Aspirin-sulfonamide hybrid as well as preparation method and application thereof

Abstract

The invention relates to the technical field of aspirin medicinal chemistry, in particular to an aspirin-sulfonamide hybrid as well as a preparation method and application thereof.According to the preparation method, a plurality of novel aspirin-sulfonamide hybrids can be synthesized through a three-step continuous method of acylating chlorination, sulfonylation and N-acylation by taking piperazine as a bridge according to the molecular heterozygosis principle; in the process, only one-time separation and purification are carried out, and the preparation steps are simple; the aspirin-sulfonamide hybrid prepared by the method is most effective to human non-small cell lung cancer cells A549, the activity of the aspirin-sulfonamide hybrid is 33 times higher than that of parent aspirin, and the activity of the aspirin-sulfonamide hybrid is close to that of an anti-cancer drug irinotecan; the aspirin-sulfonamide hybrid 3k prepared by the method has a certain inhibition effect on various cancer cells, can induce apoptosis of human non-small cell lung cancer A549 cells in a concentration-dependent manner, induces the cell cycle of the human non-small cell lung cancer A549 to stop at a G0 / G1 phase, and inhibits cell growth.

Description

Technical Field

[0001] The present invention relates to the technical field of aspirin pharmaceutical chemistry, and in particular to an aspirin-sulfonamide hybrid and a preparation method and application thereof. Background Art

[0002] Cancer is one of the major diseases that threaten human life and health worldwide. According to statistics from the International Agency for Research on Cancer (IARC), there will be approximately 20 million new cancer cases and 9.7 million deaths worldwide in 2022, and the incidence rate is increasing year by year. The pathological mechanism of cancer is complex, and its occurrence and development are closely related to many factors such as gene mutation, epigenetic abnormalities and immune escape. Current clinical treatments for cancer mainly include surgical resection, radiotherapy, chemotherapy and targeted therapy, but these methods generally have problems such as low selectivity, significant toxic side effects and easy drug resistance. For example, chemotherapy drugs can cause serious damage to normal tissues while killing tumor cells, and targeted drugs often lead to decreased efficacy after long-term use due to adaptive mutations of tumor cells. Therefore, the development of new anticancer drugs or the optimization of existing treatment options are still scientific problems that need to be overcome.

[0003] In recent years, aspirin has received increasing attention as a possible cancer treatment drug, and its anti-cancer effect has been verified in many epidemiological studies and experimental models. For example, long-term low-dose aspirin can reduce the incidence of colorectal cancer. However, aspirin has limited cytotoxicity to cancer cells. At this stage, it can only play an auxiliary therapeutic role in the treatment of cancer and cannot become a new anti-cancer drug. Summary of the invention

[0004] In view of this, it is necessary to provide an aspirin-sulfonamide hybrid and its preparation method and application, by introducing active fragments with high adaptability and strong anticancer activity into aspirin to enhance the cytotoxicity of aspirin to cancer cells, so that it can become a new anticancer drug.

[0005] In a first aspect, the present invention provides an aspirin-sulfonamide hybrid, wherein the aspirin-sulfonamide hybrid has the following general structural formula:

[0006]

[0007] Among them, R 1 Selected from aromatic or heteroaryl or hydrocarbon groups.

[0008] Preferably, the R 1 Selected from one of the following groups:

[0009]

[0010] In a second aspect, the present invention provides a method for preparing an aspirin-sulfonamide hybrid, which is used to prepare the aspirin-sulfonamide hybrid as described in the first aspect, comprising the following steps:

[0011] S1, aspirin and oxalyl chloride are subjected to chlorination reaction under the catalysis of a catalyst to obtain o-acetylsalicylic acid chloride 1;

[0012] S2, piperazine and sulfonyl chloride undergo sulfonylation reaction under the action of the first acid binding agent to obtain sulfonamide 2;

[0013] S3, o-acetylsalicylic acid chloride 1 and sulfonamide 2 are subjected to N-acylation reaction under the action of a second acid-binding agent, and then separated and purified to obtain the target product aspirin-sulfonamide hybrid 3a-1. The synthetic route is as follows:

[0014]

[0015] Among them, R 1 The definition of is the same as that of the first aspect.

[0016] Preferably, the catalyst in step S1 is N,N-dimethylformamide.

[0017] Preferably, the first acid binding agent in step S2 and the second acid binding agent in step S3 are both tertiary amines.

[0018] In a third aspect, the present invention provides the use of the aspirin-sulfonamide hybrid as described in the first aspect, comprising:

[0019] A pharmaceutically acceptable salt of an aspirin-sulfonamide hybrid as described above.

[0020] A pharmaceutical composition of an aspirin-sulfonamide hybrid or a pharmaceutically acceptable salt thereof as described above.

[0021] The pharmaceutical preparation of aspirin-sulfonamide hybrid or a pharmaceutically acceptable salt thereof as described above further comprises at least one pharmaceutically acceptable excipient or carrier.

[0022] Use of the aspirin-sulfonamide hybrid or its pharmaceutically acceptable salt or its pharmaceutical composition or its pharmaceutical preparation as described above in the preparation of anticancer drugs.

[0023] Preferably, the cancers that can be treated by the anticancer drug include: lung cancer, liver cancer, breast cancer, colorectal cancer, cervical cancer, gastric cancer and malignant glioblastoma.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. The anticancer activity of the aspirin-sulfonamide hybrid prepared by the present invention is significantly higher than that of the parent aspirin, wherein the aspirin-sulfonamide hybrid containing bromothiophene structure 3k (IC 50 =36.57 μM) was the most effective against human non-small cell lung cancer A549 cells, and its activity was higher than that of the parent aspirin (IC 50 >1200μM) is more than 33 times higher than the anticancer drug irinotecan (IC 50 =29.07 μM) and the activity of aspirin-sulfonamide hybrid 3k was similar to that of BEAS-2B cells in normal human lung epithelial cells (IC 50 =201.60 μM), its selectivity for human non-small cell lung cancer cell A549 (SI BEAS-2B / A549 =6) is much higher than irinotecan (SI BEAS-2B / A549 =1), therefore, the aspirin-sulfonamide hybrid prepared by the present invention can effectively treat lung cancer;

[0026] 2. The preparation method of aspirin-sulfonamide hybrid provided by the present invention can use piperazine as a bridge, and synthesize several novel aspirin-sulfonamide hybrids through a three-step continuous method of "acyl chlorination, sulfonylation, and N-acylation" according to the "molecular hybrid principle". In this process, only one separation and purification is performed, and the preparation steps are simple;

[0027] 3. The aspirin-sulfonamide hybrid 3k prepared by the present invention showed certain cytotoxicity to human liver cancer cells HepG2, human breast cancer cells MCF-7, human colorectal cancer cells Caco-2, human colorectal cancer cells HCT-116, human cervical cancer cells Hela, human gastric cancer cells HGC-27 and human malignant glioblastoma cells U87 (HepG2, MCF-7, Caco-2, HCT-116, Hela, HGC-27 and U87, IC 50 =41.96-376.50 μM), therefore, the aspirin-sulfonamide hybrid prepared by the present invention has a certain inhibitory effect on various cancer cells;

[0028] 4. The inhibitory effect of aspirin-sulfonamide hybrid 3k prepared by the present invention on human non-small cell lung cancer cells A549 (IC 50 =36.57 μM) was superior to the other seven cancer cells (HepG2, MCF-7, Caco-2, HCT-116, Hela, HGC-27 and U87, IC 50=41.96-376.50 μM), and at the same time, the hybrid can induce apoptosis of human non-small cell lung cancer A549 cells in a concentration-dependent manner, induce the cell cycle arrest of human non-small cell lung cancer A549 cells at the G0 / G1 phase, and inhibit the growth of the cells, indicating that aspirin-sulfonamide hybrid 3k has the potential to be specifically used for the treatment of non-small cell lung cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is the aspirin-sulfonamide hybrid 3a of the present application 1 HNMR spectrum.

[0030] Figure 2 is the aspirin-sulfonamide hybrid 3a of the present application 13 CNMR spectrum.

[0031] Figure 3 It is the HRMS spectrum of aspirin-sulfonamide hybrid 3a of the present application.

[0032] Figure 4 is the aspirin-sulfonamide hybrid 3b of the present application 1 HNMR spectrum.

[0033] Figure 5 is the aspirin-sulfonamide hybrid 3b of the present application 13 CNMR spectrum.

[0034] Figure 6 It is the HRMS spectrum of aspirin-sulfonamide hybrid 3b of the present application.

[0035] Figure 7 is the aspirin-sulfonamide hybrid 3c of the present application 1 HNMR spectrum.

[0036] Figure 8 is the aspirin-sulfonamide hybrid 3c of the present application 13 CNMR spectrum.

[0037] Fig. 9 It is the HRMS spectrum of aspirin-sulfonamide hybrid 3c of the present application.

[0038] Fig.10 is the aspirin-sulfonamide hybrid 3d of the present application 1 HNMR spectrum.

[0039] Fig.11 is the aspirin-sulfonamide hybrid 3d of the present application 13 CNMR spectrum.

[0040] Fig.12It is the HRMS spectrum of aspirin-sulfonamide hybrid 3d of the present application.

[0041] Fig.13 is the aspirin-sulfonamide hybrid 3e of the present application 1 HNMR spectrum.

[0042] Fig.14 is the aspirin-sulfonamide hybrid 3e of the present application 13 CNMR spectrum.

[0043] Fig.15 It is the HRMS spectrum of aspirin-sulfonamide hybrid 3e of the present application.

[0044] Fig.16 is the aspirin-sulfonamide hybrid 3f of the present application 1 HNMR spectrum.

[0045] Fig.17 is the aspirin-sulfonamide hybrid 3f of the present application 13 CNMR spectrum.

[0046] Fig.18 is the aspirin-sulfonamide hybrid 3f of the present application 19 FNMR spectrum.

[0047] Fig.19 This is the HRMS spectrum of the aspirin-sulfonamide hybrid 3f of the present application.

[0048] Fig. 20 It is the aspirin-sulfonamide hybrid 3g of the present application 1 HNMR spectrum.

[0049] Fig.21 It is the aspirin-sulfonamide hybrid 3g of the present application 13 CNMR spectrum.

[0050] Fig. 22 It is the aspirin-sulfonamide hybrid 3g of the present application 19 FNMR spectrum.

[0051] Fig.23 It is the HRMS spectrum of aspirin-sulfonamide hybrid 3g of the present application.

[0052] Fig.24 is the aspirin-sulfonamide hybrid 3h of the present application 1 HNMR spectrum.

[0053] Fig.25 is the aspirin-sulfonamide hybrid 3h of the present application 13 CNMR spectrum.

[0054] Fig.26 is the aspirin-sulfonamide hybrid 3h of the present application 19 FNMR spectrum.

[0055] Fig. 27 It is the HRMS spectrum of aspirin-sulfonamide hybrid 3h of the present application.

[0056] Fig.28 is the aspirin-sulfonamide hybrid 3i of the present application 1 HNMR spectrum.

[0057] Fig.29 is the aspirin-sulfonamide hybrid 3i of the present application 13 CNMR spectrum.

[0058] Fig.30 It is the HRMS spectrum of aspirin-sulfonamide hybrid 3i of the present application.

[0059] Fig.31 is the aspirin-sulfonamide hybrid 3j of the present application 1 HNMR spectrum.

[0060] Fig.32 is the aspirin-sulfonamide hybrid 3j of the present application 13 CNMR spectrum.

[0061] Fig.33 It is the HRMS spectrum of aspirin-sulfonamide hybrid 3j of the present application.

[0062] Fig.34 It is the aspirin-sulfonamide hybrid 3k of the present application 1 HNMR spectrum.

[0063] Fig.35 It is the aspirin-sulfonamide hybrid 3k of the present application 13 CNMR spectrum.

[0064] Fig.36 It is the HRMS spectrum of aspirin-sulfonamide hybrid 3k of the present application.

[0065] Fig.37 is the aspirin-sulfonamide hybrid 3l of the present application 1 HNMR spectrum.

[0066] Fig.38 is the aspirin-sulfonamide hybrid 3l of the present application 13 CNMR spectrum.

[0067] Fig.39It is the HRMS spectrum of aspirin-sulfonamide hybrid 31 of the present application.

[0068] Fig.40 This is a graph showing the inhibition rate of the aspirin-sulfonamide hybrid 3 of the present application on human non-small cell lung cancer cells A549 and human normal lung epithelial cells BEAS-2B.

[0069] Fig.41 This is a graph showing the inhibition rate of the aspirin-sulfonamide hybrid 3k of the present application on 7 types of human cancer cells.

[0070] Fig.42 This is a graph showing the apoptosis rate of human non-small cell lung cancer A549 cells induced by the aspirin-sulfonamide hybrid 3k of the present application.

[0071] Fig.43 The figure is a cell cycle diagram showing that the aspirin-sulfonamide hybrid 3k of the present application affects the growth of human non-small cell lung cancer A549 cells.

[0072] Fig.44 It is a diagram of the predicted binding model of the aspirin-sulfonamide hybrid 3k of the present application and the receptor COX-2.

[0073] Fig.45 It is a 2D diagram of the interaction between the aspirin-sulfonamide hybrid 3k of the present application and the receptor COX-2. DETAILED DESCRIPTION

[0074] The technical solutions and technical effects of the embodiments of the present invention are further described in detail below in conjunction with the accompanying drawings of the present invention.

[0075] In a first aspect, the present invention provides an aspirin-sulfonamide hybrid, and the general structural formula of the aspirin-sulfonamide hybrid is as follows:

[0076]

[0077] Among them, R 1 Selected from aromatic or heteroaryl or hydrocarbon groups.

[0078] Furthermore, R 1 Select from one of the following groups:

[0079]

[0080] The anticancer activity of the aspirin-sulfonamide hybrid prepared by the present invention is significantly higher than that of the parent aspirin, wherein the aspirin-sulfonamide hybrid containing bromothiophene structure 3k (IC 50 =36.57 μM) was the most effective against human non-small cell lung cancer A549 cells, and its activity was higher than that of the parent aspirin (IC 50>1200μM) is more than 33 times higher than the anticancer drug irinotecan (IC 50 =29.07 μM) and the activity of aspirin-sulfonamide hybrid 3k was similar to that of BEAS-2B cells in normal human lung epithelial cells (IC 50 =201.60 μM), its selectivity for human non-small cell lung cancer cell A549 (SI BEAS-2B / A549 =6) is much higher than irinotecan (SI BEAS-2B / A549 =1), therefore, the aspirin-sulfonamide hybrid prepared by the present invention can effectively treat lung cancer.

[0081] In a second aspect, the present invention provides a method for preparing an aspirin-sulfonamide hybrid, which is used to prepare the aspirin-sulfonamide hybrid as described in the first aspect, comprising the following steps:

[0082] S1, aspirin and oxalyl chloride are subjected to chlorination reaction under the catalysis of a catalyst to obtain o-acetylsalicylic acid chloride 1;

[0083] S2, piperazine and sulfonyl chloride undergo sulfonylation reaction under the action of the first acid binding agent to obtain sulfonamide 2;

[0084] S3, o-acetylsalicylic acid chloride 1 and sulfonamide 2 are subjected to N-acylation reaction under the action of a second acid-binding agent, and then separated and purified to obtain the target product aspirin-sulfonamide hybrid 3a-1. The synthetic route is as follows:

[0085]

[0086] Among them, R 1 The definition of is the same as that of the first aspect.

[0087] Furthermore, the catalyst in step S1 is N,N-dimethylformamide; the temperature required in step S1 is 10° C. to 40° C.; and the reaction time required in step S1 is 0.5 h to 3 h.

[0088] Furthermore, the first acid binding agent in step S2 and the second acid binding agent in step S3 are both tertiary amines, for example, trimethylamine, triethylamine and tripropylamine; the temperature required for the reaction in step S2 is 10° C. to 40° C.; and the time required for the reaction in step S2 is 0.5 h to 3 h.

[0089] Furthermore, the temperature required for the reaction in step S3 is -5°C to 5°C; the time required for the reaction in step S3 is 0.5h to 2h.

[0090] In a third aspect, the present invention provides the use of the aspirin-sulfonamide hybrid according to the first aspect, comprising:

[0091] A pharmaceutically acceptable salt of an aspirin-sulfonamide hybrid as described above.

[0092] A pharmaceutical composition of an aspirin-sulfonamide hybrid or a pharmaceutically acceptable salt thereof as described above.

[0093] The pharmaceutical preparation of aspirin-sulfonamide hybrid or a pharmaceutically acceptable salt thereof as described above further comprises at least one pharmaceutically acceptable excipient or carrier; the pharmaceutical preparation comprises tablets, powders, capsules, granules or injections.

[0094] Use of the aspirin-sulfonamide hybrid or its pharmaceutically acceptable salt or its pharmaceutical composition or its pharmaceutical preparation as described above in the preparation of anticancer drugs.

[0095] Furthermore, the cancers that can be treated by the above anticancer drugs include: lung cancer, liver cancer, breast cancer, colorectal cancer, cervical cancer, gastric cancer and malignant glioblastoma.

[0096] Example 1, the general synthesis method of aspirin-sulfonamide hybrids is as follows:

[0097] Experimental Materials: Commercial reagents were purchased from Adamas and Anergy and used as received unless otherwise stated. Dichloromethane was redistilled dichloromethane (DCM). Thin layer chromatography (TLC) was performed on silica GF254 plates. IR spectra were recorded on a FTIR-8400S spectrometer in the form of KBr pellets. The wavelengths were obtained using a Bruker Avance III 400 MHz spectrometer. 1 HNMR and 13 C NMR spectra. Chemical shifts (δ) are in ppm with respect to tetramethylsilane. The residual solvent signal was used as 1 H and 13 C NMR spectra reference (CDCl3:δ H =7.26ppm,δ C =77.16 ppm). The high resolution mass spectrometry (HRMS) of the target compound was tested on a Thermo Fisher LTQ Orbitrap XL. The biological activity test was conducted by the Green Pharmaceutical Collaborative Innovation Center of Zhejiang University of Technology.

[0098] Synthesis process: S101, at 25°C, aspirin (0.6 g, 3.0 mmol), DCM (10 mL), N,N-dimethylformamide (0.6 mmol / six drops), and oxalyl chloride (1.3 mL, 15.0 mmol) were added to a 50 mL flask in sequence, stirred at room temperature for 1.5 h, and concentrated under reduced pressure to obtain a crude product 1;

[0099] S201, at 25°C, take a 50mL flask and add piperazine (0.4g, 4.5mmol), DCM, triethylamine (0.6mL, 4.5mmol), and sulfonyl chloride (3.3mmol) in sequence. The reaction is monitored by TLC. After stirring at room temperature for 1h, 50mL of water is added to the reaction solution, and the reaction solution is washed with saturated NaHCO3 (30mLⅹ2) and saturated brine (30mLⅹ3). The organic phase is dried over anhydrous Na2SO4, filtered, and concentrated to remove excess solvent to obtain the crude product 2.

[0100] S301, at 0°C, crude product 2, DCM and triethylamine (0.9 mL, 6.0 mmol) were added to a 50 mL flask in sequence, and then a solution of crude product 1 in DCM was added dropwise. The reaction was monitored by TLC, and the resulting mixture was stirred at room temperature for 1 hour, and then 50 mL of water was added to quench the reaction. The organic phase was washed with brine (30 mL × 3), dried over Na2SO4, filtered and concentrated. The residue was separated and purified by silica gel column chromatography to obtain aspirin-sulfonamide hybrid 3.

[0101] The eluent used in the silica gel column chromatography was a mixture of methanol and dichloromethane in a ratio of 1:80. 1 The group is

[0102]

[0103] The target products 3 obtained from the sulfonyl chlorides of the above structural formula are numbered 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k and 3l in sequence; the target product 3 obtained by the above synthesis method is an aspirin-sulfonamide hybrid (3a-l).

[0104] Please refer to Figures 1 to 39 ,pass 1 HNMR, 13 C NMR, 19 The product prepared in Example 1 was characterized by means of F NMR, IR spectroscopy and HRMS.

[0105] Compound 3a: 2-(4-(phenylsulfonyl)piperazine-1-carbonyl)phenyl acetate(3a). White solid, yield 60% for three steps, mp189.6-191.5℃; 11H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz, 2H), 7.58 - 7.46 (m, 3H), 7.32 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 5.7 Hz, 2H), 7.03 (d, J = 8.3 Hz, 1H), 4.02 - 3.55 (m, 2H), 3.33 (s, 2H), 3.17 - 2.75 (m, 4H), 1.90 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 168.45, 166.34, 146.75, 134.76, 133.04, 130.53, 129.09, 128.20, 127.51, 127.48, 125.95, 122.80, 46.21, 45.81, 20.48; IR (KBr) ν / cm -1 : 1764, 1639, 1446, 1342, 1276, 1166, 935, 742, 574; HRMS (ESI) calcd for C 19 H 21 N2O5S [M + H] + 389.1166, found, 389.1161.

[0106] Compound 3b: 2-(4-tosylpiperazine-1-carbonyl)phenylacetate (3b). White solid, yield 63% for three steps, m.p. 191.7 - 192.8 °C; 1 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.9 Hz, 2H), 7.38 (dd, J = 15.9, 7.0 Hz, 3H), 7.23 (t, J = 4.6 Hz, 2H), 7.11 (d, J = 8.2 Hz, 1H), 3.97 - 3.66 (m, 2H), 3.39 (t, J = 5.1 Hz, 2H), 3.11 - 2.89 (m, 4H), 2.43 (s, 3H), 2.00 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 168.58, 166.50, 146.91, 144.05, 131.97, 130.67, 129.78, 128.36, 127.77, 127.60, 126.07, 122.95, 46.38, 45.86, 21.47, 20.55; IR (KBr) ν / cm -1: 1762, 1625, 1434, 1342, 1160, 933, 727, 545; HRMS(ESI) calcd for C 20 H 23 N2O5S [M+H] + 403.1322, found, 403.1320.

[0107] Compound 3c: 2-(4-((4-methoxyphenyl)sulfonyl)piperazine-1-carbonyl)phenylacetate (3c). Light yellow solid, yield 59% for three steps, m.p. 206.3 - 207.5 °C; 1 H NMR(400 MHz, CDCl3) δ 7.66 (d, J = 8.5 Hz, 2H), 7.41 - 7.34 (m, 1H), 7.24 - 7.16 (m, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 3.84 (s, 5H), 3.37 (t, J = 5.1 Hz, 2H), 2.98 (d, J = 65.9 Hz, 4H), 2.01 (s, 3H); 13 C NMR(101 MHz, CDCl3) δ 168.71, 166.62, 163.34, 147.06, 130.77, 129.98, 128.47, 127.68, 126.64, 126.15, 123.06, 114.40, 55.74, 46.49, 45.94, 20.71; HRMS(ESI) calcd for C 20 H 23 N2O6S [M+H] + 419.1271, found 419.1266.

[0108] Compound 3d: 2-(4-((4-nitrophenyl)sulfonyl)piperazine-1-carbonyl)phenylacetate (3d). White solid, yield 61% for three steps, m.p. 210.6 - 211.9 °C; 1HNMR(400MHz,CDCl3)δ8.40(d,J=8.5Hz,2H),7.95(d,J=8.6Hz,2H),7.43(t,J=7.8Hz,1H),7.27 - 7.17(m,2H),7.11(d,J=8.2Hz,1H),3.85(s,2H),3.47(t,J=5.1Hz,2H),3.20 - 3.00(m,4H),2.09(s,3H); 13 C NMR(101MHz,CDCl3)δ168.93,166.87,150.45,147.43,141.65,131.12,129.01,128.13,127.67,126.10,124.57,123.19,46.66,45.84,20.91;IR(KBr)ν / cm -1 :1764,1631,1429,1348,1184,944,738,593;HRMS(ESI)calcd for C 19 H 20 N3O7S[M + H] + 434.1016,found 434.1012.

[0109] Compound 3e: 2-(4-((3-nitrophenyl)sulfonyl)piperazine-1-carbonyl)phenylacetate (3e). White solid, yield 62% for three steps, m.p. 204.7 - 205.9 °C; 1 HNMR(400MHz,CDCl3)δ8.58(s,1H),8.48(d,J=8.3Hz,1H),8.07(d,J=7.6Hz,1H),7.79(t,J=8.0Hz,1H),7.42(t,J=6.8Hz,1H),7.21(dd,J=15.7,6.6Hz,2H),7.11(d,J=8.2Hz,1H),3.84(t,J=5.2Hz,2H),3.47(t,J=5.2Hz,2H),3.14 - 3.03(m,4H),2.08(s,3H); 13 C NMR(101MHz,CDCl3)δ168.91,166.96,148.56,147.46,138.17,133.24,131.17,130.82,128.11,127.73,127.67,126.14,123.21,122.85,46.71,46.04,20.94;IR(KBr)ν / cm-1 : 2919, 1764, 1633, 1525, 1351, 1184, 761, 572; HRMS(ESI) calcd for C 19 H 20 N3O6S [M + H] + 434.1016, found 434.1013.

[0110] Compound 3f: 2-(4-((4-fluorophenyl)sulfonyl)piperazine-1-carbonyl)phenylacetate (3f). White solid, yield 64% for three steps, m.p. 207.4 - 208.6 °C; 1 1H NMR (400 MHz, CDCl3) δ 7.80 - 7.73 (m, 2H), 7.43 - 7.38 (m, 1H), 7.27 - 7.18 (m, 4H), 7.10 (d, J = 8.2 Hz, 1H), 3.87 (d, J = 62.8 Hz, 2H), 3.41 (t, J = 5.2 Hz, 2H), 2.94 (s, 4H), 2.05 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 168.79, 166.71, 164.17, 147.21, 130.90, 130.61, 130.52, 128.35, 127.68, 126.13, 123.11, 116.46, 46.53, 45.90, 20.77; 19 19F NMR (376 MHz, CDCl3) δ -105.88; IR(KBr) ν / cm -1 : 2919, 1743, 1643, 1434, 1178, 1014, 725, 543; HRMS(ESI) calcd for C 19 H 20 F N2O5S [M + H] + 407.1071, found 407.1068.

[0111] Compound 3g: 2-(4-((3,5-difluorophenyl)sulfonyl)piperazine-1-carbonyl)phenylacetate (3g). White solid, yield 65% for three steps, m.p. 217.9 - 219.7 °C; 1HNMR(400MHz,CDCl3)δ7.42(t,J=7.7Hz,1H),7.28(d,J=2.6Hz,2H),7.10(dd,J=5.6,3.3Hz,2H),6.96(d,J=8.3Hz,1H),6.85(t,J=7.6Hz,1H),3.82(s,3H),3.45(t,J=5.1Hz,2H),3.10(t,J=5.1Hz,3H),2.11(s,3H); 13 C NMR(101MHz,CDCl3)δ171.25,168.91,166.92,159.03,147.39,133.34,131.11,128.30,127.75,126.18,123.21,119.05,118.39,116.24,46.67,46.15,45.93,41.15,20.91; 19 F NMR(376MHz,CDCl3)δ - 105.90; IR(KBr)ν / cm -1 : 2925,1766,1606,1438,1292,1187,943,763,595; HRMS(ESI)calcd for C 19 H 19 F2N2O5S[M + H] + 425.0977, found 425.0971.

[0112] Compound 3h: 2-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazine-1-carbonyl)phenyl acetate (3h). White solid, yield 60% for three steps, m.p. 202.2 - 203.5 °C; 1 H NMR(400MHz,CDCl3)δ7.83 - 7.75(m,2H),7.43 - 7.34(m,3H),7.25 - 7.17(m,2H),7.09(d,J = 8.2Hz,1H),3.78(t,J = 5.1Hz,2H),3.42(q,J = 6.2,5.3Hz,2H),3.21 - 2.81(m,4H),2.01(s,3H); 1313C NMR (101 MHz, CDCl3) δ 168.83, 166.76, 152.57, 147.27, 133.72, 130.98, 130.03, 128.34, 127.72, 126.17, 123.14, 121.16, 118.98, 46.58, 45.93, 20.71; 19 19F NMR (376 MHz, CDCl3) δ -106.09; IR (KBr) ν / cm -1 : 1766, 1633, 1187, 1157, 943, 736, 592; HRMS (ESI) calcd for C 20 H 20 F3N2O6S [M+H] + 473.0989, found 473.0983.

[0113] Compound 3i: 2-(4-(pyridin-3-ylsulfonyl)piperazine-1-carbonyl)phenylacetate (3i). Yellow solid, yield 59% for three steps, m.p. 205.9 - 207.3 °C; 1 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J = 2.3 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 8.04 (dt, J = 8.0, 2.0 Hz, 1H), 7.51 (dd, J = 8.1, 4.9 Hz, 1H), 7.40 (td, J = 7.7, 1.9 Hz, 1H), 7.25 - 7.15 (m, 2H), 7.10 (d, J = 8.2 Hz, 1H), 3.84 (s, 2H), 3.44 (t, J = 5.3 Hz, 2H), 3.17 - 2.96 (m, 4H), 2.05 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 168.83, 166.85, 153.74, 148.47, 147.34, 135.52, 133.08, 131.01, 128.27, 127.67, 126.13, 123.16, 119.09, 46.61, 45.80, 20.84; IR (KBr) ν / cm -1 : 2919, 1762, 1629, 1174, 935, 754, 580; HRMS (ESI) calcd for C 18 H 20 N3O5S [M+H] +390.1118, found 390.1109.

[0114] Compound 3j: 2-(4-(thiophen-2-ylsulfonyl)piperazine-1-carbonyl)phenyl acetate (3j). White solid, yield 56% for three steps, m.p. 204.1 - 205.6 °C; 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 3.7 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.43 (t, J = 6.4 Hz, 1H), 7.25 (t, J = 4.7 Hz, 2H), 7.22 - 7.15 (m, 1H), 7.13 (d, J = 8.2 Hz, 1H), 3.88 (d, J = 67.8 Hz, 2H), 3.45 (t, J = 5.2 Hz, 2H), 3.01 (s, 4H), 2.08 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 168.71, 166.66, 147.12, 135.47, 132.89, 132.65, 130.81, 128.41, 127.89, 127.65, 126.13, 123.06, 46.38, 45.95, 20.74; IR (KBr) ν / cm -1 ; 2919, 1764, 1627, 1274, 1187, 750, 578; HRMS (ESI) calcd for C 17 H 19 N2O5S2 [M + H] + 395.0730, found 395.0727.

[0115] Compound 3k: 2-(4-((5-bromothiophen-2-yl)sulfonyl)piperazine-1-carbonyl)phenyl acetate (3k). Light yellow solid, yield 58% for three steps, m.p. 207.5 - 209.1 °C; 11H NMR (400 MHz, CDCl3) δ 7.46 - 7.41 (m, 1H), 7.30 (d, J = 4.2 Hz, 1H), 7.26 (d, J = 6.4 Hz, 2H), 7.15 (t, J = 6.7 Hz, 2H), 3.80 (dt, J = 40.5, 5.2 Hz, 2H), 3.47 (q, J = 5.5 Hz, 2H), 3.07 (dt, J = 42.0, 5.0 Hz, 4H), 2.14 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 168.91, 166.86, 147.32, 136.42, 133.16, 131.03, 130.97, 128.34, 127.75, 126.22, 123.20, 120.66, 46.49, 45.99, 20.89; IR (KBr) ν / cm -1 : 2927, 1766, 1633, 1349, 1187, 1153, 946, 719, 590; HRMS (ESI) calcd for C 17 H 18 BrN2O5S2 [M + H] + 472.9835, found 472.9830.

[0116] Compound 3l: 2-(4-(cyclopropylsulfonyl)piperazine-1-carbonyl)phenylacetate (3l). Light yellow solid, yield 51% for three steps, m.p. 202.8 - 203.5 °C; 1 1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 15.5, 7.3 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.17 - 7.14 (m, 1H), 3.86 (s, 2H), 3.45 - 3.23 (m, 5H), 3.09 (s, 1H), 2.88 (s, 1H), 2.26 (s, 3H), 1.13 (d, J = 3.9 Hz, 2H), 1.03 - 0.95 (m, 2H); 13 13C NMR (101 MHz, CDCl3) δ 169.01, 166.90, 147.38, 130.96, 128.50, 127.75, 126.13, 123.17, 47.07, 45.99, 25.83, 21.06, 4.46; IR (KBr) ν / cm -1:2925,1749,1625,1440,1336,1199,738; HRMS(ESI)calcd for C 16 H 21 N2OS[M+H]+353.1166,found353.1159.

[0117] Example 2, Cytotoxicity Experiment of Aspirin-Sulfonamide Hybrid 3

[0118] Experimental materials: The anticancer drug irinotecan (IRT) was selected as the reference and aspirin as the parent. The MTT method was used to detect the in vitro cytotoxicity of aspirin-sulfonamide hybrid 3a-l.

[0119] Experimental methods:

[0120] Human non-small cell lung cancer cells A549 or human normal lung epithelial cells BEAS-2B (2.5×10 3 The suspension was replaced with fresh culture medium containing different doses of aspirin-sulfonamide hybrid 3, aspirin and IRT (1, 10, 25, 50, 75 and 100 μM), and the same volume of dimethyl sulfoxide was added to the drug-free medium negative control well and the solvent control well. Then, 100 μL of 0.5 mg / mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (dissolved in PBS and then diluted in fresh culture medium) was added to each well and cultured for another 4 hours. Finally, the culture medium was removed, and the MTT formazan precipitate was dissolved in 100 μL DMSO. After mechanical shaking for 10 minutes, the plate was immediately read at a wavelength of 570 nm using a microplate reader (FlexStation3, Molecular Devices).

[0121] The results are shown in Table 1, Table 2 and Table 3 below:

[0122] Table 1

[0123]

[0124] Table 2

[0125]

[0126]

[0127] Table 3

[0128]

[0129]

[0130] Wherein, ASP = aspirin, IRT = irinotecan, the values ​​in the table are the mean ± SD of three independent experiments; the data in Table 1 are the IC values ​​of each compound against human non-small cell lung cancer cells A549 and human normal lung epithelial cells BEAS-2B 50 The data in Table 2 are the inhibition rates of each compound on human non-small cell lung cancer cells A549, and the data in Table 3 are the inhibition rates of each compound on human normal lung epithelial cells BEAS-2B.

[0131] By analyzing the data in Tables 1 to 3, we can know that:

[0132] Aspirin-sulfonamide hybrids 3b, 3d, and 3f-3l (IC 50 =36.57-454.60 μM) had a greater inhibitory activity against human non-small cell lung cancer A549 cells than aspirin (IC 50 >1200μM); the inhibitory activity of aspirin-sulfonamide hybrids 3a and 3c on human non-small cell lung cancer A549 cells was poor, similar to that of aspirin; when the R 1 When m-nitrobenzene (3e) was used, the activity was significantly reduced (IC 50 >3000μM); when the R 1 When it is p-tolyl, 3,5-difluorophenyl or cyclopropyl (3b, 3g and 3l, IC 50 <100 μM), and its cytotoxicity was superior to that of aspirin-sulfonamide hybrid R 1 When it is p-nitrophenyl, p-fluorophenyl, p-trifluoromethoxyphenyl or 3-pyridyl (3d, 3f, 3h and 3i, IC 50 =142.13-454.60 μM) of cytotoxicity; aspirin-sulfonamide hybrids 3j and 3k with the introduction of thiophene groups showed the strongest cytotoxicity (IC 50 =36.57-38.21 μM), among which the aspirin-sulfonamide hybrid 3k with bromothiophene structure was the most effective against human non-small cell lung cancer A549 cells (IC 50 =36.57 μM), its cytotoxicity was higher than that of the parent aspirin (IC 50 >1200μM) was more than 33 times higher, and had little toxicity to normal human lung epithelial cells BEAS-2B (IC 50 =201.60 μM); highly selective for human non-small cell lung cancer A549 cells (SI BEAS-2B / A549 =6), much higher than irinotecan (SI BEAS-2B / A549 =1).

[0133] Calculate the cell inhibition rate and plot it as Fig.40The line graph shown, where cell inhibition rate = [A 570 (Negative control well)-A 570 (Dosing hole)] / A 570 (Negative control wells) x 100%; the values ​​in the graph are the mean ± SD of three independent experiments, each performed in triplicate.

[0134] right Fig.40 From the analysis of the data in, it can be seen that the inhibition rate of aspirin-sulfonamide hybrid 3 on human non-small cell lung cancer cells A549 and human normal lung epithelial cells BEAS-2B increases with the increase of concentration; when the concentration is 100μM, the inhibition rate of aspirin-sulfonamide hybrid 3k on human non-small cell lung cancer cells A549 can reach 63.64%, and shows a continuous growth trend; it can be seen that the inhibitory effect of aspirin-sulfonamide hybrid 3k on the proliferation of human non-small cell lung cancer A549 cells is concentration-dependent.

[0135] Example 3, Cytotoxicity Experiment of Aspirin-Sulfonamide Hybrid 3k on Different Cancer Cells

[0136] Experimental method: Human liver cancer cells HepG2 or human breast cancer cells MCF-7 or human colorectal cancer cells Caco-2 or human colorectal cancer cells HCT-116 or human cervical cancer cells Hela or human gastric cancer cells HGC-27 or human malignant glioblastoma cells U87 (2.5×10 3 The suspension was replaced with fresh medium containing different doses of aspirin-sulfonamide hybrid 3k (1, 10, 25, 50, 75 and 100 μM), and the same volume of dimethyl sulfoxide was added to the negative control wells with no drug medium and the solvent control wells. Then, 100 μL of 0.5 mg / mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (dissolved in PBS and then diluted in fresh medium) was added to each well and incubated for another 4 hours. Finally, the medium was removed, and the MTT formazan precipitate was dissolved in 100 μL DMSO. After mechanical shaking for 10 minutes, the plate was immediately read at a wavelength of 570 nm using a microplate reader (FlexStation 3, Molecular Devices).

[0137] The results are shown in Tables 4 and 5 below:

[0138] Table 4

[0139] Cancer cells HepG2 MCF-7 Caco-2 HCT-116 Hela HGC-27 U87 <![CDATA[IC 50 (μM) / 48h]]> 60.55±3.20 64.12±2.17 62.18±9.96 78.59±3.04 41.96±7.78 >300 92.77±1.86

[0140] Table 5

[0141]

[0142]

[0143] The values ​​in the table are the mean ± SD of three independent experiments; the data in Table 4 are the IC values ​​of aspirin-sulfonamide hybrid 3k against the above 7 human cancer cells. 50 Value; The data in Table 5 are the inhibition rates of aspirin-sulfonamide hybrid 3k on the above 7 types of human cancer cells.

[0144] Calculate the cell inhibition rate and plot it as Fig.41 The line graph shown, where cell inhibition rate = [A 570 (Negative control well)-A 570 (Dosing hole)] / A 570 (Negative control wells) x 100%; the values ​​in the graph are the mean ± SD of three independent experiments, each performed in triplicate.

[0145] Table 4, Table 5 and Fig.41 The data in the analysis show that the IC values ​​of aspirin-sulfonamide hybrid 3k against the above 7 human cancer cells are 50 The values ​​were 41.96-376.50 μM, which was inferior to the inhibitory effect of aspirin-sulfonamide hybrid 3k on human non-small cell lung cancer cells A549 (IC 50 =36.57 μM), therefore, aspirin-sulfonamide hybrid 3k has research value as a candidate drug in the field of anti-non-small cell lung cancer candidate drug development.

[0146] Example 4, Experiment on aspirin-sulfonamide hybrid 3k inducing apoptosis in human non-small cell lung cancer A549 cells

[0147] Experimental method: Human non-small cell lung cancer A549 cells (5×10 4 The cells were inoculated in triplicate in 12-well plates, and after culturing at 37°C for 24 hours, the old culture medium was replaced with fresh culture medium containing different concentrations of hybrid 3k (20, 80 and 140 μM), and the same volume of dimethyl sulfoxide was added to the drug-free medium negative control wells and solvent control wells; then the cells were incubated at 37°C for 48 hours, and 100 μL of preheated 0.25% trypsin without ethylenediaminetetraacetic acid (EDTA) was added to each well after the culture medium was aspirated; after trypsinization, the treated cells were stained using the Annexin V-FITC / PI cell apoptosis detection kit according to the manufacturer's instructions, and then incubated in the dark at room temperature for 5-15 minutes, and apoptotic cells were analyzed using a CytoFLEX flow cytometer.

[0148] The results of flow cytometry analysis were plotted as follows: Fig.42The percentage of AV and / or PI-positive cells shown in A, including normal cells (LL), early apoptotic cells (LR), late apoptotic cells (UR) and necrotic cells (UL); according to the analysis results of flow cytometry, the following is drawn: Fig.42 The total apoptosis rate of human non-small cell lung cancer A549 cells shown in B is the mean ± SD of three independent experiments. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0149] right Fig.42 By analyzing the data in , we can know that Fig.42 As shown in Figure A, with the increase in the concentration of aspirin-sulfonamide hybrid 3k, the number of normal cells gradually decreased, while the number of early and late apoptotic cells gradually increased; Fig.42 As shown in Figure B, when the concentration of aspirin-sulfonamide hybrid 3k was 20, 80 and 140 μM, the total apoptosis rate of human non-small cell lung cancer A549 cells was 19.99%, 36.90% and 47.73%, respectively, while that of the control group was only 4.65%; the above results indicate that aspirin-sulfonamide hybrid 3k can induce apoptosis of human non-small cell lung cancer A549 cells in a concentration-dependent manner.

[0150] Example 5, Experiment on the inhibition of growth of human non-small cell lung cancer A549 cells by aspirin-sulfonamide hybrid 3k

[0151] Experimental method: Human non-small cell lung cancer A549 cells (2.5×10 5 The cells were inoculated in triplicate in 6-well plates, and after culturing at 37°C for 24 hours, the old culture medium was replaced with fresh culture medium containing different concentrations of aspirin-sulfonamide hybrid 3k (5, 10 and 20 μM), and the same volume of dimethyl sulfoxide was added to the drug-free medium negative control wells and solvent control wells; then the cells were incubated at 37°C for 24 hours, and 200 μL of 0.25% trypsin was added to each well after the culture medium was aspirated; after trypsin treatment, the cells were fixed with 70% ethanol at 4°C overnight, and then stained using the PI cell cycle analysis kit according to the manufacturer's instructions; finally, after culturing in the dark at 37°C for 30 minutes, the cell cycle was analyzed using a CytoFLEX flow cytometer.

[0152] The results of flow cytometry analysis were plotted as follows: Fig.43 The effect of aspirin-sulfonamide hybrid 3k shown in A on the cell cycle of human non-small cell lung cancer A549 cells; the results of flow cytometry analysis were plotted as follows Fig.43Statistical analysis of cell cycle in human non-small cell lung cancer A549 cells treated with aspirin-sulfonamide hybrid 3k for 24 hours as shown in B. Statistically significant differences are indicated by *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001.

[0153] right Fig.43 The data in the analysis show that aspirin-sulfonamide hybrid 3k has an effect on the cell cycle of human non-small cell lung cancer A549 cells. As the concentration of aspirin-sulfonamide hybrid 3k gradually increases, the number of human non-small cell lung cancer A549 cells with cell cycle arrest also gradually increases; when the concentration of aspirin-sulfonamide hybrid 3k is 5, 10 and 20 μM, the proportion of human non-small cell lung cancer A549 cells entering the G0 / G1 phase is 68.30%, 71.00% and 76.77%, respectively, while the control group is 64.63%. The above experimental results show that aspirin-sulfonamide hybrid 3k can induce human non-small cell lung cancer A549 cell cycle arrest in the G0 / G1 phase and further inhibit the growth of human non-small cell lung cancer A549 cells.

[0154] Example 6, Analysis of Binding Characteristics of Aspirin-Sulfonamide Hybrid 3k to COX-2 Receptor

[0155] Purpose: Cyclooxygenase-2 (COX-2) is significantly upregulated in many cancers. In addition to its well-known ability to reduce the body's immune system function by causing inflammation, it also leads to abnormal expression of tumor-related factors Bcl-2, MMP-2 and epidermal growth factor receptor EGFR, which leads to tumor cell resistance to apoptosis, invasion of extracellular matrix causing metastasis and malignant transformation, making cancer worse. Aspirin, as a nonsteroidal anti-inflammatory drug (NSAID), can inhibit the activity of COX-2, thereby reducing the biosynthesis of prostaglandins and treating inflammation; current studies have shown that aspirin may exert anticancer effects by inhibiting the activity of COX-2, but its specific mechanism remains to be further explored. Therefore, we speculated that the synthesized aspirin-sulfonamide hybrid 3k may exert anticancer effects by inhibiting COX-2, and confirmed it through molecular docking experiments.

[0156] Experimental materials: The molecules were drawn using ChemDraw 20.0 software and adjusted using MOE (Molecular Operating Environment) software; the COX-2 receptor (PDB ID: 5F1A) downloaded from the Protein Data Bank (https: / / www.rcsb.org) was drawn using MOE software.

[0157] Experimental methods: Molecular docking analysis was performed using the molecular operating environment (MOE); the pocket involving residues Thr212, Thr206, Gln203, Ala199, and His207 was set in the solvent environment. After setting the method (placement: trianglematcher, refinement: rigid receptor), score (placement: London dG, refinement: GBVI / WSA dG), and poses (placement: 300, refinement: 5), docking was performed via MOE. The docked conformation with the lowest binding energy was selected from the 300 conformations as a representative binding energy for evaluating the potential of the corresponding compound. The best docked pose selected was used to analyze the interaction between the receptor COX-2 and the aspirin-sulfonamide hybrid 3k.

[0158] The predicted binding model of aspirin-sulfonamide hybrid 3k with receptor COX-2 (PDB ID: 5F1A) is generated as follows Fig.44 As shown, A shows the interaction between aspirin-sulfonamide hybrid 3k and receptor COX-2, and B shows the details of the interaction between aspirin-sulfonamide hybrid 3k and receptor COX-2; in the figure, aspirin-sulfonamide hybrid 3k is green; the residues involved in the interaction of aspirin-sulfonamide hybrid 3k are represented by red ball-and-stick models and named in red; hydrogen bonds are represented by cyan dotted lines; π-π and π-H interactions are represented by aqua dotted lines.

[0159] right Fig.44 The analysis revealed that the aspirin-sulfonamide hybrid 3k was well positioned in the active pocket, its ring system was well enclosed by the cavity of the receptor, and there were many good interactions.

[0160] Furthermore, draw Fig.45 2D diagram of the interaction of aspirin-sulfonamide hybrid 3k with the receptor COX-2 is shown.

[0161] right Fig.45The analysis revealed that the O atoms of the ester carbonyl and sulfonyl groups in aspirin-sulfonamide hybrid 3k interacted with the residues Thr212, Thr206, and Gln203 through hydrogen bonds; the S atom of the thienyl group in aspirin-sulfonamide hybrid 3k interacted with the residue Ala199 through hydrogen bonds; in addition, aspirin-sulfonamide hybrid 3k formed π-H interactions through residue His207, showing more interactions; these interactions greatly enhanced the binding affinity of aspirin-sulfonamide hybrid 3k with COX-2 receptor. The docking model revealed the good interaction between aspirin-sulfonamide hybrid 3k and COX-2, and supported aspirin-sulfonamide hybrid 3k as an excellent drug for the treatment of non-small cell lung cancer.

[0162] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. An aspirin-sulfonamide hybrid, characterized in that The general structural formula of the aspirin-sulfonamide hybrid is as follows: Among them, R 1 Selected from aromatic or heteroaryl or hydrocarbon groups.

2. The aspirin-sulfonamide hybrid according to claim 1, characterized in that: The R 1 Selected from one of the following groups:

3. A method for preparing an aspirin-sulfonamide hybrid, for preparing the aspirin-sulfonamide hybrid as claimed in claim 1, characterized in that: The following steps are involved: S1, aspirin and oxalyl chloride are subjected to chlorination reaction under the catalysis of a catalyst to obtain o-acetylsalicylic acid chloride 1; S2, piperazine and sulfonyl chloride undergo sulfonylation reaction under the action of the first acid binding agent to obtain sulfonamide 2; S3, o-acetylsalicylic acid chloride 1 and sulfonamide 2 are subjected to N-acylation reaction under the action of a second acid-binding agent, and then separated and purified to obtain the target product aspirin-sulfonamide hybrid 3a-1. The synthetic route is as follows: Among them, R 1 The definition is the same as that of claim 1 or 2.

4. The method for preparing aspirin-sulfonamide hybrid according to claim 3, characterized in that: The catalyst in step S1 is N,N-dimethylformamide.

5. The method for preparing aspirin-sulfonamide hybrid according to claim 3, characterized in that: The first acid binding agent in step S2 and the second acid binding agent in step S3 are both tertiary amines.

6. A pharmaceutically acceptable salt of an aspirin-sulfonamide hybrid as claimed in claim 1 or 2; Or a pharmaceutically acceptable salt of aspirin-sulfonamide hybrid obtained by the method for preparing aspirin-sulfonamide hybrid according to any one of claims 3 to 5.

7. A pharmaceutical composition comprising the aspirin-sulfonamide hybrid according to claim 1 or 2; Or a pharmaceutical composition containing an aspirin-sulfonamide hybrid obtained by the method for preparing an aspirin-sulfonamide hybrid according to any one of claims 3 to 5; Or a pharmaceutical composition containing a pharmaceutically acceptable salt of the aspirin-sulfonamide hybrid according to claim 6.

8. A pharmaceutical preparation containing the aspirin-sulfonamide hybrid as claimed in claim 1 or 2; Or a pharmaceutical preparation containing an aspirin-sulfonamide hybrid obtained by the method for preparing an aspirin-sulfonamide hybrid according to any one of claims 3 to 5; Or a pharmaceutical preparation containing a pharmaceutically acceptable salt of the aspirin-sulfonamide hybrid according to claim 6, characterized in that It also includes at least one pharmaceutically acceptable excipient or carrier.

9. Use of the aspirin-sulfonamide hybrid according to claim 1 or 2 in the preparation of anticancer drugs; Or use of the aspirin-sulfonamide hybrid obtained by the method for preparing the aspirin-sulfonamide hybrid according to any one of claims 3 to 5 in the preparation of anticancer drugs; Or use of a pharmaceutically acceptable salt of an aspirin-sulfonamide hybrid as claimed in claim 6 in the preparation of an anticancer drug; Or use of the pharmaceutical composition according to claim 7 in the preparation of anticancer drugs; Or use of the pharmaceutical preparation as claimed in claim 8 in the preparation of anticancer drugs.

10. Use of the aspirin-sulfonamide hybrid according to claim 9 in the preparation of anticancer drugs, characterized in that: The cancers that can be treated by the anticancer drug include: lung cancer, liver cancer, breast cancer, colorectal cancer, cervical cancer, gastric cancer and malignant glioblastoma.

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