Diphenyl ether compound taking kaiso protein as a target and preparation method and application thereof

Abstract

This invention relates to diphenyl ether compounds targeting Kaiso protein, their preparation methods, and applications. The molecular structure of the diphenyl ether compounds is shown in Formula I, where R is selected from any one of hydrogen atom, halogen, alkyl, hydroxyl, methoxy, ester, cyano, nitro, and 3,4-methylene. The preparation steps include: reacting isovandrin, copper acetate, and p-bromophenylboronic acid under alkaline conditions with dichloromethane as a solvent to obtain compound 1; reacting compound 1 with malonic acid and ammonium acetate under heating with ethanol as a solvent to obtain compound 2; dissolving compound 2 in ethanol as a solvent, adding sulfoxide dropwise at low temperature, and then reacting at room temperature to obtain compound 3; and reacting tetra(triphenyl)phosphine palladium, compound 3, and phenylboronic acid under alkaline conditions and a nitrogen atmosphere with water and 1,4-dioxane as solvents to obtain the target compound. The diphenyl ether compounds prepared by this invention exhibit excellent inhibitory activity against lung cancer cells.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a lung cancer inhibitor targeting the Kaiso protein, its preparation method, and its application. Background Technology

[0002] In recent years, the role of zinc finger proteins in the molecular regulation of lung cancer has been gradually discovered. Numerous studies have shown that the unique finger-like structure of zinc finger proteins can recognize and bind DNA and RNA sequences, intervening in gene transcription and expression. As important human transcription factors, they participate in biological processes such as differentiation, proliferation, metabolism, and signal transduction. [1] Furthermore, studies have demonstrated that zinc finger proteins play a crucial role in the development of various cancers, including lung cancer, and are important targets for the diagnosis and treatment of malignant tumors. Kaiso, as an important member of the zinc finger protein family, possesses dual DNA sequence recognition and plays a role in promoting cancer development in lung cancer. [2] .

[0003] The transcription factor kaiso, a newly discovered important member of the BTB-POZ protein family, is a specific binding partner of Armadillo catenin and the cell helper adhesion factor P120-catenin (P120ctn), and has been shown to possess transcriptional repressive functions. P120ctn can relieve kaiso-mediated transcriptional repression, and the subcellular localization of P120ctn in tumors affects lung cancer activity. [3] Unlike other typical POZ proteins, Kaiso possesses dual DNA sequence recognition, and its cytoplasmic and nuclear localization depends on the tumor tissue microenvironment. For P120ctn, its roles vary depending on its intracellular location, including cadherin-dependent cell adhesion, actin cytoskeleton remodeling, and its influence on Kaiso activity when located in the nucleus. [4] In lung cancer cells, kaiso can inhibit the expression of the tumor suppressor gene CDKN2A (p16 / INK4A). The C2H2 structure of kaiso can recognize the hypermethylated promoter of p16, leading to its downregulation and cell cycle initiation. This is a possible factor in the etiology of lung cancer. [5] In 2012, Eloisi et al. demonstrated that inhibiting kaiso with siRNA affects p16 expression and proposed that inhibiting kaiso could improve the efficacy of lung cancer treatment. They also investigated the effects of inhibiting CDH1 gene expression. CDH1 encodes E-cadherin, a calcium-dependent cell adhesion protein belonging to the cadherin family. The CDH1 gene is involved in regulating cell adhesion, migration, and epithelial cell proliferation; its loss of function leads to increased cell invasion and metastasis.[6] Currently, inhibition of Kaiso is mainly achieved through the regulation of its specific binding partner, P120 catenin, with few studies on inhibitors directly targeting the Kaiso structure. Therefore, the search for and discovery of novel, safe, and effective lung cancer inhibitors is of great significance for the treatment of lung cancer and its related complications.

[0004] References:

[0005] [1]AHMED S,KHAN S,QURESHI MA,et al.Expressional variations of Kaiso:an association with pathological characteristics and field cancerization ofOSCC[J].Bmc Cancer,2022,22(1).

[0006] [2]AHMED SU,DAVIS B,ADDAI BA,et al.Kaiso influences immunesignaling of breast cancer exosomes[J].Cancer Epidemiology Biomarkers&Prevention,2020,29(6).

[0007] [3]BASSEY-ARCHIBONG BI,HERCULES SM,RAYNER LGA,et al.Kaiso is highly expressed in TNBC tissues of women of African ancestry compared to Caucasian women[J].Cancer Causes&Control,2017,28(11):1295-304.

[0008] [4]BASSEY-ARCHIBONG BI,RAYNER LGA,HERCULES S,et al.High Kaisoexpression correlates with increased TGF beta signaling and aggressive TNBCin women of African Ancestry(WAA)[J].Cancer Epidemiology Biomarkers&Prevention,2017,26(2).

[0009] [5]BASSEY-ARCHIBONG BI,RAYNER LGA,HERCULES SM,et al.Kaisodepletion attenuates the growth and survival of triple negative breast cancer cells[J].Cell Death&Disease,2017,8.

[0010] [6]Daniel JM,Reynolds A B.The catenin p120(ctn)interacts with Kaiso, a novel BTB / POZ domain zinc finger transcription factor.[J].Molecular and cellular biology, 1999,19(5). Summary of the Invention

[0011] The purpose of this invention is to overcome the defects of the prior art by providing a diphenyl ether compound targeting Kaiso protein, its preparation method, and its application.

[0012] The objective of this invention can be achieved through the following technical solutions:

[0013] One of the technical solutions of the present invention is to provide a diphenyl ether compound targeting the Kaiso protein, the molecular structure of which is shown in Formula I:

[0014]

[0015] R is selected from any one of hydrogen atom, halogen, alkyl, hydroxyl, methoxy, ester, cyano, nitro, and 3,4-methylene.

[0016] Preferably, R is a hydroxyl, methoxy, or ester group.

[0017] The second technical solution of the present invention provides a method for preparing diphenyl ether compounds targeting Kaiso protein as described in one of the above technical solutions, comprising the following steps:

[0018] S1. Compound 1 was obtained by reacting isovanthanin as the starting material, dichloromethane as the solvent, and copper acetate as the catalyst with p-bromophenylboronic acid under alkaline conditions and heating.

[0019] S2. Using ethanol as a solvent, compound 1 obtained in step S1 is reacted with malonic acid and ammonium acetate by stirring and heating to obtain compound 2.

[0020] S3. Using ethanol as a solvent, dissolve compound 2 obtained in step S2, add thionyl chloride dropwise at low temperature, and then react at room temperature to obtain compound 3.

[0021] S4. Using water and 1,4-dioxane as solvents and tetra(triphenyl)phosphine palladium as catalyst, under alkaline conditions and in a nitrogen atmosphere, compound 3 obtained in step S3 was reacted with a phenylboronic acid compound to obtain the final product, namely a diphenyl ether compound.

[0022] The structural formulas of compounds 1, 2, and 3 are shown in formulas II, III, and IV, respectively:

[0023]

[0024] In some specific embodiments, in step S1, alkaline conditions are achieved by adding triethylamine (TEA); the molar ratio of isovandrin, p-bromophenylboronic acid, triethylamine, and copper acetate is 1:1.1:2:0.1-1:2:3:0.5.

[0025] In some specific embodiments, in step S1, the process conditions for the heating reaction are: the heating temperature is 25-55°C, and the heating time is 12-48h.

[0026] In some specific embodiments, in step S2, the molar ratio of compound 1 to malonic acid and ammonium acetate is 1:2:2-1:3:3.

[0027] In some specific embodiments, in step S2, the process conditions for stirring and heating the reaction are: the reaction temperature is 70-95℃ and the reaction time is 12-36h.

[0028] In some specific embodiments, in step S3, the molar ratio of compound 2 to sulfoxide is 1:2 to 1:8.

[0029] In some specific embodiments, in step S3, the reaction temperature is 0-25°C and the reaction time is 12-36 hours.

[0030] In some specific embodiments, in step S4, the phenylboronic acid compound is a compound with the following general structural formula: R is selected from any one of hydrogen atom, halogen, alkyl, hydroxyl, methoxy, ester, cyano, nitro, and 3,4-methylene.

[0031] In some specific embodiments, in step S4, alkaline conditions are achieved by adding triethylamine; the molar ratio of compound 3, phenylboronic acid, triethylamine, and tetra(triphenyl)phosphine palladium is 1:1.1:2:0.05-1:2:4:0.1.

[0032] In some specific embodiments, in step S4, the ratio of compound 3, water and 1,4-dioxane is 1 mmol:(1.5-2 mL):(5-10) mL.

[0033] In some specific embodiments, in step S4, the reaction temperature is 80-110°C and the reaction time is 12-48 hours.

[0034] In some specific embodiments, in step S4, after compound 3 reacts with phenylboronic acid, it is further purified by column chromatography, with ethyl acetate and petroleum ether as eluents, and the volume ratio of ethyl acetate to petroleum ether is 1:20-1:5.

[0035] The synthesis route of this technical solution is shown in the following formula:

[0036]

[0037] The third technical solution of the present invention is to provide an application of a diphenyl ether compound targeting Kaiso protein as described in one of the above technical solutions, wherein the diphenyl ether compound targeting Kaiso protein is used to prepare a drug that inhibits the activity of lung cancer cells.

[0038] In some specific embodiments, the drug is a lung cancer inhibitor targeting the kaiso protein.

[0039] Compounds acting on the C2H2 domain of the Kaiso protein exhibit better inhibitory activity and selectivity. This invention, based on computer-aided drug design, synthesizes diphenyl ether compounds targeting the Kaiso protein in lung cancer cells. These compounds exhibit better binding to the protein pocket, thereby enhancing their inhibitory activity and selectivity.

[0040] Compared with existing technologies, the diphenyl ether compounds prepared by this invention have excellent lung cancer cell inhibitory activity. Detailed Implementation

[0041] The present invention will now be described in detail with reference to specific embodiments. These embodiments are based on the technical solution of the present invention and provide detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments.

[0042] Unless otherwise specified, the raw materials or processing techniques used in the following embodiments and comparative examples are all conventional commercially available raw materials or conventional processing techniques in the art.

[0043] Example 1:

[0044] Example 1 provides a method for preparing a diphenyl ether compound (compound 4-1) targeting the Kaiso protein, comprising the following steps:

[0045] (1) Accurately weigh 152 mg (1.0 mmol) of isovandrin, 261 mg (1.3 mmol) of p-bromophenylboronic acid, 19.9 mg (0.1 mmol) of copper acetate, and 0.4 mL (3 mmol) of triethylamine into a round-bottom flask. Then add 10.0 mL of dichloromethane to dissolve and mix, stir well, and react at 45 °C for 12 hours. After the reaction, evaporate the solvent, extract with ethyl acetate, and wash three times with saturated sodium chloride solution to obtain compound 1.

[0046] (2) Weigh 307 mg (1 mmol) of compound 1, 208 mg (2 mmol) of malonic acid and 144 mg (2 mmol) of ammonium acetate, dissolve them in 5 mL of ethanol, react at 90 °C for 24 hours, filter after reaction to obtain a white solid, and dry to obtain compound 2.

[0047] (3) Weigh 365 mg (1 mmol) of compound 2 and dissolve it in 5 mL of ethanol. Slowly add 0.36 mL (5 mmol) of thionyl chloride at 0 °C and stir at 0 °C for 0.5 hours. Then stir at room temperature for 12 hours. After stirring, remove excess thionyl chloride and ethanol by rotary evaporation and extract with ethyl acetate. Adjust the pH to 7-8 with saturated sodium bicarbonate solution. Dry the ethyl acetate to obtain compound 3.

[0048] (4) Weigh out 3393 mg (1 mmol) of compound 3, 179 mg (1.3 mmol) of p-hydroxyphenylboronic acid, 0.4 mL (3 mmol) of triethylamine, and 115 mg (0.1 mmol) of tetra(triphenyl)phosphine palladium, and dissolve them in 1.5 mL of water and 6 mL of 1,4-dioxane. Purge the mixture three times with nitrogen and react at 110 °C for 12 hours. After 12 hours of reaction, evaporate the solvent to dryness, extract with ethyl acetate, and wash three times with saturated sodium chloride solution. Purify by column chromatography, washing with ethyl acetate:petroleum ether = 1:10 to give compound 4-1 in 83.5% yield.

[0049] The obtained target compound 4-1 is an off-white powder with the structure shown below:

[0050]

[0051] Its NMR data are as follows:

[0052] 1 H NMR (500MHz, CDCl3) δ7.64,7.64,7.61,7.50,7.49,7.46,7.45,7.44,7.33,7.32,7.31,7.31,7.23,7.22,7.03,7.01,6.95,6.94,6.93,6.93,6 .92,4.30,4.29,4.28,4.27,4.27,4.26,4.25,4.19,4.19,4.18,4.18, 4.16,4.15,4.15,3.91,2.34,2.33,2.29,2.09,2.09,1.36,1.34,1.33.

[0053] 13 C NMR (126MHz, CDCl3) δ171.64,167.56,156.33,155.46,153.15,145.70,144.0 5,135.95,132.91,129.60,128.07,128.00,127.92,127.83,125.57,119.47, 117.80,117.53,116.53,115.77,112.72,77.35,77.10,76.84,60.67,60.55,56.15,51.80,51.60,51.43,51.25,41.63,41.50,41.46,41.12,14.31,14.18.

[0054] HRMS(ESI)calcd for C 24 H 25 NO5[M+H] + :408.1766; Found:408.17665.

[0055] Example 2:

[0056] This embodiment provides a method for preparing a diphenyl ether compound (compound 4-2) targeting the Kaiso protein. It is mostly the same as that in Example 1, except that "179 mg (1.3 mmol) of p-hydroxyphenylboronic acid" in step (4) is replaced with an equimolar amount of "p-methoxyphenylboronic acid".

[0057] The obtained target compound 4-2, a white powder, has the following structure:

[0058]

[0059] Its NMR data are as follows:

[0060] 1 H NMR (501MHz, CDCl3) δ7.63,7.60,7.54,7.53,7.52,7.51,7.33,7.33,7.31,7.29,7.22,7.04,7 .03,7.01,6.99,6.98,6.29,6.25,4.29,4.28,4.26,4.25,3.92,3.89,3.88,1.35,1.34,1.32.

[0061] 13 C NMR (126MHz, CDCl3) δ171.54,164.03,158.95,156.43,153.75,153.16,149. 62,148.37,145.68,144.03,135.85,133.22,127.98,127.94,125.61,119.5 1,117.81,116.57,116.10,114.93,114.27,112.74,77.30,77.05,76.79,60.65,56.14,55.85,55.40,51.05,51.02,41.67,41.57,41.51,41.39,14.29.

[0062] HRMS(ESI)calcd for C 25 H 27 NO5[M+H] + :422.1923; Found:422.19672.

[0063] Example 3:

[0064] This embodiment provides a method for preparing a diphenyl ether compound (compound numbered 4-3) targeting the Kaiso protein. It is mostly the same as that in Example 1, except that "179 mg (1.3 mmol) of p-hydroxyphenylboronic acid" in step (4) is replaced with an equimolar amount of "phenylboronic acid".

[0065] The obtained target compound 4-3, a white powder, has the following structure:

[0066]

[0067] Its NMR data are as follows:

[0068] 1 H NMR (501MHz, CDCl3) δ7.61,7.60,7.59,7.58,7.58,7.56,7.47,7.46,7.44,7.37,7.35,7.33,7.33,7 .29,7.26,7.25,7.24,7.06,7.05,7.03,6.29,6.26,4.29,4.27,4.26,4.24,3.92,1.35,1.34,1.32.

[0069] 13 C NMR (126MHz, CDCl3) δ169.65,169.46,167.11,157.01,153.18,145.50,143.66,140.56,136.09,129.63,128.77,128.40,127.00,126.91 ,125.64,119.67,117.67,116.76,115.33,112.73,77.30,77.05,76.79,60.57,60.44,56.14,51.45,51.32,51.21,51.13,51.07,14.33.

[0070] HRMS(ESI)calcd for C 24 H 25 NO4[M+H] + :392.1817; Found:392.18176.

[0071] Example 4:

[0072] This embodiment provides a method for preparing a diphenyl ether compound (compound 4-4) targeting the Kaiso protein. It is mostly the same as that in Example 1, except that "179 mg (1.3 mmol) of p-hydroxyphenylboronic acid" in step (4) is replaced with an equimolar amount of "p-cyanophenylboronic acid".

[0073] The obtained target compound 4-4, a yellow powder, has the following structure:

[0074]

[0075] Its NMR data are as follows:

[0076] 1H NMR (501MHz, CDCl3) δ7.73,7.72,7.68,7.67,7.57,7.55,7.53,7.51,7.37,7.37,7.36,7.35,7.26,7.2 5,7.06,7.06,7.05,7.04,6.94,6.93,6.30,6.26,4.28,4.27,4.25,4.24,3.90,1.35,1.33,1.32,0.11.

[0077] 13 C NMR (126MHz, CDCl3) δ171.95,167.22,158.32,153.28,145.00,144.77,143.63,134.1 5,133.64,132.63,128.60,128.44,127.96,127.37,127.29,126.18,120.18,119.00, 117.60,117.27,116.81,116.41,112.84,110.45,77.35,77.10,76.84,60.59,60.30,56.11,51.79,51.41,51.09,50.59,50.38,41.94,41.64,41.49,41.19,29.71,14.32.

[0078] HRMS(ESI)calcd for C 25 H 24 N₂O₄[M+H] + :417.1770; Found:417.17703.

[0079] Example 5:

[0080] This embodiment provides a method for preparing diphenyl ether compounds (compounds 4-5) targeting the Kaiso protein. It is mostly the same as that in Example 1, except that "179 mg (1.3 mmol) of p-hydroxyphenylboronic acid" in step (4) is replaced with an equimolar amount of "3,4-methylenephenylboronic acid".

[0081] The obtained target compounds 4-5 are white powders, and their structures are shown below:

[0082]

[0083] Its NMR data are as follows:

[0084] 1H NMR (501MHz, CDCl3) δ7.63,7.59,7.48,7.47,7.34,7.33,7.32,7.32,7.23,7.23,7.07,7.06,7.05,7.05,7.04,7.04,7 .03,7.02,7.01,7.01,6.89,6.87,6.29,6.25,6.00,5.30,4.28,4.26,4.25,4.24,3.90,3.87,3.72,1.35,1.33,1.32.

[0085] 13 C NMR (126MHz, CDCl3) δ171.24,167.03,156.72,153.16,148.14,146.88,145.51, 143.62,135.83,134.96,128.11,127.94,125.61,120.33,119.64,117.66,117. 41,116.76,112.72,108.57,107.48,101.13,77.37,77.12,76.86,60.61,60.40,56.12,56.09,53.92,53.48,53.46,53.01,41.65,41.31,41.28,41.19,14.34.

[0086] HRMS(ESI)calcd for C 25 H 25 NO6[M+H] + :436.1715; Found:436.17152.

[0087] Example 6:

[0088] This embodiment provides a method for preparing diphenyl ether compounds (compounds 4-6) targeting the Kaiso protein. It is mostly the same as that in Example 1, except that "179 mg (1.3 mmol) of p-hydroxyphenylboronic acid" in step (4) is replaced with an equimolar amount of "p-chlorophenylboronic acid".

[0089] The obtained target compounds 4-6 are white powders, and their structures are shown below:

[0090]

[0091] Its NMR data are as follows:

[0092] 1H NMR (501MHz, CDCl3) δ7.53,7.52,7.51,7.51,7.42,7.41,7.35,7.33,7.24,7.19,7.1 7,7.05,7.03,6.80,6.79,6.30,6.27,4.28,4.26,4.25,3.91,3.91,1.35,1.34,1.32.

[0093] 13 C NMR (126MHz, CDCl3) δ171.77,167.31,161.92,160.52,157.29,154.93,143.77,13 4.77,129.72,129.39,128.92,128.78,128.40,128.27,128.13,128.06,126.91,1 25.82,119.80,117.69,117.58,117.39,116.77,112.77,77.32,77.07,76.81,60.55,60.54,56.13,51.94,51.79,51.73,51.43,41.26,41.08,41.01,40.62,14.32.

[0094] HRMS(ESI)calcd for C 24 H 24 NClO4[M+H] + :427.1364; Found:427.13642.

[0095] Example 7:

[0096] This embodiment provides a method for preparing diphenyl ether compounds (compounds 4-7) targeting the Kaiso protein. It is mostly the same as that in Example 1, except that "179 mg (1.3 mmol) of p-hydroxyphenylboronic acid" in step (4) is replaced with an equimolar amount of "methyl p-formate phenylboronic acid".

[0097] The obtained target compounds 4-7 are white powders, and their structures are shown below:

[0098]

[0099] Its NMR data are as follows:

[0100] 1H NMR (501MHz, CDCl3) δ8.12,8.10,7.66,7.64,7.63,7.60,7.59,7.59,7.36,7.35,7.34,7.34,7.25,7.25,7 .06,7.04,7.03,7.02,6.29,6.26,4.28,4.26,4.25,4.23,3.95,3.90,3.89,3.88,3.86,1.34,1.33,1.31.

[0101] 13 C NMR (126MHz, CDCl3) δ171.57,167.05,157.85,153.22,145.09,144.94,1 43.56,134.61,130.14,128.58,128.48,127.99,126.69,125.91,119.97, 117.59,117.38,116.84,112.80,77.32,77.07,76.82,60.49,60.44,56.1 1,52.10,52.01,51.80,51.64,51.48,41.25,41.04,40.96,40.86,14.32.

[0102] HRMS(ESI)calcd for C 26 H 27 NO6[M+H] + Found: 450.1872;

[0103] Example 8:

[0104] This embodiment provides a method for preparing diphenyl ether compounds (compounds 4-8) targeting the Kaiso protein. It is mostly the same as that in Example 1, except that "179 mg (1.3 mmol) of p-hydroxyphenylboronic acid" in step (4) is replaced with an equimolar amount of "p-fluorophenylboronic acid".

[0105] The obtained target compounds 4-8 are white powders, and their structures are shown below:

[0106]

[0107] Its NMR data are as follows:

[0108] 1H NMR (501MHz, CDCl3) δ7.62,7.59,7.55,7.54,7.54,7.53,7.52,7.50,7.35,7.34,7.33,7.33,7.2 3,7.23,7.15,7.14,7.12,7.05,7.03,6.28,6.25,4.28,4.27,4.25,4.24,3.92,1.35,1.33,1.32.

[0109] 13 C NMR (126MHz, CDCl3) δ171.00,167.06,163.28,156.97,153.13,145.43,143.6 2,136.71,135.13,128.61,128.47,128.40,128.29,127.94,125.69,119.60, 117.75,116.77,115.70,115.53,112.70,77.31,77.05,76.80,60.44,60.43,56.14,52.06,51.88,51.64,51.44,51.13,41.50,41.32,41.26,41.10,14.33.

[0110] HRMS(ESI)calcd for C 24 H 24 NFO4[M+H] + :410.1723; Found:410.17238.

[0111] Example 9:

[0112] This embodiment provides a method for preparing diphenyl ether compounds (compounds 4-9) targeting the Kaiso protein. It is mostly the same as that in Example 1, except that "179 mg (1.3 mmol) of p-hydroxyphenylboronic acid" in step (4) is replaced with an equimolar amount of "p-nitrophenylboronic acid".

[0113] The obtained target compounds 4-9 are yellow liquids, and their structures are shown below:

[0114]

[0115] Its NMR data are as follows:

[0116] 1H NMR (501MHz, CDCl3) δ8.44,8.44,8.20,8.19,8.18,8.18,8.17,7.92,7.90,7.63,7.61,7.60,7.60,7.59,7.57,7.57,7.38,7.37,7.36,7.3 5,7.26,7.26,7.09,7.07,7.06,7.05,7.04,6.30,6.27,4.28,4.27,4 .25,4.24,4.18,4.17,4.17,4.16,4.15,4.15,3.91,1.35,1.33,1.32.

[0117] 13 C NMR (126MHz, CDCl3) δ171.04,167.06,158.16,153.22,148.77,144.87,143.51, 142.24,133.26,132.72,129.72,128.53,128.41,128.01,126.10,121.71,121. 64,120.06,117.71,117.41,116.88,112.81,77.31,77.06,76.80,60.53,60.48,56.12,51.90,51.65,51.54,51.37,51.11,41.73,41.60,41.59,41.31,14.33.

[0118] HRMS(ESI)calcd for C 24 H 24 N₂O₆[M+H] + :437.1668; Found:437.16683.

[0119] The target compounds synthesized in Examples 1-9 were tested for their inhibitory activity against lung cancer cells, and the results are shown in Table 1 below:

[0120] Table 1

[0121]

[0122]

[0123] Compared with reported lung cancer cell inhibitors targeting the Kaiso protein, such as gemcitabine (IC50 = 2.7 μM) and MIRA-1 (IC50 = 654.065 μM), the synthesized compounds showed good inhibitory activity. In particular, the three preferred compounds, 4-1, 4-2, and 4-7, had IC50 values ​​of 0.34 μM, 0.68 μM, and 0.87 μM, respectively.

[0124] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A diphenyl ether compound targeting the Kaiso protein, characterized in that, The molecular structure of the diphenyl ether compound is as shown in either Formula I or Formula V: ， ， Wherein, R is selected from hydrogen atom, halogen, hydroxyl, methoxy, -COOCH3, cyano, nitro, Any one of them.

2. A method for preparing a diphenyl ether compound targeting Kaiso protein as described in claim 1, characterized in that, Includes the following steps: S1. Compound 1 was obtained by reacting isovanthanin as the starting material, dichloromethane as the solvent, and copper acetate as the catalyst with p-bromophenylboronic acid under alkaline conditions and heating. S2. Using ethanol as a solvent, compound 1 obtained in step S1 is reacted with malonic acid and ammonium acetate by stirring and heating to obtain compound 2. S3. Using ethanol as a solvent, dissolve compound 2 obtained in step S2, add thionyl chloride dropwise at low temperature, and then react at room temperature to obtain compound 3. S4. Using water and 1,4-dioxane as solvents and tetra(triphenyl)phosphine palladium as catalyst, under alkaline conditions and in a nitrogen atmosphere, compound 3 obtained in step S3 was reacted with a phenylboronic acid compound to obtain the final product, namely a diphenyl ether compound. The structural formulas of compounds 1, 2, and 3 are shown in formulas II, III, and IV, respectively: ； The phenylboronic acid compound is a compound with the following general structural formula: or R is selected from hydrogen atom, halogen, hydroxyl, methoxy, -COOCH3, cyano, nitro, Any one of them.

3. The method for preparing diphenyl ether compounds targeting Kaiso protein according to claim 2, characterized in that, In step S1, alkaline conditions are achieved by adding triethylamine; the molar ratio of isovandrin, p-bromophenylboronic acid, triethylamine, and copper acetate is 1:1.1:2:0.1-1:2:3:0.

5. For step S1, the process conditions for the heating reaction are: the heating temperature is 25-55℃, and the heating time is 12-48 h.

4. The method for preparing diphenyl ether compounds targeting Kaiso protein according to claim 2, characterized in that, In step S2, the molar ratio of compound 1 to malonic acid and ammonium acetate is 1:2:2-1:3:3; In step S2, the process conditions for stirring and heating the reaction are: the reaction temperature is 70-95℃ and the reaction time is 12-36h.

5. The method for preparing diphenyl ether compounds targeting Kaiso protein according to claim 2, characterized in that, In step S3, the molar ratio of compound 2 to sulfoxide is 1:2-1:

8.

6. The method for preparing diphenyl ether compounds targeting Kaiso protein according to claim 2, characterized in that, In step S3, the reaction temperature is 0-25℃ and the reaction time is 12-36 h.

7. The method for preparing diphenyl ether compounds targeting Kaiso protein according to claim 2, characterized in that, In step S4, alkaline conditions are achieved by adding triethylamine; the molar ratio of compound 3, phenylboronic acid compound, triethylamine, and tetra(triphenyl)phosphine palladium is 1:1.1:2:0.05-1:2:4:0.1; the ratio of compound 3, water, and 1,4-dioxane is 1 mmol : (1.5-2 mL) : (5-10) mL.

8. The method for preparing diphenyl ether compounds targeting Kaiso protein according to claim 2, characterized in that, In step S4, the reaction temperature is 80-110℃ and the reaction time is 12-48 h.

9. The application of a diphenyl ether compound targeting Kaiso protein as described in claim 1, characterized in that, The diphenyl ether compounds targeting the Kaiso protein are used to prepare drugs that inhibit the activity of lung cancer cells.

Images