CN110467551B - 4-methoxy-N- (1-naphthyl) benzenesulfonamide STAT3 small-molecule inhibitor and preparation and application thereof - Google Patents
4-methoxy-N- (1-naphthyl) benzenesulfonamide STAT3 small-molecule inhibitor and preparation and application thereof Download PDFInfo
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Abstract
The invention discloses a 4-methoxy-N- (1-naphthyl) benzene sulfonamide STAT3 small molecule inhibitor, and preparation and application thereof, wherein the 4-methoxy-N- (1-naphthyl) benzene sulfonamide compound shows a certain antitumor activity. According to the results of the antitumor activity test, the compounds DL14, DL15 and DL16 showed better biological activity than the positive control drug C188-9; among them, the compound DL14 with the best activity shows excellent activity on A549, MDA-MB-231 and HCT-116 cells highly expressed by STAT3 (IC50 is 1.15-3.28 mu M), and is superior to the positive control C188-9; experiments prove that DL14 can inhibit phosphorylation of STAT3 in A549.
Description
Technical Field
The invention relates to the technical field of medical chemistry, and particularly relates to a 4-methoxy-N- (1-naphthyl) benzenesulfonamide STAT3 small-molecule inhibitor, and a preparation method and application thereof.
Background
Signal transduction and activators of transcription, STAT3, is a member of the STAT family of proteins, a potential transcription factor located in the cytoplasm and directly related to the transmission of signals from the cell membrane to the nucleus. There are 7 members of the STAT protein family: STAT1-4, STAT5A, STAT5B and STAT6, which range in size from 750 to 850 amino acids. The entire STAT family can be divided into two groups according to its function. The first group consists of STAT2, STAT4 and STAT6, which are involved in T cell development and IFN- γ signaling through small amounts of cytokines. The second group comprises STAT1, STAT3 and STAT5, which are activated in different tissues by various ligands and are involved in IFN- γ signaling, breast and embryo development. The latter group of STATs plays a key role in tumorigenesis, as they also control cell cycle progression and apoptosis. In contrast to the oncogenic effects of STAT3, STAT1 inhibits tumor cell proliferation and promotes tumor cell apoptosis, and the selectivity of compounds for STAT1 should be considered in designing small molecule inhibitors of STAT 3. In addition, STAT3 also controls many physiological processes, including proliferation, differentiation, immunity, metabolism, and is expressed abnormally in many cancers. Therefore, STAT3 is receiving increasing attention as one of the important targets for research on antitumor drugs.
The above formula is several important STAT3 inhibitors. C188-9 is an effective STAT3 inhibitor, targets the SH2 domain of STAT3, can be combined with STAT3 with high affinity, has a Kd value of 4.7 +/-0.4 nM, and has no obvious inhibition effect on upstream kinase JAK or Src. The research shows that C188-9 can inhibit the phosphorylation of STAT3 and also has certain inhibition effect on the phosphorylation of STAT 1. However, the IC50 value of the tumor cell is higher, and the dosage of the tumor allograft model is larger. There is also room for improvement.
Disclosure of Invention
The invention provides a 4-methoxy-N- (1-naphthyl) benzene sulfonamide compound, and a preparation method and an application thereof, wherein the 4-methoxy-N- (1-naphthyl) benzene sulfonamide compound can better inhibit tumor cells.
The technical scheme of the invention is as follows:
A4-methoxy-N- (1-naphthyl) benzene sulfonamide compound has a structure shown in formula (I) or (II):
in the formulas (I) to (II), R is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyrimidyl and C1～C5Alkyl radical, C2～C5Alkenyl or methoxyethyl;
the substituent on the phenyl or the pyrimidyl is selected from one or more of methoxy, methyl, halogen and trifluoromethyl.
Preferably, the compound is one of compounds DL01 to DL 20;
the structures of DL 01-DL 20 are as follows:
the definition of R is shown in the following table:
preferably, compound DL01 has the following structural formula:
most preferably, compound DL14 has the following structural formula:
the invention also provides a preparation method of the 4-methoxy-N- (1-naphthyl) benzene sulfonamide compound, which comprises the following steps:
(1) under the action of alkali, carrying out amidation reaction on p-methoxybenzenesulfonyl chloride and 1-naphthylamine to obtain a sulfonamide intermediate;
(2) under the action of tetrabutylammonium hydrogen sulfate and inorganic alkali, a sulfonamide intermediate reacts with an acyl chloride compound or a halogenated hydrocarbon compound to obtain the 4-methoxy-N- (1-naphthyl) benzene sulfonamide compound.
Preferably, the compound DL1 is prepared by the following steps:
(1) adding p-methoxybenzenesulfonyl chloride, 1-naphthylamine and pyridine into dichloromethane, stirring at normal temperature overnight, extracting with an HCl aqueous solution after reaction is finished, drying an organic layer with anhydrous sodium sulfate, performing vacuum filtration, and drying filter residues to obtain a sulfonamide intermediate;
(2) dissolving the sulfonamide intermediate, tetrabutylammonium hydrogen sulfate and potassium carbonate in dichloromethane, stirring at normal temperature, adding benzoyl chloride, continuously stirring overnight, after the reaction is finished, respectively adding saturated sodium bicarbonate and saturated sodium chloride solutions for extraction, drying an organic layer with anhydrous sodium sulfate, carrying out rotary drying to prepare sand, and carrying out separation and purification through column chromatography to obtain the target compound DL 01.
Preferably, the compound DL14 is prepared by the following steps:
(1) adding p-methoxybenzenesulfonyl chloride, 1-naphthylamine and pyridine into dichloromethane, stirring at normal temperature overnight, extracting with an HCl aqueous solution after reaction is finished, drying an organic layer with anhydrous sodium sulfate, performing vacuum filtration, and drying filter residues to obtain a sulfonamide intermediate;
(2) dissolving the sulfonamide intermediate, tetrabutylammonium hydrogen sulfate and potassium carbonate in dichloromethane, stirring at normal temperature, adding acryloyl chloride, continuously stirring overnight, after the reaction is finished, respectively adding saturated sodium bicarbonate and saturated sodium chloride solution for extraction, drying an organic layer with anhydrous sodium sulfate, carrying out spin drying to prepare sand, and carrying out separation and purification by column chromatography to obtain the target compound DL 14.
The invention also provides application of the 4-methoxy-N- (1-naphthyl) benzene sulfonamide compound in preparing antitumor drugs.
Preferably, the antitumor drug is used for inhibiting breast cancer, colon cancer or lung cancer.
The 4-methoxy-N- (1-naphthyl) benzene sulfonamide derivative shows certain antitumor activity. According to the results of the antitumor activity test, the compounds DL14, DL15 and DL16 show the biological activity equivalent to or even superior to that of the positive control medicament C188-9; among them, the compound DL14 with the best activity shows excellent activity on A549, MDA-MB-231 and HCT-116 highly expressed by STAT3 (IC50 is 1.15-3.28 mu M), and is superior to a positive control C188-9; experiments prove that DL14 can inhibit phosphorylation of STAT3 in A549.
Drawings
Figure 1 is the result of STAT3 phosphorylation inhibition of a549 by compound DL 14;
figure 2 is the result of STAT1 phosphorylation inhibition of a549 by compound DL 14.
Detailed Description
The following examples are further detailed descriptions of the present invention.
Synthesis of the Compound of example 1
1.1A specific synthetic route for the compounds is shown below:
the specific reaction conditions are as follows: a, pyridine, DCM and rt are stirred overnight; TBAHS, K2CO3DCM, rt, stirred overnight; c is K2CO3DMF, rt, stirring overnight;
1.2 synthetic procedure
Synthesis of DL series compounds
a. The starting materials p-methoxybenzenesulfonyl chloride (207mg,1mmol), 1-naphthylamine (288mg,2mmol) and pyridine (200. mu.L) were weighed out and added to dichloromethane (5mL), stirred overnight at room temperature, and the progress of the reaction was monitored by TLC. After the reaction was completed, extraction was performed with 1M HCl (10X 3mL), and the organic layer was dried over anhydrous sodium sulfate, suction-filtered under reduced pressure, and the dried residue was weighed to obtain intermediate (TG 03).
b. Intermediate TG03 (125mg, 0.4mmol), tetrabutylammonium hydrogen sulfate (TBAHS, 6mg, 0.015mmol) and potassium carbonate (125mg, 0.9mmol) were weighed out and dissolved in dichloromethane (10mL), and after stirring at room temperature for 30min, the corresponding substituted acid chloride (0.7mmol) was added and stirring was continued overnight, and the progress of the reaction was monitored by TLC. After completion of the reaction, saturated sodium bicarbonate (15X 3mL) and a saturated sodium chloride solution (15X 3mL) were added and extracted, respectively. And drying the organic layer by using anhydrous sodium sulfate, preparing sand by spin drying, and separating and purifying by using column chromatography to obtain the target compound (DL 01-17). The melting point was measured, and the yield was calculated, and the results were confirmed by UPLC-MS, 1H-NMR, 13C-NMR.
c. Intermediate TG03 (125mg, 0.4mmol) and potassium carbonate (170mg, 1.23mmol) were weighed and dissolved in N, N-dimethylformamide (DMF, 3mL), stirred at room temperature for 10min, then added with the corresponding bromo linear alkane (0.8mmol), stirred overnight, and the progress of the reaction was monitored by TLC. After completion of the reaction, ultrapure water (15X 3mL) and ethyl acetate (15X 3mL) were added to conduct extraction. And drying the organic layer by using anhydrous sodium sulfate, carrying out spin drying to prepare sand, and separating and purifying by using column chromatography to obtain the target compound (DL 18-20). The melting point was measured, the yield was calculated, and the results were confirmed by UPLC-MS, 1H-NMR, 13C-NMR.
1.3 results of the experiment
The synthesized target compound is a compound DL 01-20, and has the following chemical structure:
the substituents of DL series compounds in Table 1-1 are as follows
UPLC-MS of a portion of the target compound synthesized including the active compound,1H-NMR and13the physicochemical data such as C-NMR are as follows:
N-((4-methoxyphenyl)sulfonyl)-N-(naphthalen-1-yl)benzamide (DL 01)
Chemical Formula:C24H19NO4S；MP:157.6～158.5℃；ESI-MS:418.22[M+H]+；1H-NMR(500MHz,DMSO-d6)δ(ppm):7.946(t,4H,J＝6.0Hz Ar-H),7.895(d,1H,J＝8.5Hz,Ar-H),7.626(t,1H,J＝7.5Hz Ar-H),7.545(m,2H,Ar-H),7.485(m,1H,Ar-H),7.276(d,2H,J＝7.5Hz,Ar-H),7.197(t,3H,J＝8.5Hz Ar-H),7.045(t,2H,J＝7.5Hz Ar-H),3.905(s,3H,-OCH3)；13C-NMR(125MHz,DMSO-d6):169.800,163.812,133.940,133.769,132.960,131.714,131.300,130.208,129.969,129.214,129.030,128.505,128.355,127.748,127.567,127.350,126.552,125.428,122.886,114.304,55.898；
3-methoxy-N-((4-methoxyphenyl)sulfonyl)-N-(naphthalen-1-yl)benzamide(DL 03)
Chemical Formula:C25H21NO5S；MP:155.7～156.4℃；ESI-MS:448.11[M+H]+；1H-NMR(500MHz,DMSO-d6)δ(ppm):8.024(d,1H,J＝8.5Hz Ar-H),7.954(m,4H,Ar-H),7.668(t,1H,J＝7.5Hz Ar-H),7.579(t,1H,J＝7.5Hz Ar-H),7.456(m,2H,Ar-H),7.214(d,2H,J＝9.0Hz,Ar-H),6.987(m,1H,Ar-H),6.873(d,1H,J＝7.5Hz Ar-H),6.746(d,2H,J＝6.5Hz,Ar-H),3.907(s,3H,-OCH3),3.318(s,3H,-OCH3)；13C-NMR(125MHz,DMSO-d6):169.417,163.814,158.073,135.054,133.798,133.189,131.899,131.754,130.238,129.588,129.090,129.002,128.360,127.617,126.580,125.464,123.212,119.890,117.784,114.309,111.985,55.897,55.778；
2-bromo-N-((4-methoxyphenyl)sulfonyl)-N-(naphthalen-1-yl)benzamide(DL 08)
Chemical Formula:C24H18BrNO4S；MP:152.5～153.9℃；ESI-MS:496.20[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):8.167(d,1H,J＝8.8Hz,Ar-H),8.063(d,2H,J＝9.2Hz,Ar-H),7.961(d,2H,J＝8.4Hz,Ar-H),7.726(m,2H,Ar-H),7.623(t,1H,J＝7.6Hz,Ar-H),7.487(t,1H,J＝8.0Hz,Ar-H),7.398(d,1H,J＝8.0Hz,Ar-H),7.285(m,2H,Ar-H),7.118(d,1H,J＝6.4Hz,Ar-H),7.050(m,1H,Ar-H),6.944(t,1H,J＝7.6Hz,Ar-H),3.949(s,3H,-OCH3)；13C-NMR(125MHz,DMSO-d6):167.041,164.033,135.886,133.624,132.377,132.106,131.800,131.675,131.299,130.524,128.886,128.229,127.955,127.684,127.030,126.731,126.610,125.305,123.173,118.198,114.422,55.957；
2-fluoro-N-((4-methoxyphenyl)sulfonyl)-N-(naphthalen-1-yl)benzamide(DL 09)
Chemical Formula:C24H18FNO4S；MP:151.4～152.5℃；ESI-MS:436.21[M+H]+；1H-NMR(500MHz,DMSO-d6)δ(ppm):8.006(d,2H,J＝9.0Hz,Ar-H),7.915(m,3H,Ar-H),7.628(m,2H,Ar-H),7.526(m,2H,Ar-H),7.336(m,4H,Ar-H),6.931(t,1H,J＝9.5Hz,Ar-H),6.810(t,1H,J＝7.0Hz,Ar-H),3.949(s,3H,-OCH3)；13C-NMR(125MHz,DMSO-d6):165.616,164.025,133.609,132.484,132.419,131.799,131.611,131.515,130.465,129.075,128.900,128.244,127.955,127.545,126.620,125.328,123.745,122.575,115.486,115.323,114.488,55.946；
N-((4-methoxyphenyl)sulfonyl)-N-(naphthalen-1-yl)-2-(trifluoromethyl)benzamide(DL 11)
Chemical Formula:C25H18F3NO4S；MP:154.9～157.3℃；ESI-MS:486.19[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):8.253(d,1H,J＝8.4Hz,Ar-H),7.988(m,4H,Ar-H),7.809(m,1H,Ar-H),7.662(m,1H,Ar-H),7.607(d,1H,J＝8.0Hz,Ar-H),7.468(t,1H,J＝8.0Hz,Ar-H),7.397(m,1H,Ar-H),7.353(d,1H,J＝6.8Hz,Ar-H),7.285(m,2H,Ar-H),7.234(d,2H,J＝4.0Hz,Ar-H),3.955(s,3H,-OCH3)；13C-NMR(125MHz,DMSO-d6):166.755,164.082,133.697,132.390,132.050,131.674,131.515,130.583,130.547,128.578,128.318,128.208,127.828,126.825,126.618,126.231,125.418,123.181,114.379,55.971；
N-((4-methoxyphenyl)sulfonyl)-N-(naphthalen-1-yl)acrylamide(DL 14)
Chemical Formula:C20H17NO4S；MP:150.5～152.0℃；ESI-MS:368.09[M+H]+；1H-NMR(500MHz,DMSO-d6)δ(ppm):8.177(d,1H,J＝8.5Hz,Ar-H),8.118(d,1H,J＝7.5Hz,Ar-H),8.009(d,2H,J＝8.5Hz,Ar-H),7.786(d,1H,J＝8.0Hz,Ar-H),7.683(m,3H,Ar-H),7.564(d,1H,J＝7.0Hz,Ar-H),7.225(d,2H,J＝8.5Hz,Ar-H),6.250(d,1H,J＝16.5Hz,-CH＝CH2),5.564(m,2H,＝CH2),3.910(s,3H,-OCH3)；13C-NMR(125MHz,DMSO-d6):164.308,163.798,134.095,132.242,131.796,131.559,130.658,129.602,128.734,128.557,128.087,127.589,127.017,126.049,122.390,114.341,55.901；
N-((4-methoxyphenyl)sulfonyl)-N-(naphthalen-1-yl)but-2-enamide(DL 16)
Chemical Formula:C21H19NO4S；MP:153.8～154.2℃；ESI-MS:382.09[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):8.191(d,1H,J＝8.4Hz,Ar-H),8.135(m,1H,Ar-H),8.014(m,2H,Ar-H),7.830(m,1H,Ar-H),7.694(m,3H,Ar-H),7.556(m,1H,Ar-H),7.231(m,2H,Ar-H),6.892(m,1H,＝CH-CH3),5.255(m,1H,＝CH-CONH-),3.925(s,3H,-OCH3),1.555(m,3H,-CH3)；13C-NMR(100MHz,DMSO-d6):169.100,164.579,150.234,139.456,134.217,132.452,132.302,131.439,130.628,129.975,128.685,128.249,126.957,123.932,122.678,121.747,116.818,114.727,112.651,56.346,18.355；
N-((4-methoxyphenyl)sulfonyl)-3-methyl-N-(naphthalen-1-yl)but-2-enamide(DL 17)
Chemical Formula:C22H21NO4S；MP:151.5～153.3℃；ESI-MS:396.09[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):8.137(m,2H,Ar-H),8.005(d,2H,J＝8.8Hz,Ar-H),7.844(d,1H,J＝8.0Hz,Ar-H),7.677(t,3H,J＝7.6Hz,Ar-H),7.538(d,1H,J＝7.2Hz,Ar-H),7.228(d,2H,J＝8.8Hz,Ar-H),5.088(＝CH-CONH-),3.921(s,3H,-OCH3),1.988(s,3H,-CH3),1.485(s,3H,-CH3)；13C-NMR(100MHz,DMSO-d6):169.201,165.353,163.892,139.943,133.858,132.868,132.299,131.271,130.360,128.619,128.264,127.120,125.980,121.223,115.092,56.324,27.762,17.892；
4-methoxy-N-methyl-N-(naphthalen-1-yl)benzenesulfonamide(DL 18)
Chemical Formula:C18H17NO3S；MP:157.9～159.1℃；ESI-MS:328.19[M+H]+；1H-NMR(500MHz,DMSO-d6)δ(ppm):8.172(d,1H,J＝8.0Hz,Ar-H),7.985(d,1H,J＝7.5Hz,Ar-H),7.938(d,1H,J＝8.5Hz,Ar-H),7.611(m,4H,Ar-H),7.433(t,1H,J＝8.0Hz,Ar-H),7.174(d,2H,J＝9.0Hz,Ar-H),6.897(d,1H,J＝7.5Hz,Ar-H),3.884(s,3H,-OCH3),3.215(s,3H,-CH3)；13C-NMR(125MHz,DMSO-d6):162.802,138.220,134.137,131.719,129.896,128.570,128.446,127.962,126.667,126.476,125.450,124.605,123.596,114.479,55.716；
N-ethyl-4-methoxy-N-(naphthalen-1-yl)benzenesulfonamide(DL19)
Chemical Formula:C19H19NO3S；MP:158.9～159.0℃；ESI-MS:342.12[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):8.137(m,2H,Ar-H),8.005(d,2H,J＝8.8Hz,Ar-H),7.844(d,1H,J＝8.0Hz,Ar-H),7.677(t,3H,J＝7.6Hz,Ar-H),7.538(d,1H,J＝7.2Hz,Ar-H),7.228(d,2H,J＝8.8Hz,Ar-H),5.088(＝CH-CONH-),3.921(s,3H,-OCH3),1.988(s,3H,-CH3),1.485(s,3H,-CH3)；13C-NMR(100MHz,DMSO-d6):166.233,141.511,135.351,134.040,131.153,130.179,130.096,129.997,128.950,127.732,127.042,126.616,126.030,125.808,119.115,114.920,56.141,42.601,14.216；
the properties and solubility of the target compound synthesized by the present invention are as follows:
most of target compounds have ideal yield, and are mostly white, light yellow and brown; all compounds were soluble in DMSO, DCM, EA, MeOH and EtOH.
The target compound synthesized by the invention, the mass spectrum result, the [ M + H ] can be seen]+A molecular ion peak;1H-NMR spectrum results show that all the compound hydrogen numbers and corresponding chemical shifts, coupling constants and the like can be matched with theoretical values of corresponding compoundsMatching;13C-NMR spectrum results show that all compound carbon peak shifts and numbers accord with theoretical data;
EXAMPLE 2 antitumor cell Activity of Compounds
2.1 MTT assay for testing antitumor Activity of Compounds
And (3) detecting the cell proliferation of the breast cancer cell MDA-MB-231, the colon cancer cell HCT-116 and the non-small cell lung cancer cell A549 by an MTT colorimetric method. The test tumor cells (MDA-MB-231, HCT-116, A549) were added at a concentration of 6X 103Wells, inoculated separately in 96-well plates, filled with 5% CO at 37 ℃2Continuously culturing for 24h under the condition of an incubator; then adding a positive compound C188-9 prepared by DMSO and having a concentration of 10 mu M and 1 mu L of 20 target compounds (detecting the cell inhibition rate); or positive compound C188-9 with different concentrations and compound with better activity 1 μ L (detecting IC50 value); after 48h of administration, 20. mu.L of 5mg/mL MTT solution dissolved in PBS was added to each well and incubation was continued for 4 h; purple formazan precipitate visible to the naked eye can be observed, the solution in the wells is discarded, 150 μ L of DMSO is added to each well and shaken on a shaker for 10 min; detecting the light absorption value of ultraviolet absorption wavelength at 490nm with enzyme-labeling instrument, and calculating to obtain the inhibition ratio or IC of corresponding cell50Values, etc. This experiment requires at least three replicates.
2.2 results of the experiment
All the screened active compounds and a positive control C188-9 are subjected to determination of IC50 values in breast cancer MDA-MB-231, colon cancer cell HCT-116 and non-small cell lung cancer cell A549 which are highly activated by STAT3 through an MTT method, and corresponding experimental results are shown in a table 2-1; the results show that:
(1) IC of Compound DL1550The value is in the range of 2.829-6.905 mu M and is superior to that of a positive control C188-9(IC50 is 9.101-10.951 mu M); DL16 has a lower IC50 value in A549 and MDA-MB-231 cells than C188-9, but a higher IC50 value in HCT-116 cells than C188-9.
(2) Compound DL14 showed the best antiproliferative effect, IC50 values for MDA-MB-231, HCT-116 and A549 cells were 2.852 + -0.34, 3.041 + -0.24, 1.352 + -0.20. mu.M, respectively, and were superior to the positive control and to the positive control C188-9. Therefore, a one-step biological activity study was performed on DL 14.
Table 2-1: partially active Compound IC50 (. mu.M)
EXAMPLE 3 inhibition of STAT3 in A549 by Compound DL14
3.1 immunoblotting of STAT3/STAT1 phosphorylation inhibition
The effect of the compounds on the protein level was examined by Western blot. Non-small cell lung cancer cell A549 is paved in a 6-well plate and continuously cultured in an incubator; the next day, adding 10 μ M target compound or DMSO to be detected, and culturing for 0.5h,1h,2h,3h and 4h respectively; then adding 50ng/mLIL-6 for stimulating for 45 min; washing with PBS for three times, adding lysate (total protein extraction reagent: phosphatase inhibitor: PMSF ═ 100: 1: 1), placing on ice for lysis for 10min, scraping and collecting cells, then centrifuging for 20min at-4 ℃ and 12000r/min by a high-speed low-temperature centrifuge, and collecting supernatant to a new EP tube; detecting the protein concentration by a standard protein curve method, loading the collected protein, performing SDS-PAGE electrophoresis, and then rotating the membrane for 90min under 85V voltage and then applying the membrane to a PVDF membrane; in TBST solution, after being sealed by skimmed milk for one hour, corresponding primary antibody is added, and the mixture is incubated in a refrigerator at4 ℃ overnight; recovering the primary antibody and incubating the corresponding secondary antibody; and finally, adding exposure liquid and detecting by an exposure instrument.
3.2 results of the experiment
In order to explore the optimal time of the target compound on the phosphorylation of STAT3 protein, non-small cell lung cancer cells A549 are utilized, and the influence of the optimal compound DL14 on the phosphorylation of STAT3 protein when the concentration is 10 mu M and the action time is 0.5, 1, 2, 3 and 4h is detected by a Western blot method.
As shown in figure 1, 10 μ M compound DL14 inhibited STAT3 phosphorylation to varying degrees at the 5 time points selected, with no apparent effect on STAT3 protein total. When the action time is 1h, DL14 has the strongest effect of inhibiting STAT3 phosphorylation. Therefore, the action time of DL14 in the subsequent Western blot experiment is 1 h. As shown in figure 2, compound DL14 has no obvious inhibition effect on IL-6 induced STAT1 phosphorylation, but positive control C188-9 has more obvious inhibition effect on IL-6 induced STAT1 phosphorylation. Therefore, DL14 was able to selectively inhibit IL-6-induced phosphorylation of STAT3 compared to C188-9.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (7)
1. A4-methoxy-N- (1-naphthyl) benzene sulfonamide compound is characterized by being one of compounds DL 01-DL 20;
structures of DL 01-DL 20 are as follows:
the definition of R is shown in the following table:
。
2. The compound of 4-methoxy-N- (1-naphthyl) benzenesulfonamide according to claim 1, wherein compound DL01 has the following structural formula:
3. the compound of 4-methoxy-N- (1-naphthyl) benzenesulfonamide according to claim 1, which is compound DL14, having the following structural formula:
4. a process for producing a 4-methoxy-N- (1-naphthyl) benzenesulfonamide compound as claimed in any one of claims 1 to 3,
the 4-methoxy-N- (1-naphthyl) benzene sulfonamide compound is a compound D L1, and the preparation method is as follows:
(1) adding p-methoxybenzenesulfonyl chloride, 1-naphthylamine and pyridine into dichloromethane, stirring at normal temperature overnight, extracting with an HCl aqueous solution after reaction is finished, drying an organic layer with anhydrous sodium sulfate, performing vacuum filtration, and drying filter residues to obtain a sulfonamide intermediate;
(2) dissolving the sulfonamide intermediate, tetrabutylammonium hydrogen sulfate and potassium carbonate in dichloromethane, stirring at normal temperature, adding benzoyl chloride, continuously stirring overnight, after the reaction is finished, respectively adding saturated sodium bicarbonate and saturated sodium chloride solutions for extraction, drying an organic layer with anhydrous sodium sulfate, carrying out rotary drying to prepare sand, and carrying out separation and purification through column chromatography to obtain the target compound DL 01.
5. A method for preparing 4-methoxy-N- (1-naphthyl) benzenesulfonamide compounds as claimed in any one of claims 1 to 3, wherein the 4-methoxy-N- (1-naphthyl) benzenesulfonamide compounds are compound DL14, and the preparation method is as follows:
(1) adding p-methoxybenzenesulfonyl chloride, 1-naphthylamine and pyridine into dichloromethane, stirring at normal temperature overnight, extracting with an HCl aqueous solution after reaction is finished, drying an organic layer with anhydrous sodium sulfate, performing vacuum filtration, and drying filter residues to obtain a sulfonamide intermediate;
(2) dissolving the sulfonamide intermediate, tetrabutylammonium hydrogen sulfate and potassium carbonate in dichloromethane, stirring at normal temperature, adding acryloyl chloride, continuously stirring overnight, after the reaction is finished, respectively adding saturated sodium bicarbonate and saturated sodium chloride solutions for extraction, drying an organic layer with anhydrous sodium sulfate, carrying out rotary drying to prepare sand, and carrying out separation and purification through column chromatography to obtain the target compound DL 14.
6. Use of 4-methoxy-N- (1-naphthyl) benzenesulfonamide compounds as claimed in any one of claims 1 to 3 in the preparation of antitumor drugs.
7. The use of 4-methoxy-N- (1-naphthyl) benzenesulfonamide compounds as claimed in claim 6 in the preparation of antitumor drugs for inhibiting breast, colon or lung cancer.
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