CN110698367B - N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compound and preparation and application thereof - Google Patents
N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compound and preparation and application thereof Download PDFInfo
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract
The invention discloses an N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compound acting on breast cancer resistance and preparation and application thereof, wherein 4-methoxybenzenesulphonyl chloride is used as a raw material and firstly reacts with 4-bromo-1-naphthylamine, and then a target product of VI series is prepared through Suzuki reaction; the N- (1-naphthyl) -4-methoxy benzene sulfonamide compound shows certain antitumor activity. According to the result of the anti-tumor activity test, the compounds VI01 and VI10 show the biological activity equivalent to or even better than that of the positive control drug C188-9; among them, the compound VI10 with the best activity shows excellent activity (IC50 is 4.13-6.55 mu M) on A549, MDA-MB-231 and HCT-116 highly expressed by STAT3, and is superior to the positive control C188-9.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to an N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide STAT3 small-molecule inhibitor and a preparation method and application thereof.
Background
The structure of STAT3 is typical of the STAT family and includes an N-terminal domain, Coiled Coil Domain (CCD), linker domain (linker domain), Src homology domain 2(SH2), DNA Binding Domain (DBD) and C-terminal transactivation domain. The N-terminal coiled domain forms a dimer-dimer interaction interface in STAT 3-driven gene expression; the SH2 structural domain contains three important subunit groups, and can stabilize STAT-STAT dimer interaction and STAT 3-receptor binding interaction; the DNA binding domain provides a protein-DNA binding interface. Cytokines such as interleukin-6 (IL-6) and growth factors such as Epidermal Growth Factor (EGF), Hepatocyte Growth Factor (HGF), may mediate the activation of STAT3 through phosphorylation. When stimulated by an extracellular signal factor, the STAT3 monomer can be phosphorylated at a tyrosine residue (Tyr705), the activated STAT3 monomer can form a homodimer through the interaction of pTyr-SH2 domain, and then the p-STAT3 dimer can be translocated into cell nucleus and combined with a specific site on a target gene promoter to regulate the expression of a target gene, such as the proliferation, differentiation, immunity, angiogenesis and the like of cells, so the STAT3 is increasingly focused as one of important targets for research of antitumor drugs.
The above formula is several important STAT3 inhibitors. Wherein, 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. Research shows that C188-9 can inhibit phosphorylation of STAT3 and also has certain inhibition effect on 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 an N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide compound and a preparation method and application thereof, wherein the N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide compound has better antitumor activity.
The technical scheme of the invention is as follows:
an N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compound has a structure shown in a formula (I):
in the formula (I), R is H, C 1 ～C 5 Alkyl radical, C 1 ～C 5 One or more of alkoxy, halogen and cyano.
Preferably, the compound is one of compounds VI01 to VI 10;
the structures of compounds VI 01-VI 10 are as follows:
the definition of R is shown in the following table:
| compound (I) | R |
| VI01 | H |
| VI02 | 2' -methyl group |
| VI03 | 3' -methyl group |
| VI04 | 4' -methyl group |
| VI05 | 4' -methoxy radical |
| VI06 | 3 ', 4 ', 5 ' -trimethoxy |
| VI07 | 4’-F |
| VI08 | 4’-Cl |
| VI09 | 4’-CN |
| VI10 | 3’-F-4’-CN |
Preferably, compound VI01 has the following structural formula:
preferably, compound VI10 has the following structural formula:
the invention also provides a preparation method of the N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide compound, which comprises the following steps:
(1) under the action of alkali, carrying out amidation reaction on p-methoxybenzenesulfonyl chloride and 4-bromo-1-naphthylamine to obtain N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide;
(2) under the action of a palladium catalyst and alkali, N- (4-bromo-1-naphthyl) -4-methoxybenzenesulphonamide and substituted phenylboronic acid are subjected to coupling reaction to obtain the N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compound.
Preferably, compound VI10 is prepared as follows:
(1) adding p-methoxybenzenesulfonyl chloride, 4-bromo-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, carrying out vacuum filtration, and drying filter residues to obtain an intermediate N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide;
(2) dissolving N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide, 3-fluoro-4-cyanobenzene sulfonamide, tetrakis (triphenylphosphine) palladium and potassium carbonate in a mixed solvent of tetrahydrofuran and ultrapure water, heating and refluxing at 70 ℃ in a nitrogen-filled environment, detecting the reaction process by TLC (thin layer chromatography), after the reaction is finished, respectively adding saturated sodium bicarbonate and saturated sodium chloride solutions for extraction, drying an organic layer by anhydrous sodium sulfate, carrying out spin drying to prepare sand, and carrying out separation and purification by column chromatography to obtain the N- (1-substituted naphthyl) -4-methoxybenzenesulfonamide compound.
The invention also provides application of the N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide compound in preparing antitumor drugs.
Preferably, the antitumor drug is used for inhibiting breast cancer, colon cancer or lung cancer.
The N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide derivative shows certain antitumor activity. According to the result of the anti-tumor activity test, the compounds VI01 and VI10 show the biological activity equivalent to or even better than that of the positive control drug C188-9; among them, the compound VI10 with the best activity shows excellent activity on A549, MDA-MB-231 and HCT-116 highly expressed by STAT3 (IC50 is 4.13-6.55 mu M), and is superior to a positive control C188-9.
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; b is N 2 ,pd(pph 3 ) 4 ,K 2 CO 3 , THF,H 2 O,70℃；
1.2 synthetic procedure
Synthesis of VI series compounds
a. The starting materials p-methoxybenzenesulfonyl chloride (207mg,1mmol), 4-bromo-1-naphthylamine (444 mg,2mmol), and pyridine (200 μ L) were weighed into dichloromethane (5mL), stirred overnight at room temperature, and the progress of the reaction was monitored by TLC. After the reaction, the mixture was extracted with 1M HCl (10X 3mL), and the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the residue was dried and weighed to give intermediate N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide.
b. The intermediates N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide (200mg, 0.6mmol), the corresponding substituted phenylboronic acid (0.72mmol), tetrakis (triphenylphosphine) palladium [ pd (pph3)4, 46mg, 0.04 mmol ], and potassium carbonate (207mg, 1.5mmol) were weighed out and dissolved in tetrahydrofuran: ultrapure water 2: 1 (THF: H2O ═ 10:5mL), under a nitrogen-filled atmosphere, the mixture was heated under reflux at 70 ℃ and the progress of the reaction was checked 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, carrying out spin-drying to prepare sand, and separating and purifying by using column chromatography to obtain the target compound (VI 01-12). 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 VI 01-10, and the structure is as follows:
the definition and yield of R are shown in the following table:
| compound (I) | R | Yield of％ |
| VI 01 | H | 42.44 |
| VI 02 | 2’-methyl | 46.28 |
| VI 03 | 3’-methyl | 50.14 |
| VI 04 | 4’-methyl | 42.50 |
| VI 05 | 4’-methoxy | 40.16 |
| VI 06 | 3’,4’,5’-trimethoxy | 27.30 |
| VI 07 | 4’-fluoro | 43.54 |
| VI 08 | 4’-chloro | 36.33 |
| VI 09 | 4’-cyanide | 15.26 |
| VI 10 | 3’-fluoro-4’-cyanide | 30.52 |
UPLC-MS of a portion of the target compound synthesized including the active compound, 1 H-NMR and 13 the physicochemical data such as C-NMR are as follows:
4-methoxy-N-(4-phenylnaphthalen-1-yl)benzenesulfonamide(VI 01)
Chemical Formula:C23H19NO3S；MP:156.6～157.1℃；ESI-MS:390.07 [M+H]+；1H-NMR(500MHz,DMSO-d6)δ(ppm):10.188(s,1H,-SO2NH-), 8.166(d,1H,J＝8.0Hz,Ar-H),7.755(d,1H,J＝7.5Hz,Ar-H),7.699(d, 1H,J＝19.0Hz,Ar-H),7.544(m,7H,Ar-H),7.327(d,1H,J＝7.5Hz,Ar-H),7.208 (d,1H,J＝8.0Hz,Ar-H),7.058(d,2H,J＝9.0Hz,Ar-H),3.796(s,3H,-OCH3)； 13C-NMR(125MHz,DMSO-d6):162.335,139.567,138.018,132.210, 131.941,131.588,129.727,129,676,128.902,128.432,127.452,126.463, 126.390,125.847,125.490,123.677,122.353,114.296,55.597；
4-methoxy-N-(4-(o-tolyl)naphthalen-1-yl)benzenesulfonamide(VI02)
Chemical Formula:C24H21NO3S；MP:148.4～149.8℃；ESI-MS:404.22 [M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):10.189(s,1H,-SO2NH-), 8.180(d,1H,J＝8.0Hz,Ar-H),7.705(m,2H,Ar-H),7.468(m,2H,Ar-H),7.387 (m,2H,Ar-H),7.309(m,2H,Ar-H),7.244(d,2H,J＝4.5Hz,Ar-H),7.198(m, 1H,Ar-H),7.070(m,2H,Ar-H),3.817(s,3H,-OCH3),1,919(s,3H,-CH3)； 13C-NMR(125MHz,DMSO-d6):162.324,139.177,137.535,135.936, 132.106,131.999,131.891,129.933,129.384,128.868,127.757,126.419, 126.070,125.781,125.746,125.477,123.632,122.278,114.240,55.594, 19.556；
4-methoxy-N-(4-(4-methoxyphenyl)naphthalen-1-yl)benzenesulfonam ide(VI05)
Chemical Formula:C24H21NO4S；MP:155.1～157.0℃；ESI-MS:420.32 [M+H]+；1H-NMR(500MHz,DMSO-d6)δ(ppm):10.171(s,1H,-SO2NH-), 8.178(m,1H,Ar-H),7.813(m,1H,Ar-H),7.719(m,2H,Ar-H),7.500(m, 2H,Ar-H),7.380(m,2H,Ar-H),7.319(d,1H,J＝8.0Hz,Ar-H),7.210(d, 1H,J＝9.5Hz,Ar-H),7.091(m,4H,Ar-H),3.856(s,3H,-OCH3),3.822(s,3H, -OCH3)；13C-NMR(125MHz,DMSO-d6):162.316,158.702,137.819, 131.969,131.826,131.784,131.731,130.863,129.790,128.896,126.296, 125.766,125.587,123.662,122.513,114.281,113.919,55.590,55.155；
N-(4-(4-fluorophenyl)naphthalen-1-yl)-4-methoxybenzenesulfonamid e(VI 07)
Chemical Formula:C23H18FNO3S；MP:151.9～152.2℃；ESI-MS: 408.28[M+H]+；1H-NMR(500MHz,DMSO-d6)δ(ppm):10.202(s, 1H,-SO2NH-),8.167(d,1H,J＝8.0Hz Ar-H),7.704(t,3H,J＝9.0HzAr-H), 7.482(m,4H,Ar-H),7.336(m,3H,Ar-H),7.202(d,1H,J＝8.0Hz,Ar-H), 7.055(d,2H,J＝8.5Hz,Ar-H),3.793(s,3H,-OCH3)；13C-NMR(125MHz, DMSO-d6):162.339,160.680,136.847,135.847,132.396,131.935,131.726, 131.662,131.633,129.635,128.896,128.576,126.548,125.891,125.350, 123.705,122.239,115.380,115.209,114.293,55.595；
N-(4-(4-cyanophenyl)naphthalen-1-yl)-4-methoxybenzenesulfonamide (VI 09)
Chemical Formula:C24H18N2O3S；MP:153.9～155.1℃；ESI-MS: 415.23[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(ppm):10.294(s, 1H,-SO2NH-),8.215(dt,1H,J＝4.4Hz Ar-H),8.000(d,2H,J＝8.4Hz,Ar-H), 7.719(m,3H,Ar-H),7.666(d,2H,J＝8.0Hz Ar-H),7.538(m,2H,Ar-H), 7.403(d,1H,J＝7.6Hz,Ar-H),7.277(d,1H,J＝7.6Hz,Ar-H),7.080(d, 2H,J＝8.8Hz,Ar-H),3.816(s,3H,-OCH3)；13C-NMR(125MHz,DMSO-d6): 162.383,144.481,136.026,133.166,132.372,131.840,131.086,130.816, 129.400,128.901,126.951,126.757,126.121,125.039,123.772,121.901, 118.754,114.328,110.311；
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 method has a mass spectrum result, and a [ M + H ] + molecular ion peak can be seen; 1H-NMR spectrogram results show that all compound hydrogen numbers, corresponding chemical shifts, coupling constants and the like can accord with corresponding compound theoretical values; the results of 13C-NMR spectra show that the carbon peak shifts and the number of all compounds are consistent with theoretical data;
EXAMPLE 2 antitumor cell Activity of Compounds
2.1 testing the antitumor Activity of Compounds by the MTT method
The cell proliferation of the breast cancer cell MDA-MB-231, the colon cancer cell HCT-116, the non-small cell lung cancer cell A549 and the human normal mammary epithelial cell MCF-10A is detected by an MTT colorimetric method. Respectively inoculating the tumor cells to be detected (MDA-MB-231, HCT-116, A549 and MCF-10A) with the concentration of 6 multiplied by 103/hole into a 96-hole plate, and continuously culturing for 24 hours under the condition that an incubator is filled with 5 percent CO2 at 37 ℃; then adding a positive compound C188-9 prepared by DMSO and having a concentration of 10 mu M and 1 mu L of 10 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; macroscopic purple formazan precipitate 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; and detecting the light absorption value of ultraviolet absorption wavelength at 490nm by using a microplate reader, and calculating to obtain the inhibition rate or IC50 value of the corresponding cell. This experiment requires at least three replicates.
2.2 results of the experiment
IC50 values and survival rates of all screened active compounds and positive control C188-9 highly activated by STAT3 in breast cancer MDA-MB-231, colon cancer cell HCT-116, non-small cell lung cancer cell A549 and human normal mammary epithelial cell MCF-10A are measured by an MTT method, and corresponding experimental results are shown in the following table; the results show that: compound VI10 had an IC50 value of 5.88. mu.M for breast cancer MDA-MB-231, and IC50 values of 4.46. mu.M and 4.83. mu.M for non-small cell lung carcinoma A549 and colon cancer HCT-116, respectively.
Partially active compound IC50 (mu M) and survival rate of human normal mammary epithelial cells
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. An N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide compound is characterized by being one of compounds VI01, VI03, VI04, VI07, VI08 and VI 10;
the structures of compounds VI01, VI03, VI04, VI07, VI08 and VI10 are as follows:
the definition of R is shown in the following table:
。
2. The N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compound according to claim 1 which is compound VI01 and has the following structural formula:
3. the compound of the formula N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide type according to claim 1, which is compound VI10 and has the following structural formula:
4. a method for preparing N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compounds according to any one of claims 1 to 3, characterized in that the method comprises the following steps:
(1) under the action of alkali, carrying out amidation reaction on p-methoxybenzenesulfonyl chloride and 4-bromo-1-naphthylamine to obtain N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide;
(2) under the action of a palladium catalyst and alkali, N- (4-bromo-1-naphthyl) -4-methoxybenzenesulphonamide and substituted phenylboronic acid are subjected to coupling reaction to obtain the N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compound.
5. The method for producing an N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compound according to claim 4, which is a compound VI10, the method for producing the compound is as follows:
(1) adding p-methoxybenzenesulfonyl chloride, 4-bromo-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, carrying out vacuum filtration, and drying filter residues to obtain an intermediate N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide;
(2) dissolving N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide, 3-fluoro-4-cyanobenzenesulfonimide, tetrakis (triphenylphosphine) palladium and potassium carbonate in a mixed solvent of tetrahydrofuran and ultrapure water, heating and refluxing at 70 ℃ in an environment filled with nitrogen, detecting the reaction progress by TLC (thin layer chromatography), after the reaction is finished, respectively adding saturated sodium bicarbonate and saturated sodium chloride solutions for extraction, drying an organic layer by anhydrous sodium sulfate, carrying out rotary drying to prepare sand, and carrying out separation and purification by column chromatography to obtain the N- (1-substituted naphthyl) -4-methoxybenzenesulfonamide compound.
6. An application of the N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide compound as defined in any one of claims 1 to 3 in preparing an antitumor medicament.
7. The use of N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compounds according to claim 6 in the preparation of anti-tumor medicaments, characterized in that the anti-tumor medicaments are used for inhibiting breast, colon or lung cancer.
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| CN101836971A (en) * | 2010-05-21 | 2010-09-22 | 徐学军 | Application of compound in aspect of preparing drug for treating cancer or psoriasis |
| EP2998294A1 (en) * | 2014-09-16 | 2016-03-23 | Sanofi | Naphthyl sulfonamide phenyl derivatives as KEAP-1 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders |
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| WO2005005387A1 (en) * | 2003-07-10 | 2005-01-20 | Aston University | Sulfonamide derivatives as 5ht7 receptor antagonists |
| CN101836971A (en) * | 2010-05-21 | 2010-09-22 | 徐学军 | Application of compound in aspect of preparing drug for treating cancer or psoriasis |
| EP2998294A1 (en) * | 2014-09-16 | 2016-03-23 | Sanofi | Naphthyl sulfonamide phenyl derivatives as KEAP-1 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders |
| CN108498503A (en) * | 2017-02-24 | 2018-09-07 | 河南省锐达医药科技有限公司 | The preparation and use of a kind of novel cell signal transduction and 3 type of the gene transcriptional activation factor (STAT3) inhibitor |
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