Use of methanesulfonamide-based chalcone derivatives

Abstract

The application provides an application of a sulfamoyl-based chalcone derivative, the compound contains a methylsulfonyl structure and is substituted by a benzene ring or other heterocyclic groups at an alpha position, has higher inhibiting capability on Hela cells than glycyrrhiza chalcone A, is a compound with significant antitumor activity, and provides a research basis for screening of new antitumor drugs.

Description

Technical Field

[0001] This invention relates to a chalcone derivative, its preparation method, and its application in antitumor drugs. Background Technology

[0002] Chalcones are present in most natural compounds and serve as important intermediates in the biosynthesis of flavonoids and flavonoids. Chalcones are plant-derived polyphenols with good biological activity. They have attracted widespread attention due to their biological activity, relatively easy structural manipulation, and the synthesis of new compounds. Several chalcone derivatives have been shown to possess broad biological activities.

[0003] The classic method for the chemical synthesis of chalcones is the Claisen-Schmidt reaction, which involves the condensation of benzaldehyde and methyl ketones into chalcones via base or acid catalysis. This synthesis can be divided into two types depending on the catalyst: under base catalysis, chalcone is produced by dehydration from the aldol product via an olefinic acid mechanism; under acid catalysis, it is produced via an enol mechanism. However, this method has a long reaction time, is incomplete, and easily produces byproducts, making product separation difficult. Besides the Claisen-Schmidt reaction, there is also a cross-coupling method for synthesizing chalcones. This method was first reported in 1979 and first applied to chalcone synthesis in 2003. The synthetic methods include coupling cinnamoyl chloride with phenylboronic acid or coupling benzoyl chloride with styrylboronic acid. Research on the synthesis of chalcones using cross-coupling methods extends beyond this, including Suzuki-Miyaura coupling, Heck coupling and carbonyl Heck coupling, the Wittig reaction, and the Julia-Kocienski olefination reaction. Besides cross-coupling methods, chalcones can also be synthesized using acylation reactions and Photo-Fries rearrangements. Furthermore, chalcones and their various derivatives can be synthesized biosynthetically using chalcone synthases.

[0004] The basic skeleton of chalcones is 1,3-diphenylpropenone. The benzene ring attached to the ketone group is called the A ring, and the ring attached to the double-bonded olefin is called the B ring. The acrylone structure lies between the two benzene rings. This structure can bind to different receptors, thus exhibiting diverse biological activities. Chalcones are an important component of flavonoids and can inhibit a range of enzymes in the body, including monooxygenases, xanthine oxidases, and cyclooxygenases, through their antioxidant activity of scavenging free radicals. By adjusting the compound structure and modifying different compounds, it is possible to synthesize target compounds with higher bioavailability and stronger in vivo tolerance. Many naturally occurring chalcone derivatives possess various biological activities; for example, isoliquiritigenin, 2',3,4,4'-tetrahydroxychalcone, and taxine have anticancer activities; hematoxylin and cinnamyl chalcone has anti-inflammatory effects; psoralen has antioxidant effects; and pavachalcone has antibacterial properties.

[0005] Organic chemists often use chalcones as lead compounds, introducing other active groups to enhance their bioactivity. In recent years, significant progress has been made in modifying the basic chalcone skeleton to improve its bioactivity. In 2010, Daniela Ilieva Batovska, while researching the pharmacological potential of chalcone compounds, discovered that by introducing α-substituents and replacing the A ring with a heterocyclic ring, the synthesized chalcone derivatives exhibited significant effects in antioxidation and anti-inflammation. In 2023, Shaimaa M. Aboukhatwa and his team designed and synthesized 15 chalcone-sulfonamide compounds by replacing the benzene ring in the chalcone structure with an aromatic ring containing a sulfonamide substituent, which showed good antitumor activity.

[0006] This invention utilizes gold catalysis and replaces the A-ring structure in chalcone with a nitrogen-containing p-methanesulfonyl structure under mild reaction conditions to synthesize a series of chalcone derivatives containing a methanesulfonyl structure and with the α-position substituted by a benzene ring or other heterocyclic group in a one-step reaction. These derivatives have been tested and found to have antitumor activity. Summary of the Invention

[0007] The purpose of this invention is to provide a chalcone derivative containing a methanesulfonyl structure with the α-position substituted by a benzene ring or other heterocyclic group, its preparation method, and the application of this type of compound in antitumor drugs. The synthesis process of this type of compound is simple, the reaction conditions are mild, the reaction is rapid, and the product is easily separated, which is beneficial for industrial production. This type of compound has a significant inhibitory effect on cervical cancer cells and low toxicity to normal cells, showing good application prospects in antitumor drugs.

[0008] The technical solution adopted in this invention

[0009] In a first aspect, the present invention provides the use of the sulfone amino chalcone derivative of formula (I) in the preparation of antitumor drugs:

[0010]

[0011] In formula (Ⅰ), R1 is a cyclohexenyl, naphthyl, or phenyl group in which the H on the benzene ring is replaced by a halogen, a C1-C3 alkyl group, or a C1-C3 alkoxy group;

[0012] R2 is a thiophene group, a C1-C7 alkyl group, or a phenyl group in which the H atom on the benzene ring is replaced by a halogen or a C1-C3 alkyl group.

[0013] Furthermore, R1 is a phenyl group in which one H atom on a cyclohexenyl, naphthyl, or benzene ring is replaced by fluorine, chlorine, methyl, or methoxy groups;

[0014] R2 is a thienyl, octyl, or phenyl group in which one H atom on the benzene ring is replaced by fluorine, chlorine, or methyl.

[0015] Furthermore, the sulfone amino chalcone derivative is one of the following:

[0016]

[0017] Preferably, the methylsulfonyl chalcone derivative is compound (I-1), (I-3), (I-4), (I-7), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15), (I-16) or (I-18); more preferably, compound (I-4), (I-7), (I-9), (I-10), (I-12), (I-13), (I-14), (I-16) or (I-18), and most preferably, compound (I-18).

[0018] Preferably, the tumor cells are cervical cancer cells.

[0019] Furthermore, the antitumor drug is composed of a sulfone amino chalcone derivative of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, and a pharmaceutically acceptable carrier.

[0020] The pharmaceutically acceptable carrier is one or more of the following: diluent, filler, binder, humectant, disintegrant, absorption enhancer, surfactant, adsorbent, lubricant, and thickener. Flavoring agents, sweeteners, etc., may also be added if necessary. The pharmaceutically acceptable carrier refers to conventional drug carriers in the pharmaceutical field, including conventional pharmaceutical diluents such as water, fillers such as starch, binders such as cellulose derivatives and gelatin, humectants such as glycerin, disintegrants such as agar and calcium carbonate, absorption enhancers such as quaternary ammonium compounds, surfactants such as hexadecyl alcohol, adsorbents such as kaolin and soap clay, lubricants such as talc, and thickeners such as sodium carboxymethyl cellulose.

[0021] Pharmaceutical formulations are suitable for administration via any appropriate route, such as oral (including sublingual or sublingual), rectal, nasal, topical (including sublingual, sublingual, or transdermal), or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal injection). These formulations can be prepared by any method known in the field of pharmaceutics, such as by mixing the active ingredient with a carrier or excipient.

[0022] Thirdly, the present invention provides a method for preparing the above-mentioned sulfoneamine chalcone derivatives, wherein the method comprises:

[0023] Catalyst A and catalyst B are dissolved in an organic solvent, and reactants 2.1 and 2.2 are added. The mixture is stirred at 5-80°C under a protective atmosphere (generally for 2-12 hours, preferably 8 hours at 40°C). After the reaction is complete, the resulting reaction solution is post-treated to obtain the sulfone amino chalcone derivative shown in formula (Ⅰ). The molar ratio of catalyst A, catalyst B, reactant 2.1 and reactant 2.2 is 0.005-0.015:0.02-0.05:1:1-3 (preferably 0.015:0.02:1:2).

[0024] Catalyst A is one or more of IPrAuCl, WangPhosAuCl, JhonPhosAuCl, PPh3AuCl, and (PhO)3PAuCl (preferably PPh3AuCl); catalyst B is one or more of AgSbF6, NaBARF, AgOTf, and AgOAc (preferably AgSbF6).

[0025]

[0026] In formulas 2.1, 2.2, and (Ⅰ), R1 is a cyclohexenyl, naphthyl, or phenyl group in which the H atom on the benzene ring is substituted by a halogen, a C1-C3 alkyl group, or a C1-C3 alkoxy group;

[0027] R2 is a thiophene group, a C1-C7 alkyl group, or a phenyl group in which the H atom on the benzene ring is replaced by a halogen or a C1-C3 alkyl group.

[0028] The preferred formula (Ⅰ) is one of the methyl sulfone amino chalcone derivatives (I-1) to (I-18).

[0029] Note that the reaction of this invention is carried out under anhydrous conditions.

[0030]

[0031] Furthermore, the post-processing involves: filtering the reaction solution, washing the filter cake with dichloromethane, combining the filtrates, concentrating, and purifying by silica gel column chromatography using petroleum ether as the eluent. The eluent containing the target compound is collected, and the solvent is removed under reduced pressure to obtain the sulfoneamine chalcone derivative shown in formula (I). Further, the filtration is performed using diatomaceous earth as the packing material to separate catalysts, etc.

[0032] In one embodiment of the present invention, the protective atmosphere is a nitrogen atmosphere.

[0033] Furthermore, the organic solvent is one or more of dichloroethane (DCE), toluene, and tetrahydrofuran (THF), preferably dichloroethane.

[0034] Furthermore, the volume of the organic solvent, based on the amount of reactant 2.1, is 15–30 mL / mmol (preferably 20 mL / mmol).

[0035] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0036] (1) This invention provides a novel chalcone derivative containing a methanesulfonyl structure and having the α-position substituted with a benzene ring or other heterocyclic group;

[0037] (2) This type of compound is a compound with significant anti-tumor activity, which provides a research basis for screening new anti-tumor drugs. Detailed Implementation

[0038] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto:

[0039] Example 1: Synthesis of Sample I-1

[0040] The reaction formula is as follows:

[0041]

[0042] Add 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) sequentially to an anhydrous, dry small reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), add 0.0209 g reaction substrate 2.1 (0.1 mmol) and 0.0212 g reaction substrate 2.2 (0.2 mmol) sequentially to the reaction flask. Stir the reaction at 40 °C under a nitrogen atmosphere. Detect the reaction of reaction substrate 2.1 after it has completely reacted by thin-layer chromatography (TLC). The reaction solution was filtered through diatomaceous earth (diatomaceous earth 535 adamas, hereinafter the same). The filter cake was washed multiple times with dichloromethane (DCM). The filtrates were combined and concentrated in a vacuum rotary evaporator. The filtrate was then passed through a silica gel column, washed with petroleum ether (PET), monitored by TLC, and the eluent was collected. The solvent was removed by vacuum evaporation to give 0.0269 g of white solid (Ⅰ-1), with a yield of 85.2% and a purity >99%.

[0043] Ⅰ-1, white solid. 1 H NMR(500MHz,Chloroform-d)δ7.37–7.35(m,3H),7.33–7.30(m,2H),7.28(s,1H),7.24–7.21(m,3H),7.16–7.14(m,2H),3.16(s,3H),3.14(s,3H). 13 CNMR(126MHz,Chloroform-d)δ172.35,136.25,135.93,134.29,134.02,129.88,129.50,129.01,128.90,128.68,128.31,40.89,34.35.GC-MS(EI):m / z 315.09[M + ].

[0044] Example 2: Synthesis of Sample I-2

[0045] The reaction formula is as follows:

[0046]

[0047] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0223 g of substrate 2.3 (0.1 mmol) and 0.0212 g of substrate 2.2 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.3 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0303 g of white solid (Ⅰ-2), with a yield of 92.3% and a purity >99%.

[0048] Ⅰ-2, white solid. 1 H NMR (500MHz, Chloroform-d) δ7.23(dddd,J=13.6,8.7,7.4,1.5Hz,5H),7.18–7.15(m,3H),7.10(d,J=5.2Hz,2H),3.17(d,J=16.3Hz,6H),2.32(s,3H). 13 C NMR(126MHz,Chloroform-d)δ172.43,138.78,136.31,135.57,134.36,133.87,129.44 ,128.85,128.69,128.58,128.25,128.12,126.57,40.93,34.38,21.37.GC-MS(EI):m / z 329.41[M + ].

[0049] Example 3: Synthesis of Sample I-3

[0050] The reaction formula is as follows:

[0051]

[0052] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0245 g of substrate 2.4 (0.1 mmol) and 0.0281 g of substrate 2.5 (0.2 mmol) were added sequentially to the reaction flask. The reaction was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.4 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0322 g of white solid (Ⅰ-3), with a yield of 83.3% and a purity >99%.

[0053] Ⅰ-3, white solid. 1 H NMR(500MHz,Chloroform-d)δ7.47–7.42(m,1H),7.32–7.30(m,3H),6.89(d,J=1.2Hz,1H),3.44(s,3H),3.37(s,3H),2.47– 2.43(m,2H),1.44(p,J=7.3Hz,2H),1.36(d,J=6.9Hz,2H),1.27(d,J=3.9Hz,2H),1.23-1.20(m,6H),0.87(t,J=7.1Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ173.09,139.09,133.90,133.43,130.81,130.08,129.85,129.62, 129.52,126.69,41.14,34.90,31.76,29.40,29.11,28.78,27.99,22.60,14.07.GC-MS(EI):m / z 385.15[M + ].

[0054] Example 4: Synthesis of Sample I-4

[0055] The reaction formula is as follows:

[0056]

[0057] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0227 g substrate 2.6 (0.1 mmol) and 0.0212 g substrate 2.2 (0.2 mmol) were added sequentially to the reaction flask. The reaction was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.6 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed repeatedly with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0291 g of white solid (Ⅰ-4), with a yield of 87.6% and a purity >99%.

[0058] Ⅰ-4, white solid. 1 H NMR (500MHz, Chloroform-d) δ7.31–7.25(m,3H),7.24–7.21(m,2H),7.14–7.12(m,3H),7.08–7.04(m,2H),3.18(d,J=20.2Hz,6H). 13 CNMR(126MHz,Chloroform-d)δ172.17,136.13,135.17,134.06,131.42,131.36,129.79,129.04,128.43,116.25,116.08,41.01,34.38.GC-MS(EI):m / z 333.08[M + ].

[0059] Example 5: Synthesis of Samples I-5

[0060] The reaction formula is as follows:

[0061]

[0062] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0223 g of substrate 2.7 (0.1 mmol) and 0.0212 g of substrate 2.2 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.7 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0298 g of white solid (Ⅰ-5), with a yield of 90.5% and a purity >99%.

[0063] Ⅰ-5, white solid. 1 H NMR (500MHz, Chloroform-d) δ7.23–7.19(m,5H),7.16(d,J=1.8Hz,3H),7.09(s,1H),7.01(s,1H),3.17(s,3H),3.12(s,3H),2.37(s,3H). 13 CNMR (126MHz, Chloroform-d) δ172.58, 138.70, 136.29, 135.29, 134.49, 130.94, 129 .84,129.74,129.31,128.78,128.29,40.92,34.35,21.34.GC-MS(EI):m / z329.11[M + ].

[0064] Example 6: Synthesis of Samples I-6

[0065] The reaction formula is as follows:

[0066]

[0067] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0227 g substrate 2.8 (0.1 mmol) and 0.0212 g substrate 2.2 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.8 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0289 g of white solid (Ⅰ-6), with a yield of 86.8% and a purity >99%.

[0068] Ⅰ-6, white solid. 1 H NMR(500MHz,Chloroform-d)δ7.34(tdd,J=7.6,6.0,1.4Hz,1H),7.26–7.17(m, 4H),7.14–7.10(m,3H),7.07–7.03(m,2H),3.19(d,J=13.2Hz,6H),2.94(s,1H). 13 C NMR(126MHz,Chloroform-d)δ171.81,136.68,133.77,130.70,130.64,129.83,129 .59,129.23,128.47,128.30,127.19,125.29,125.27,40.96,34.46.GC-MS(EI):m / z 333.08[M + ].

[0069] Example 7: Synthesis of Samples I-7

[0070] The reaction formula is as follows:

[0071]

[0072] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0215 g of substrate 2.9 (0.1 mmol) and 0.0212 g of substrate 2.2 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.9 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0258 g of white solid (Ⅰ-7), with a yield of 80.2% and a purity >99%.

[0073] Ⅰ-7, white solid. 1 H NMR(500MHz,Chloroform-d)δ7.35–7.28(m,6H),7.08–7.00(m,3H),3.28(s,3H),3.24(s,3H). 13 C NMR(126MHz,Chloroform-d)δ171.33,134.98,134.69,134.15,130.10,129.53,129.10,128.87,128.52,127.79,127.28,41.12,34.29.GC-MS(EI):m / z 321.05[M + ].

[0074] Example 8: Synthesis of Samples I-8

[0075] The reaction formula is as follows:

[0076]

[0077] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0243 g of substrate 2.10 (0.1 mmol) and 0.0212 g of substrate 2.2 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.10 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the eluent was collected and evaporated under reduced pressure to remove the solvent, yielding 0.0298 g of a white solid (Ⅰ-8), with a yield of 85.2% and a purity >99%.

[0078] Ⅰ-8, white solid. 1 H NMR (500MHz, Chloroform-d) δ7.35–7.32(m,2H),7.28–7.23(m,5H),7.15–7.12(m,3H),3.18(d,J=24.6Hz,6H). 13 C NMR(126MHz,Chloroform-d)δ171.97,136.38,135.04,134.75,133.92,132.49,130.86,129.80,129.31,129.14,128.48,41.02,34.39.GC-MS(EI):m / z 349.05[M + ].

[0079] Example 9: Synthesis of Samples I-9

[0080] The reaction formula is as follows:

[0081]

[0082] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0209 g of substrate 2.1 (0.1 mmol) and 0.0272 g of substrate 2.11 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.1 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0308 g of white solid (Ⅰ-9), with a yield of 89.2% and a purity >99%.

[0083] Ⅰ-9, white solid. 1 H NMR (500MHz, Chloroform-d) δ7.38–7.32(m,5H),7.17–7.10(m,2H),6.82–6.74(m,2H),6.63(t,J=2.1Hz,1H),3.56(s,3H),3.15(d,J=5.7Hz,6H). 13 CNMR(126MHz,Chloroform-d)δ172.27,159.21,136.36,135.89,135.49,134.09,129.56,129 .34,129.00,128.69,122.73,115.45,114.31,54.93,40.88,34.40.GC-MS(EI):m / z345.10[M + ].

[0084] Example 10: Synthesis of Sample I-10

[0085] The reaction formula is as follows:

[0086]

[0087] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0209 g of substrate 2.1 (0.1 mmol) and 0.0281 g of substrate 2.12 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.1 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0287 g (Ⅰ-10) of white solid, with a yield of 82.0% and a purity >99%.

[0088] Ⅰ-10, white solid. 1 H NMR(500MHz,Chloroform-d)δ7.41(dd,J=8.1,1.1Hz,1H),7.31–7.29(m,2H),7.28(t,J=2.4 Hz,1H),7.25–7.22(m,2H),7.22–7.17(m,2H),7.00–6.89(m,2H),3.25(s,3H),3.16(s,3H). 13 C NMR(126MHz,Chloroform-d)δ171.72,138.29,134.48,133.33,133.01,131.60,130 .97,129.73,129.50,129.24,128.89,128.81,126.42,41.19,34.26.GC-MS(EI):m / z 349.05[M + ].

[0089] Example 11: Synthesis of Sample I-11

[0090] The reaction formula is as follows:

[0091]

[0092] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0209 g of substrate 2.1 (0.1 mmol) and 0.0240 g of substrate 2.13 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.1 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0305 g of white solid (Ⅰ-11), with a yield of 92.5% and a purity >99%.

[0093] Ⅰ-11, white solid. 1 H NMR (500MHz, Chloroform-d) δ7.30–7.23(m,3H),7.21–7.13(m,5H),6.97–6.88(m,2H),3.13(s,3H),3.12(s,3H),2.34(s,3H). 13 C NMR(126MHz,Chloroform-d)δ172.23,137.33,137.05,134.53,130.17,129.39,129 .34,128.75,128.49,128.45,125.57,40.89,34.18,20.02.GC-MS(EI):m / z329.11[M + ].

[0094] Example 12: Synthesis of Sample I-12

[0095] The reaction formula is as follows:

[0096]

[0097] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0209 g of substrate 2.14 (0.1 mmol) and 0.0312 g of substrate 2.2 (0.2 mmol) were added sequentially to the reaction flask. The reaction was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.1 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0327 g of white solid (Ⅰ-12), with a yield of 89.6% and a purity >99%.

[0098] Ⅰ-12, white solid. 1 H NMR(500MHz,Chloroform-d)δ7.76(dd,J=7.4,1.8Hz,1H),7.72(s,1H),7.70(d,J=1.9Hz,1H),7.61(d,J=8.6Hz,1H),7 .50–7.44(m,3H),7.36(d,J=1.6Hz,3H),7.32(s,1H),7.14(dd,J=8.6,1.8Hz,1H),5.31(s,1H),3.17(d,J=6.8Hz,6H). 13 C NMR (126MHz, Chloroform-d) δ172.40, 136.42, 136.04, 134.11, 133.26, 133.05, 131.94, 130.44, 129.65, 129 .22,129.04,128.88,128.78,128.29,127.69,127.62,126.96,126.55,126.41,40.90,34.40.GC-MS(EI):m / z 319.12[M + ].

[0099] Example 13: Synthesis of Sample I-13

[0100] The reaction formula is as follows:

[0101]

[0102] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0209 g of substrate 2.1 (0.1 mmol) and 0.0280 g of substrate 2.15 (0.2 mmol) were added sequentially to the reaction flask. The reaction was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.1 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed repeatedly with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0293 g (Ⅰ-10) of white solid, with a yield of 83.9% and a purity >99%.

[0103] Ⅰ-13, white solid. 1 H NMR(500MHz,Chloroform-d)δ7.38–7.36(m,3H),7.30–7.28(m,2H),7.21(dd,J= 2.1,1.1Hz,1H),7.14–7.11(m,2H),7.05–6.97(m,2H),3.13(s,3H),3.10(s,3H). 13 C NMR(126MHz,Chloroform-d)δ171.81,137.81,136.17,134.22,133.85,133.40,129 .66,129.53,129.38,129.12,129.02,128.79,127.85,40.81,34.20.GC-MS(EI):m / z 349.05[M + ].

[0104] Example 14: Synthesis of Sample I-14

[0105] The reaction formula is as follows:

[0106]

[0107] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0209 g of substrate 2.1 (0.1 mmol) and 0.0240 g of substrate 2.16 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.1 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by evaporation under reduced pressure to obtain 0.0315 g of white solid (Ⅰ-14), with a yield of 95.7% and a purity >99%.

[0108] Ⅰ-14, white solid. 1 H NMR(500MHz,Chloroform-d)δ7.38–7.35(m,3H),7.34–7.32(m,2H),7.13(s,1H),7 .05–7.00(m,4H),3.28(s,0H),3.17(s,3H),3.12(s,3H),2.88(s,0H),2.31(s,3H). 13 C NMR(126MHz,Chloroform-d)δ172.58,143.72,139.25,136.45,135.20,134.32,131.38 ,129.95,129.54,129.05,129.01,128.57,127.17,40.88,34.47,21.34.GC-MS(EI):m / z 329.11[M + ].

[0109] Example 15: Synthesis of Sample I-15

[0110] The reaction formula is as follows:

[0111]

[0112] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry small reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0209 g of substrate 2.1 (0.1 mmol) and 0.0248 g of substrate 2.17 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.1 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0290 g of white solid (Ⅰ-15), with a yield of 87.1% and a purity >99%.

[0113] Ⅰ-15, white solid. 1 H NMR (500MHz, Chloroform-d) δ7.38–7.35(m,3H),7.31–7.29(m,2H),7.13–7.08(m,3H),6.92–6.87(m,2H),3.12(d,J=0.8Hz,6H). 13 CNMR(126MHz,Chloroform-d)δ172.19,136.16,134.83,133.83,131.82,131.75,130.39,129.49,129.13,128.80,115.36,40.79,34.33.GC-MS(EI):m / z 333.08[M + ].

[0114] Example 16: Synthesis of Sample I-16

[0115] The reaction formula is as follows:

[0116]

[0117] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0209 g of substrate 2.1 (0.1 mmol) and 0.0280 g of substrate 2.18 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.1 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0324 g of a white solid (Ⅰ-16), with a yield of 92.8% and a purity >99%.

[0118] Ⅰ-16, white solid. 1 H NMR(500MHz,Chloroform-d)δ7.36(ddt,J=5.6,3.9,2.1Hz,3H),7.30–7.27(m,2H),7.19–7.15(m,2H),7.08–7.04(m,3H),3.11(d,J=5.3Hz,6H). 13 C NMR(126MHz,Chloroform-d)δ172.01,136.97,134.72,134.40,133.68,132.81,131.11,129.43,129.15,128.91,128.59,40.79,34.28.GC-MS(EI):m / z 349.05[M + ].

[0119] Example 17: Synthesis of Sample I-17

[0120] The reaction formula is as follows:

[0121]

[0122] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0209 g of substrate 2.1 (0.1 mmol) and 0.0240 g of substrate 2.19 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.1 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0308 g of a white solid (Ⅰ-17), with a yield of 93.7% and a purity >99%.

[0123] Ⅰ-17, white solid. 1 H NMR(500MHz,Chloroform-d)δ7.52–7.49(m,1H),7.46–7.42(m,1H),7.35(d,J=2.9Hz,2H),7.33–7.31(m,2H),7.11(s, 1H),7.07(d,J=1.5Hz,1H),6.97(d,J=1.4Hz,1H),6.92(dt,J=7.2,1.9Hz,1H),3.17(s,3H),3.14(s,3H),2.23(s,3H). 13 C NMR(126MHz,Chloroform-d)δ172.44,137.93,136.22,134.18,130.72,129.70,129.49 ,129.21,128.94,128.84,128.62,128.14,126.89,40.89,34.40,21.25.GC-MS(EI):m / z 329.11[M + ].

[0124] Example 18: Synthesis of Sample I-18

[0125] The reaction formula is as follows:

[0126]

[0127] 0.0007 g PPh3AuCl (1.5 μmol) and 0.0007 g AgSbF6 (2 μmol) were added sequentially to an anhydrous, dry reaction flask. After dissolving in 2 mL of anhydrous dichloroethane (DCE), 0.0209 g of substrate 2.1 (0.1 mmol) and 0.0220 g of substrate 2.20 (0.2 mmol) were added sequentially to the reaction flask. The mixture was stirred at 40 °C under a nitrogen atmosphere. Thin-layer chromatography (TLC) was used to detect the reaction after substrate 2.1 had completely reacted. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with dichloromethane (DCM). The filtrates were collected and combined, concentrated in a vacuum rotary evaporator, and then passed through a silica gel column. After washing with petroleum ether (PET), the solution was monitored by TLC. The eluent was collected, and the solvent was removed by vacuum evaporation to obtain 0.0244 g of a white solid (Ⅰ-18), with a yield of 76.4% and a purity >99%.

[0128] Ⅰ-18, white solid. 1 H NMR(500MHz,Chloroform-d)δ7.39–7.34(m,5H),6.08(d,J=10.3Hz,1H),5.74–5.68(m,2H),3.26(d,J=2.2Hz,3H) ,3.15(s,3H),3.00–2.92(m,1H),2.55(dddd,J=15.8,10.5,5.2,3.2Hz,1H),2.02–1.81(m,4H),1.59–1.54(m,1H). 13 C NMR(126MHz,Chloroform-d)δ170.66,137.48,135.50,134.81,129.14,128.46,1 26.99,125.62,125.11,41.47,35.23,33.29,30.93,28.29,24.01.GC-MS(EI):m / z 319.12[M + ].

[0129] Example 19: Antitumor Activity Test

[0130] (1) HeLa cells from our own laboratory were transferred to T25 cell culture dishes and cultured at 37°C in a 5% CO2 environment. After the cells reached the logarithmic growth phase, the supernatant was aspirated, and 1 ml of trypsin-EDTA digestion solution was added to the flask. After digestion for 90 seconds, the digestion solution was aspirated, and 1 ml of complete culture medium was added. The cells were then pipetted from the flask.

[0131] (2) Centrifuge the cell suspension at 1200 rpm for 3 min, carefully aspirate the supernatant, and add culture medium to resuspend the pellet to achieve a cell density of 1×10⁻⁶ cells / mL. 4 / mL, add the cell suspension evenly to each well of a 96-well plate, adding 100μL of cell suspension to each well. Place the 96-well plate containing the cell suspension in a culture environment containing 5% CO2 and incubate at 37℃. (3) Dissolve the sample in dimethyl sulfoxide (DMSO) and dilute with complete culture medium to make the drug concentrations 320, 160, 80, 40, 20, and 10 μmol / L.

[0132] When the cell density reached 80%, 100 μL of culture medium containing different concentrations of the drug was added, resulting in drug concentrations of 160, 80, 40, 20, 10, and 5 μmol / L. Three replicates were set up for each experiment. The 96-well plates were cultured in a cell culture incubator. The blank control consisted of 100 μL of culture medium without the drug, and the positive control was glycyrrhizin A compound.

[0133] (4) 36 hours after drug addition, add 20 μL of 5 mg / ml thiazolyl blue DMSO solution to each well, continue culturing for 4-6 hours and then stop the culture. Carefully remove the remaining liquid from each well, add 150 μL of DMSO to each well, and shake on a shaker at low speed for 10 min to fully dissolve the crystals. Finally, place the 96-well plate at 490 nm and measure the absorbance (OD).

[0134] (5) The inhibition rate was calculated using an Excel spreadsheet: cell viability = (experimental group OD / control group OD) × 100%; cell inhibition rate = (1 - cell viability) × 100%. IC50 was calculated using Graphpad Prism.

[0135] Table 1: Inhibitory effects of chalcone derivatives on HeLa cells

[0136] sample IC50 (μmol / L) sample IC50 (μmol / L) Ⅰ-1 192.7 Ⅰ-12 99.54 Ⅰ-3 232.2 Ⅰ-13 72.18 Ⅰ-4 82.45 Ⅰ-14 74.45 Ⅰ-7 31.9 Ⅰ-15 119.2 Ⅰ-9 72.74 Ⅰ-16 68.65 Ⅰ-10 69.74 Ⅰ-18 13.44 Ⅰ-11 172.7 Glycyrrhizin A 116

[0137] As shown in Table 1, compounds I-1, I-3, I-4, I-7, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, and I-18 all exhibit inhibitory effects on HeLa cells. Among them, compounds I-4, I-7, I-9, I-10, I-12, I-13, I-14, I-16, and I-18 have higher inhibitory effects on HeLa cells than glycyrrhizin A. The compound with the strongest inhibitory effect on HeLa cells is I-18.

Claims

1. Application of the sulfoneamine chalcone derivative shown in formula (Ⅰ) in the preparation of antitumor drugs: the tumor cells are cervical cancer cells; The sulfonylamine chalcone derivatives are compounds (I-1), (I-3), (I-4), (I-7), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15), (I-16), or (I-18): 。 2. The application as described in claim 1, characterized in that: The methyl sulfone amino chalcone derivatives are compounds (I-4), (I-7), (I-9), (I-10), (I-12), (I-13), (I-14), (I-16), or (I-18).

3. The application as described in claim 2, characterized in that: The methyl sulfone amino chalcone derivative is compound (I-18).

4. The application as described in claim 1, characterized in that: The antitumor drug is composed of a methylsulfonyl chalcone derivative or a pharmaceutically acceptable salt thereof as shown in formula (I) and a pharmaceutically acceptable carrier.

5. The application as described in claim 1, characterized in that: The pharmaceutically acceptable carrier is one or more of the following: diluent, filler, binder, wetting agent, disintegrant, absorption promoter, surfactant, adsorbent, lubricant, and thickener.

6. The application as described in claim 4, characterized in that: The diluent is water, the filler is starch, the binder is a cellulose derivative or gelatin, the humectant is glycerol, the disintegrant is agar or calcium carbonate, the absorption promoter is a quaternary ammonium compound, the surfactant is hexadecyl alcohol, the adsorbent carrier is kaolin or soap clay, the lubricant is talc, and the thickener is sodium carboxymethyl cellulose.

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