCT-116, A549, MCF-7) and senescent cells. In particular, compounds 1 and 2 showed higher activity against tumor cells and senescent cells than the natural long pepperamide. Compounds 3 and 4 showed better activity against some tumor cells than the natural long pepperamide. Compounds 5 and 6, which do not contain the long pepperamide pharmacophore, showed almost no activity against tumor cells and senescent cells.

[0037]

[0038] Example 10: Study on the in vivo antitumor activity of compounds 1 and 2 prepared in Example 1 and long pepper amide.

[0039] The in vivo antitumor activities of compounds 1, 2, and long pepperamide were tested using a nude mouse model of colon cancer cell transplantation. The results are as follows: Figure 3 As shown, compounds 1 and 2 exhibited tumor volume inhibition rates of 59.7% and 49.5% respectively in vivo, significantly improving their antitumor effects compared to the natural product long pepperamide (33.1%). Furthermore, the body weight of mice treated with compounds 1 and 2 did not change significantly, demonstrating that compounds 1 and 2 possess excellent in vivo antitumor activity and low biotoxicity.

[0040] Example 11 Validation experiment on the targeted elimination of senescent cells in naturally aging mice by compound 1 prepared in Example 1.

[0041] The prepared compound 1 and long peppermint were used to treat naturally aging mice (18 months and 0 months) to investigate their ability to clear senescent cells and delay aging in vivo.

[0042] Mice were divided into a young control group (3 months), an aging control group (18 months), a compound 1 group, and a long peppermint group. Mice in the young and aging control groups received intraperitoneal injections of lysozyme, mice in the compound 1 group received intraperitoneal injections of compound 1 (5 mg / kg), and mice in the long peppermint group received intraperitoneal injections of long peppermint (5 mg / kg). Administered to mice every two days for four weeks. The solvent was physiological saline containing 1% Tween 80. Figure 4 As shown, compared with young control mice, aged control mice showed increased expression of aging-related markers (p53, p21) in the brain and liver. Treatment with compound 1 or long pepperamide significantly reduced the expression of aging-related markers in the brain and liver of mice, with compound 1 showing a significantly greater improvement than long pepperamide. Simultaneously, behavioral experiments indicated ( Figure 5(A) After treatment with compound 1 or long pepperamide, the decline in physiological functions caused by aging in mice was improved, with compound 1 showing a greater improvement effect than long pepperamide. Furthermore, transcriptome sequencing results (5B) showed that after compound treatment, the expression of aging-related genes in mice was reversed. In conclusion, compound 1 treatment can eliminate senescent cells in naturally aging mice, reverse the expression of aging-related markers and genes, and improve the decline in physiological functions caused by aging.

[0043] It should be understood that, within the scope of this invention, the various technical features described above and in the embodiments can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose.

Claims

1. Piperazine derivatives represented by general structural formula (Ⅰ), ； Wherein R is selected from C1-C10 alkyl or C3-C10 alkynylalkyl; R' is selected from H, halogen, nitro, amino, C1-C10 alkylamino, C1-C10 alkoxy.

2. The method for synthesizing the piperazine derivative according to claim 1, characterized by comprising the following synthetic steps: ； (1) Compound (A) is subjected to acyl chloride reaction to obtain compound (B); ； (2) Compound (B) was condensed with 3-R'-5,6-dihydro-2(1H)-pyridone under organic base catalysis to obtain the compound shown in formula (I).

3. The method for synthesizing the piperazine derivative according to claim 2, characterized in that: In step (1), the acyl chloride reagent is selected from thionyl chloride, oxalyl chloride, acetyl chloride, and propionyl chloride.

4. The method for synthesizing the piperazine derivative according to claim 2, characterized in that: In step (1), the organic solvent used in the reaction is selected from acetonitrile, dichloromethane, 1,4-dioxane, tetrahydrofuran, benzene, and toluene.

5. The method for synthesizing the piperazine derivative according to claim 2, characterized in that: In step (2), the organic base is selected from triethylamine, pyridine, and piperidine.

6. The method for synthesizing the piperazine derivative according to claim 2, characterized in that: In step (2), the organic solvent used in the reaction is selected from acetonitrile, dichloromethane, 1,4-dioxane, tetrahydrofuran, benzene, and toluene.

7. The use of the piperazine derivative of claim 1 in the preparation of drugs, health foods or cosmetics for lipid droplet imaging in tumor and senescent cells, or for selectively clearing tumor and senescent cells, for in vivo anti-tumor treatment, or for selectively clearing replicating senescent cells and aging-related diseases.

8. Pharmaceutical compositions, cosmetic compositions, food compositions or health product compositions containing the piperazine derivative of claim 1.

9. The composition according to claim 8, characterized in that... The composition contains a compound of general structural formula (1) and a pharmaceutically acceptable carrier or excipient.

10. The composition according to claim 8, characterized in that... The composition is in the form of tablets, capsules, granules, suspensions, pills, solutions, syrups, or injections.

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