Aspirin-sulfonamide hybrids, processes for their preparation and use

Abstract

The application relates to the technical field of aspirin pharmaceutical chemistry, in particular to an aspirin-sulfonamide hybrid, a preparation method and application thereof. The preparation method can synthesize a plurality of novel aspirin-sulfonamide hybrids by taking piperazine as a bridge, and by a three-step continuous method of "acyl chlorination, sulfonamidation and N-acylation" according to a "molecular hybridization principle". In the process, only one separation and purification is performed, and the preparation steps are simple. The aspirin-sulfonamide hybrid prepared by the method is most effective on human non-small cell lung cancer cells A549, and the activity is more than 33 times higher than that of a parent aspirin, and is similar to the activity of an anticancer drug irinotecan. The aspirin-sulfonamide hybrid 3k prepared by the method has a certain inhibitory effect on various cancer cells. The hybrid can induce human non-small cell lung cancer A549 cell apoptosis in a concentration-dependent manner, and can induce human non-small cell lung cancer A549 cell cycle arrest in the G0 / G1 phase, and inhibit cell growth.

Description

Technical Field

[0001] This invention relates to the field of aspirin pharmaceutical chemistry, and more particularly to an aspirin-sulfonamide hybrid, its preparation method, and its application. Background Technology

[0002] Cancer is one of the leading diseases threatening human life and health worldwide. According to statistics from the International Agency for Research on Cancer (IARC), approximately 20 million new cancer cases and 9.7 million cancer deaths occurred globally in 2022, and the incidence rate is showing an upward trend year by year. The pathological mechanisms of cancer are complex, and its occurrence and development are closely related to multiple factors such as gene mutations, epigenetic abnormalities, and immune escape. Current clinical treatments for cancer mainly include surgical resection, radiotherapy, chemotherapy, and targeted therapy. However, these methods generally suffer from low selectivity, significant toxic side effects, and a tendency to develop drug resistance. For example, chemotherapy drugs can cause severe damage to normal tissues while killing tumor cells, and long-term use of targeted drugs often leads to decreased efficacy due to adaptive mutations in tumor cells. Therefore, developing new anticancer drugs or optimizing existing treatment regimens remains a pressing scientific challenge that needs to be overcome.

[0003] In recent years, aspirin has received increasing attention as a potential cancer treatment drug. Its anti-cancer effects have been verified in a number of epidemiological studies and experimental models. For example, long-term low-dose aspirin use can reduce the incidence of colorectal cancer. However, aspirin has limited cytotoxicity to cancer cells. At present, it can only play an adjunctive role in cancer treatment and cannot be developed into a new anti-cancer drug. Summary of the Invention

[0004] In view of this, it is necessary to provide an aspirin-sulfonamide hybrid, its preparation method and application, which enhances the cytotoxicity of aspirin against cancer cells by introducing an active fragment with high adaptability and strong anticancer activity into aspirin, thus enabling it to become a novel anticancer drug.

[0005] In a first aspect, the present invention provides an aspirin-sulfonamide hybrid, the general structural formula of which is as follows:

[0006]

[0007] Among them, R 1 Selected from aromatic, 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, for preparing the aspirin-sulfonamide hybrid as described in the first aspect, comprising the following steps:

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

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

[0013] S3, o-acetylsalicylic acid chloride 1 and sulfonamide 2 undergo N-acylation reaction under the action of a second acid-binding agent, followed by separation and purification to obtain the target product aspirin-sulfonamide hybrid 3a-l. The synthetic route is as follows:

[0014]

[0015] Among them, R 1 The definition is the same as 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] Thirdly, the present invention provides applications of the aspirin-sulfonamide hybrid as described in the first aspect, including:

[0019] Pharmaceutically acceptable salts of the aspirin-sulfonamide hybrid as described above.

[0020] Pharmaceutical compositions of aspirin-sulfonamide hybrids or pharmaceutically acceptable salts thereof, as described above.

[0021] Pharmaceutical formulations of aspirin-sulfonamide hybrids or pharmaceutically acceptable salts thereof, as described above, also include at least one pharmaceutically acceptable excipient or carrier.

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

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

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] 1. The anticancer activity of the aspirin-sulfonamide hybrid prepared in this invention is significantly higher than that of the parent aspirin. Specifically, the aspirin-sulfonamide hybrid containing a bromothiophene structure 3k(IC) 50 =36.57μM) was most effective against human non-small cell lung cancer cells A549, and its activity was higher than that of the parent aspirin (IC50). 50 The concentration of irinotecan (>1200μM) was more than 33 times higher than that of the anticancer drug irinotecan (IC50). 50 The activity of aspirin-sulfonamide hybrid 3k (29.07 μM) is similar; the cytotoxicity of aspirin-sulfonamide hybrid 3k to normal human lung epithelial cells BEAS-2B is low (IC50). 50 =201.60 μM), its selectivity for human non-small cell lung cancer cells A549 (SI) BEAS-2B / A549 =6) much higher than irinotecan (SI BEAS-2B / A549 =1), therefore, the aspirin-sulfonamide hybrid prepared in this invention can effectively treat lung cancer;

[0026] 2. The method for preparing aspirin-sulfonamide hybrids provided by this invention can synthesize several novel aspirin-sulfonamide hybrids through a three-step continuous method of "acyl chloride, sulfonation, and N-acylation" based on the "molecular hybrid principle" using piperazine as a bridge. In this process, only one separation and purification is performed, and the preparation steps are simple.

[0027] 3. The aspirin-sulfonamide hybrid 3k prepared in this invention exhibited certain cytotoxicity against human hepatocellular carcinoma 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 glioblastoma cells U87 (IC50, 100 mg / kg / kg for HepG2, MCF-7, Caco-2, HCT-116, HeLa, HGC-27, and U87). 50 =41.96-376.50μM), therefore, the aspirin-sulfonamide hybrid prepared in this invention has a certain inhibitory effect on a variety of cancer cells;

[0028] 4. The inhibitory effect (IC50) of the aspirin-sulfonamide hybrid 3k prepared in this invention on human non-small cell lung cancer cells A549. 50 =36.57μM) was superior to seven other cancer cell types (HepG2, MCF-7, Caco-2, HCT-116, HeLa, HGC-27, and U87, IC50). 50The aspirin-sulfonamide hybrid 3k exhibited an inhibitory effect at concentrations ranging from 41.96 to 376.50 μM. Furthermore, this hybrid induced apoptosis in human non-small cell lung cancer (NSCLC) A549 cells in a concentration-dependent manner and induced cell cycle arrest in the G0 / G1 phase, inhibiting cell growth. This suggests that the aspirin-sulfonamide hybrid 3k has the potential to be specifically used to treat NSCLC. Attached Figure Description

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

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

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

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

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

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

[0035] Figure 7 This application relates to aspirin-sulfonamide hybrid 3c. 1 HNMR spectrum.

[0036] Figure 8 This application relates to aspirin-sulfonamide hybrid 3c. 13 CNMR spectrum.

[0037] Figure 9 This is the HRMS spectrum of aspirin-sulfonamide hybrid 3c of this application.

[0038] Figure 10 This application relates to the aspirin-sulfonamide hybrid 3D. 1 HNMR spectrum.

[0039] Figure 11 This application relates to the aspirin-sulfonamide hybrid 3D. 13 CNMR spectrum.

[0040] Figure 12This is the HRMS spectrum of the aspirin-sulfonamide hybrid 3d of this application.

[0041] Figure 13 This is the aspirin-sulfonamide hybrid 3e of this application. 1 HNMR spectrum.

[0042] Figure 14 This is the aspirin-sulfonamide hybrid 3e of this application. 13 CNMR spectrum.

[0043] Figure 15 This is the HRMS spectrum of the aspirin-sulfonamide hybrid 3e of this application.

[0044] Figure 16 This is the aspirin-sulfonamide hybrid 3f of this application. 1 HNMR spectrum.

[0045] Figure 17 This is the aspirin-sulfonamide hybrid 3f of this application. 13 CNMR spectrum.

[0046] Figure 18 This is the aspirin-sulfonamide hybrid 3f of this application. 19 FNMR spectrum.

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

[0048] Figure 20 This application contains 3g of aspirin-sulfonamide hybrid. 1 HNMR spectrum.

[0049] Figure 21 This application contains 3g of aspirin-sulfonamide hybrid. 13 CNMR spectrum.

[0050] Figure 22 This application contains 3g of aspirin-sulfonamide hybrid. 19 FNMR spectrum.

[0051] Figure 23 This is the HRMS spectrum of 3g of the aspirin-sulfonamide hybrid of this application.

[0052] Figure 24 This application relates to the aspirin-sulfonamide hybrid 3h. 1 HNMR spectrum.

[0053] Figure 25 This application relates to the aspirin-sulfonamide hybrid 3h. 13 CNMR spectrum.

[0054] Figure 26 This application relates to the aspirin-sulfonamide hybrid 3h. 19 FNMR spectrum.

[0055] Figure 27 This is the HRMS spectrum of the aspirin-sulfonamide hybrid of this application at 3h.

[0056] Figure 28 This application relates to the aspirin-sulfonamide hybrid 3i. 1 HNMR spectrum.

[0057] Figure 29 This application relates to the aspirin-sulfonamide hybrid 3i. 13 CNMR spectrum.

[0058] Figure 30 This is the HRMS spectrum of the aspirin-sulfonamide hybrid 3i of this application.

[0059] Figure 31 This is the aspirin-sulfonamide hybrid 3j of this application. 1 HNMR spectrum.

[0060] Figure 32 This is the aspirin-sulfonamide hybrid 3j of this application. 13 CNMR spectrum.

[0061] Figure 33 This is the HRMS spectrum of aspirin-sulfonamide hybrid 3j of this application.

[0062] Figure 34 This application relates to the aspirin-sulfonamide hybrid 3k. 1 HNMR spectrum.

[0063] Figure 35 This application relates to the aspirin-sulfonamide hybrid 3k. 13 CNMR spectrum.

[0064] Figure 36 This is the HRMS spectrum of the aspirin-sulfonamide hybrid 3k of this application.

[0065] Figure 37 This is the aspirin-sulfonamide hybrid 3l of this application. 1 HNMR spectrum.

[0066] Figure 38 This is the aspirin-sulfonamide hybrid 3l of this application. 13 CNMR spectrum.

[0067] Figure 39This is the HRMS spectrum of aspirin-sulfonamide hybrid 3l of this application.

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

[0069] Figure 41 This is a graph showing the inhibition rate of the aspirin-sulfonamide hybrid 3k of this application against seven types of human cancer cells.

[0070] Figure 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 described in this application.

[0071] Figure 43 This is a cell cycle diagram showing the effect of aspirin-sulfonamide hybrid 3k on the growth of human non-small cell lung cancer A549 cells, as described in this application.

[0072] Figure 44 This is a diagram illustrating the predicted binding model of aspirin-sulfonamide hybrid 3k to the receptor COX-2 in this application.

[0073] Figure 45 This is a 2D diagram of the interaction between the aspirin-sulfonamide hybrid 3k and the receptor COX-2 of this application. Detailed Implementation

[0074] The technical solutions and effects of the embodiments of the present invention will be further described in detail below with reference to the accompanying drawings.

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

[0076]

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

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

[0079]

[0080] The anticancer activity of the aspirin-sulfonamide hybrid prepared by this invention is significantly higher than that of the parent aspirin. Among them, the aspirin-sulfonamide hybrid containing the bromothiophene structure 3k(IC) 50 =36.57μM) was most effective against human non-small cell lung cancer cells A549, and its activity was higher than that of the parent aspirin (IC50). 50The concentration of irinotecan (>1200μM) was more than 33 times higher than that of the anticancer drug irinotecan (IC50). 50 The activity of aspirin-sulfonamide hybrid 3k (29.07 μM) is similar; the cytotoxicity of aspirin-sulfonamide hybrid 3k to normal human lung epithelial cells BEAS-2B is low (IC50). 50 =201.60 μM), its selectivity for human non-small cell lung cancer cells A549 (SI) BEAS-2B / A549 =6) much higher than irinotecan (SI BEAS-2B / A549 =1), therefore, the aspirin-sulfonamide hybrid prepared in this invention can effectively treat lung cancer.

[0081] In a second aspect, the present invention provides a method for preparing an aspirin-sulfonamide hybrid, comprising the following steps:

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

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

[0084] S3, o-acetylsalicylic acid chloride 1 and sulfonamide 2 undergo N-acylation reaction under the action of a second acid-binding agent, followed by separation and purification to obtain the target product aspirin-sulfonamide hybrid 3a-l. The synthetic route is as follows:

[0085]

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

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

[0088] Furthermore, the first acid-binding agent in step S2 and the second acid-binding agent in step S3 are both tertiary amines, such as trimethylamine, triethylamine, and tripropylamine; the reaction temperature required in step S2 is 10℃~40℃; and the reaction time required in step S2 is 0.5h~3h.

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

[0090] Thirdly, the present invention provides applications of aspirin-sulfonamide hybrids as described in the first aspect, including:

[0091] Pharmaceutically acceptable salts of the aspirin-sulfonamide hybrid as described above.

[0092] Pharmaceutical compositions of aspirin-sulfonamide hybrids or pharmaceutically acceptable salts thereof, as described above.

[0093] Pharmaceutical formulations of aspirin-sulfonamide hybrids or pharmaceutically acceptable salts thereof, as described above, further include at least one pharmaceutically acceptable excipient or carrier; said pharmaceutical formulation includes tablets, powders, capsules, granules, or injections.

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

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

[0096] Example 1: The general method for synthesizing aspirin-sulfonamide hybrids is as follows:

[0097] Experimental materials: Commercial reagents were purchased from Adamas and Energie; unless otherwise specified, they were used as received. Redistilled dichloromethane (DCM) was used. Thin-layer chromatography (TLC) was performed on silica GF254 plates. Infrared spectra were recorded on an FTIR-8400S spectrometer using KBr pellets. Results were obtained using a Bruker Avance III 400MHz spectrometer. 1 HNMR and 13 C10 NMR spectroscopy. Chemical shift (δ) is expressed in ppm with tetramethylsilane as a reference. Residual solvent signal is used as... 1 H and 13 Reference for 1000- ... H =7.26ppm,δ C =77.16 ppm). High-resolution mass spectrometry (HRMS) of the target compound was performed on a Thermo Fisher LTQ Orbitrap XL. Bioactivity assays were conducted by the Collaborative Innovation Center for Green Pharmaceuticals, Zhejiang University of Technology.

[0098] Synthesis process: S101, at 25℃, aspirin (0.6g, 3.0mmol), DCM (10mL), N,N-dimethylformamide (0.6mmol / six drops), and oxaloyl chloride (1.3mL, 15.0mmol) were added sequentially to a 50mL flask. After stirring at room temperature for 1.5h, the mixture was concentrated under reduced pressure to obtain crude product 1.

[0099] In S201, at 25℃, piperazine (0.4 g, 4.5 mmol), DCM, triethylamine (0.6 mL, 4.5 mmol), and sulfonyl chloride (3.3 mmol) were added sequentially to a 50 mL flask. The reaction was detected by TLC. After stirring at room temperature for 1 h, 50 mL of water was added to the reaction solution. The mixture was washed with saturated NaHCO3 (30 mL x2) and saturated saline (30 mL x3). The organic phase was dried with anhydrous Na2SO4, filtered, and concentrated to remove excess solvent to obtain crude product 2.

[0100] In S301, at 0°C, crude product 2, DCM, and triethylamine (0.9 mL, 6.0 mmol) were added sequentially to a 50 mL flask, followed by the dropwise addition of a solution of crude product 1 in DCM. The reaction was monitored by TLC. After stirring the resulting mixture at room temperature for 1 hour, 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 purified by silica gel column chromatography to give aspirin-sulfonamide hybrid 3.

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

[0102] The target products 3 obtained by sulfonyl chloride of the above-mentioned structural formula are numbered sequentially as 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k and 3l; the target products 3 obtained by the above synthesis method are aspirin-sulfonamide hybrids (3a-l).

[0103] Please refer to Figures 1 to 39 ,pass 1 HNMR, 13 C NMR, 19 The product prepared in Example 1 was characterized by 1F NMR, IR spectroscopy and HRMS.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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) δ 8.40 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.6 Hz, 2H), 7.43 (t, J = 7.8 Hz, 1H), 7.27 - 7.17 (m, 2H), 7.11 (d, J = 8.2 Hz, 1H), 3.85 (s, 2H), 3.47 (t, J = 5.1 Hz, 2H), 3.20 - 3.00 (m, 4H), 2.09 (s, 3H); 13 C NMR(101MHz, CDCl3) δ 168.93, 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.

[0108] 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) δ 8.58 (s, 1H), 8.48 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.42 (t, J = 6.8 Hz, 1H), 7.21 (dd, J = 15.7, 6.6 Hz, 2H), 7.11 (d, J = 8.2 Hz, 1H), 3.84 (t, J = 5.2 Hz, 2H), 3.47 (t, J = 5.2 Hz, 2H), 3.14 - 3.03 (m, 4H), 2.08 (s, 3H); 13 C NMR(101MHz, CDCl3) δ 168.91, 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.

[0109] 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 FN2O5S [M + H] + 407.1071, found 407.1068.

[0110] 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; 11H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 7.7 Hz, 1H), 7.28 (d, J = 2.6 Hz, 2H), 7.10 (dd, J = 5.6, 3.3 Hz, 2H), 6.96 (d, J = 8.3 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 3.82 (s, 3H), 3.45 (t, J = 5.1 Hz, 2H), 3.10 (t, J = 5.1 Hz, 3H), 2.11 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 171.25, 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 19F NMR (376 MHz, 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.

[0111] 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 1H NMR (400 MHz, CDCl3) δ 7.83 - 7.75 (m, 2H), 7.43 - 7.34 (m, 3H), 7.25 - 7.17 (m, 2H), 7.09 (d, J = 8.2 Hz, 1H), 3.78 (t, J = 5.1 Hz, 2H), 3.42 (q, J = 6.2, 5.3 Hz, 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.

[0112] 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.

[0113] 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.

[0114] 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 1H 18 BrN2O5S2 [M + H] + 472.9835, found 472.9830.

[0115] 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.

[0116] Example 2, Cytotoxicity test of aspirin-sulfonamide hybrid 3

[0117] Experimental materials: Irinotecan (IRT), an anticancer drug, was used as a reference, and aspirin was used as the parent compound. The in vitro cytotoxicity of aspirin-sulfonamide hybrid 3a-l was detected by the MTT assay.

[0118] Experimental methods:

[0119] First, human non-small cell lung cancer cells A549 or human normal lung epithelial cells BEAS-2B (2.5×10⁻⁶) were used. 3 Three copies (100 μL each) were inoculated into 96-well plates; then incubated at 37°C for 24 hours. The suspension was replaced with fresh 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 negative control wells and solvent control wells. Then, 100 μL of 0.5 mg / mL 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazol bromide (MTT) (dissolved in PBS and then diluted with fresh medium) was added to each well, and the plates were incubated for another 4 hours. Finally, the medium was removed, and the MTT formazan precipitate was dissolved in 100 μL of LDMSO. After mechanical shaking for 10 minutes, the plate was immediately read at 570 nm using a microplate reader (FlexStation3, Molecular Devices).

[0120] The results are shown in Tables 1, 2, and 3 below:

[0121] Table 1

[0122]

[0123] Table 2

[0124]

[0125]

[0126] Table 3

[0127]

[0128]

[0129] Where ASP = aspirin, IRT = irinotecan, and the values ​​in the table are the mean ± SD of three independent experiments; the data in Table 1 are the IC50 values ​​of each compound against human non-small cell lung cancer cells A549 and normal human lung epithelial cells BEAS-2B. 50 The data in Table 2 represent the inhibition rates of each compound on human non-small cell lung cancer cells A549, and the data in Table 3 represent the inhibition rates of each compound on human normal lung epithelial cells BEAS-2B.

[0130] Analysis of the data in Tables 1 to 3 reveals the following:

[0131] Aspirin-sulfonamide hybrids 3b, 3d, and 3f-3l (IC) 50 =36.57-454.60 μM) has greater inhibitory activity against human non-small cell lung cancer A549 cells than aspirin (IC50). 50 >1200μM); Aspirin-sulfonamide hybrids 3a and 3c showed poor inhibitory activity against human non-small cell lung cancer A549 cells, similar to aspirin; when the R of the aspirin-sulfonamide hybrid... 1 When the form is m-nitrobenzene (3e), the activity is significantly reduced (IC). 50 >3000 μM); when the R of aspirin-sulfonamide hybrid 1 When it is p-tolyl, 3,5-difluorophenyl or cyclopropyl (3b, 3g and 3l, IC) 50 <100 μM), its cytotoxicity is 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 The cytotoxicity was 142.13-454.60 μM; the aspirin-sulfonamide hybrids 3j and 3k with the introduction of a thiophene group showed the strongest cytotoxicity (IC50 = 142.13-454.60 μM). 50 =36.57-38.21 μM), among which, the aspirin-sulfonamide hybrid 3k with a bromothiophene structure was most effective against human non-small cell lung cancer A549 cells (IC50-36.57-38.21 μM). 50 =36.57μM), its cytotoxicity is higher than that of the parent aspirin (IC50). 50 The toxicity of BEAS-2B to normal human lung epithelial cells was more than 33 times higher than that of >1200μM (IC50), and very low (IC50-1200μM). 50 =201.60μM); High selectivity for human non-small cell lung cancer A549 cells (SI BEAS-2B / A549 =6), much higher than irinotecan (SI). BEAS-2B / A549 =1).

[0132] Calculate the cell inhibition rate and plot as shown Figure 40The line graph shown indicates that the cell inhibition rate = [A] 570 (Negative control well)-A 570 (Drug administration port) / A 570 (Negative control well) × 100%; the values ​​in the figure are the average of three independent experiments ± SD, with each experiment performed in triplicate.

[0133] right Figure 40 Analysis of the data revealed that the inhibition rate of aspirin-sulfonamide hybrid 3 on human non-small cell lung cancer cells A549 and normal human lung epithelial cells BEAS-2B increased with increasing concentration. At a concentration of 100 μM, the inhibition rate of aspirin-sulfonamide hybrid 3k on human non-small cell lung cancer cells A549 reached 63.64%, and showed a continuous increasing trend. Therefore, the inhibitory effect of aspirin-sulfonamide hybrid 3k on the proliferation of human non-small cell lung cancer cells A549 is concentration-dependent.

[0134] Example 3: Cytotoxicity experiment of aspirin-sulfonamide hybrid 3k against different cancer cells.

[0135] Experimental method: First, 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, or human glioblastoma cells U87 (2.5×10⁻⁶) were used. 3 Three copies (100 μL each) were inoculated into 96-well plates; then incubated at 37°C for 24 hours. 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 and solvent control wells. Then, 100 μL of 0.5 mg / mL 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazol bromide (MTT) (dissolved in PBS and then diluted with fresh medium) was added to each well, and the plates were incubated for another 4 hours. Finally, the medium was removed, and the MTT formazan precipitate was dissolved in 100 μL of LDMSO. After mechanical shaking for 10 minutes, the plate was immediately read at 570 nm using a microplate reader (FlexStation 3, Molecular Devices).

[0136] The results are shown in Tables 4 and 5 below:

[0137] Table 4

[0138] Cancercells 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

[0139] Table 5

[0140]

[0141]

[0142] The values ​​in the table are the mean ± SD of three independent experiments; the data in Table 4 are the IC50 values ​​of aspirin-sulfonamide hybrid 3k against the above seven human cancer cells. 50 Values; the data in Table 5 represent the inhibition rates of aspirin-sulfonamide hybrid 3k against the aforementioned seven types of human cancer cells.

[0143] Calculate the cell inhibition rate and plot as shown Figure 41 The line graph shown indicates that the cell inhibition rate = [A] 570 (Negative control well)-A 570 (Drug administration port) / A 570 (Negative control well) × 100%; the values ​​in the figure are the average of three independent experiments ± SD, with each experiment performed in triplicate.

[0144] For Tables 4 and 5 and Figure 41 Analysis of the data revealed that aspirin-sulfonamide hybrid 3k had an IC50 effect on the aforementioned seven types of human cancer cells. 50 The inhibitory effect was 41.96-376.50 μM, which was less effective than aspirin-sulfonamide hybrid 3kJ against human non-small cell lung cancer cells A549 (IC50). 50 =36.57μM), therefore, aspirin-sulfonamide hybrid 3k has research value as a candidate drug in the field of anti-non-small cell lung cancer drug development.

[0145] Example 4: Experiment on aspirin-sulfonamide hybrid 3k inducing apoptosis in human non-small cell lung cancer A549 cells.

[0146] Experimental method: First, human non-small cell lung cancer A549 cells (5×10⁻⁶) were used. 4 Three aliquots (1000 μL each) were seeded into 12-well plates and cultured at 37°C for 24 hours. The old medium was then replaced with fresh medium containing different concentrations of hybrid 3k (20, 80, and 140 μM). The same volume of dimethyl sulfoxide was added to the negative control wells and the solvent control wells. The cells were then cultured at 37°C for 48 hours. After aspirating the medium, 100 μL of pre-warmed 0.25% trypsin without EDTA was added to each well. Following trypsinization, the treated cells were stained using the Annexin V-FITC / PI apoptosis detection kit according to the manufacturer's instructions. The cells were then cultured in the dark at room temperature for 5–15 minutes, and apoptotic cells were analyzed using a CytoFLEX flow cytometer.

[0147] Based on the analysis results of flow cytometry, plot as follows Figure 42The percentage of AV and / or PI positive cells shown in A includes normal cells (LL), early apoptotic cells (LR), late apoptotic cells (UR), and necrotic cells (UL); plotted based on flow cytometry analysis results as shown below. Figure 42 The total apoptosis rate of human non-small cell lung cancer A549 cells shown in Figure B is the mean ± SD of three independent experiments. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0148] right Figure 42 Analyzing the data in the middle reveals that, for example Figure 42 As shown in Figure A, with increasing concentrations of aspirin-sulfonamide hybrid 3k, the number of normal cells gradually decreased, while the number of early and late apoptotic cells gradually increased; Figure 42 As shown in Figure B, when the concentrations of aspirin-sulfonamide hybrid 3k were 20, 80, and 140 μM, the total apoptosis rates of human non-small cell lung cancer A549 cells were 19.99%, 36.90%, and 47.73%, respectively, while the control group had only 4.65%. These results indicate that aspirin-sulfonamide hybrid 3k can induce apoptosis in human non-small cell lung cancer A549 cells in a concentration-dependent manner.

[0149] Example 5: Experiment on the inhibition of human non-small cell lung cancer A549 cell growth by aspirin-sulfonamide hybrid 3k

[0150] Experimental method: First, human non-small cell lung cancer A549 cells (2.5 × 10⁻⁶) were used. 5 Three copies (2500 μL each) were seeded into 6-well plates and cultured at 37°C for 24 hours. The old medium was replaced with fresh medium containing different concentrations of aspirin-sulfonamide hybrid 3k (5, 10, and 20 μM). The same volume of dimethyl sulfoxide was added to the negative control wells and the solvent control wells. The plates were then cultured at 37°C for another 24 hours. After aspirating the medium, 200 μL of 0.25% trypsin was added to each well. Following trypsin treatment, the cells were fixed overnight at 4°C with 70% ethanol. Staining was then performed using the PI Cell Cycle Analysis Kit according to the manufacturer's instructions. Finally, after incubation in the dark at 37°C for 30 minutes, the cell cycle was analyzed using a CytoFLEX flow cytometer.

[0151] Based on the analysis results of flow cytometry, plot as follows Figure 43 The effect of aspirin-sulfonamide hybrid 3k (shown in Figure A) on the cell cycle of human non-small cell lung cancer A549 cells; plotted based on flow cytometry analysis results as shown below. Figure 43Statistical analysis of cell cycle in human non-small cell lung cancer A549 cells after treatment with aspirin-sulfonamide hybrid 3k for 24 hours (Figure B). Statistically significant differences are expressed as *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001.

[0152] right Figure 43 Analysis of the data revealed that aspirin-sulfonamide hybrid 3k affects the cell cycle of human non-small cell lung cancer (NSCLC) A549 cells. As the concentration of aspirin-sulfonamide hybrid 3k gradually increased, the number of NSCLC A549 cells with arrested cell cycles also gradually increased. When the concentrations of aspirin-sulfonamide hybrid 3k were 5, 10, and 20 μM, the proportions of NSCLC A549 cells entering the G0 / G1 phase were 68.30%, 71.00%, and 76.77%, respectively, compared to 64.63% in the control group. These experimental results indicate that aspirin-sulfonamide hybrid 3k can induce cell cycle arrest in the G0 / G1 phase in NSCLC A549 cells and further inhibit their growth.

[0153] Example 6: Binding characteristics analysis of aspirin-sulfonamide hybrid 3k to COX-2 receptor

[0154] Experimental Objective: Cyclooxygenase-2 (COX-2) is significantly upregulated in many cancers. Besides its well-known ability to reduce the body's immune system function by inducing inflammation, it also leads to abnormal expression of tumor-associated factors Bcl-2, MMP-2, and epidermal growth factor receptor EGFR, thereby causing tumor cells to resist apoptosis, invade the extracellular matrix leading to metastasis, and malignant transformation, thus worsening cancer. Aspirin, as a nonsteroidal anti-inflammatory drug (NSAID), can inhibit COX-2 activity, thereby reducing prostaglandin biosynthesis and treating inflammation. Current research suggests that aspirin may exert its anticancer effect by inhibiting COX-2 activity, but the specific mechanism still needs further investigation. Therefore, we hypothesize that the synthesized aspirin-sulfonamide hybrid 3k may exert its anticancer effect by inhibiting COX-2, and we will confirm this through molecular docking experiments.

[0155] Experimental materials: Molecules were drawn using ChemDraw 20.0 software and adjusted using MOE (Molecular Manipulation Environment) software; the COX-2 receptor (PDB ID: 5F1A) downloaded from the protein database (https: / / www.rcsb.org) was drawn using MOE software.

[0156] Experimental Methods: Molecular docking analysis was performed using a molecular manipulation environment (MOE). Pockets involving residues Thr212, Thr206, Gln203, Ala199, and His207 were set up in a solvent environment. After setting up (placement: trianglematcher, refinement: rigid receptor), scores (placement: London dG, refinement: GBVI / WSA dG), and poses (placement: 300, refinement: 5), docking was performed via MOE. The docking conformation with the lowest binding energy was selected from 300 conformations as representative binding energies for assessing the potential of the corresponding compounds. The selected optimal docking pose was used to analyze the interaction between the receptor COX-2 and the aspirin-sulfonamide hybrid 3k.

[0157] The predicted binding model of the generated aspirin-sulfonamide hybrid 3k to the receptor COX-2 (PDB ID: 5F1A) is as follows: Figure 44 As shown, A illustrates the interaction between aspirin-sulfonamide hybrid 3k and its receptor COX-2, while B shows the details of this interaction. Aspirin-sulfonamide hybrid 3k is depicted in green. 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 dashed lines, and π-π and π-H interactions are represented by aquamarine dashed lines.

[0158] right Figure 44 Analysis revealed that the aspirin-sulfonamide hybrid 3k was well-positioned in the active pocket, its cyclic system was well encapsulated by the receptor cavity, and there were many good interactions.

[0159] Furthermore, drawing as Figure 45 The diagram shows a 2D representation of the interaction between aspirin-sulfonamide hybrid 3k and the receptor COX-2.

[0160] right Figure 45Analysis revealed that the O atoms of the ester carbonyl and sulfonyl groups in aspirin-sulfonamide hybrid 3k interact with hydrogen bonds of residues Thr212, Thr206, and Gln203; the S atom of the thiophene group in aspirin-sulfonamide hybrid 3k interacts with the hydrogen bond of residue Ala199; furthermore, aspirin-sulfonamide hybrid 3k forms a π-H interaction through residue His207, exhibiting more interactions. These interactions significantly enhance the binding affinity of aspirin-sulfonamide hybrid 3k to the COX-2 receptor. This docking model reveals the favorable interaction between aspirin-sulfonamide hybrid 3k and COX-2, supporting its potential as an excellent therapeutic agent for non-small cell lung cancer.

[0161] The above are merely 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 within 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 one of the following groups: ； 。 2. A method for preparing an aspirin-sulfonamide hybrid, used to prepare the aspirin-sulfonamide hybrid as described in claim 1, characterized in that, Includes the following steps: S1, Aspirin and oxalyl chloride are subjected to acyl chloride reaction under the catalysis of a catalyst to obtain o-acetylsalicylic acid chloride 1; S2, piperazine and sulfonyl chloride undergo sulfonation reaction under the action of the first binding acid to give sulfonamide 2; S3, o-acetylsalicylic acid chloride 1 and sulfonamide 2 undergo N-acylation reaction under the action of a second acid-binding agent, followed by separation and purification to obtain the target product aspirin-sulfonamide hybrid 3a–l. The synthetic route is as follows: ； ； ； Among them, R 1 The definition is the same as in claim 1.

3. The method for preparing the aspirin-sulfonamide hybrid as described in claim 2, characterized in that, The catalyst in step S1 is N,N-dimethylformamide.

4. The method for preparing the aspirin-sulfonamide hybrid as described in claim 2, characterized in that, The first acid-binding agent in step S2 and the second acid-binding agent in step S3 are both tertiary amines.

5. A pharmaceutically acceptable salt of the aspirin-sulfonamide hybrid as described in claim 1; Or a pharmaceutically acceptable salt of the aspirin-sulfonamide hybrid obtained by the preparation method of the aspirin-sulfonamide hybrid according to any one of claims 2 to 4.

6. A pharmaceutical composition containing the aspirin-sulfonamide hybrid as described in claim 1; Or a pharmaceutical composition containing an aspirin-sulfonamide hybrid prepared by any of the methods described in claims 2 to 4; Or a pharmaceutical composition containing a pharmaceutically acceptable salt of the aspirin-sulfonamide hybrid as described in claim 5.

7. A pharmaceutical preparation containing the aspirin-sulfonamide hybrid as described in claim 1; Or a pharmaceutical preparation containing an aspirin-sulfonamide hybrid obtained by the preparation method of any one of claims 2 to 4; Or a pharmaceutical formulation containing a pharmaceutically acceptable salt of the aspirin-sulfonamide hybrid of claim 5, characterized in that, It also includes at least one pharmaceutically acceptable excipient or carrier.

8. The use of the aspirin-sulfonamide hybrid as described in claim 1 in the preparation of anticancer drugs; Or the use of the aspirin-sulfonamide hybrid obtained by the preparation method of any one of claims 2 to 4 in the preparation of anticancer drugs; Or the use of a pharmaceutically acceptable salt of the aspirin-sulfonamide hybrid as described in claim 5 in the preparation of anticancer drugs; Or the use of the pharmaceutical composition as described in claim 6 in the preparation of anticancer drugs; Or the use of the pharmaceutical formulation as described in claim 7 in the preparation of anticancer drugs; in, The anticancer drugs described can treat lung cancer, liver cancer, breast cancer, colorectal cancer, cervical cancer, stomach cancer, and malignant glioblastoma.

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